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1. A Search for Undiagnosed Charcot-Marie-Tooth Disease Among Patients Registered with Unspecified Polyneuropathy in the Danish National Patient Registry

Author: Vaeth S, Andersen H, Christensen R, and Jensen UB
Subjects: registries, international classification of disease codes, epidemiology, hereditary neuropathy, Infectious and parasitic diseases, RC109-216
Abstract: Signe Vaeth,1 Henning Andersen,2 Rikke Christensen,1 Uffe Birk Jensen1 1Department of Clinical Genetics, Aarhus University Hospital, Aarhus N, Denmark; 2Department of Neurology, Aarhus University Hospital, Aarhus C, DenmarkCorrespondence: Signe VaethDepartment of Clinical Genetics, Aarhus University Hospital, Brendstrupgaardsvej 21 C, Skejby, Aarhus N, DK-8200, DenmarkTel + 45 78455510Fax +45 86783181Email vaeth@dadlnet.dkPurpose: In a recent study based on data from the Danish National Patients Registry (DNPR), we reported the prevalence of Charcot-Marie-Tooth disease (CMT) in Denmark to be 22.5 per 100.000. This prevalence is most likely a minimum estimate, as many cases of CMT may be misdiagnosed or remain undiagnosed due to the heterogeneous nature of the disorder. The aim of this study was to investigate the possible number of undiagnosed CMT cases among patients registered with unspecified polyneuropathy (UP) diagnoses in the DNPR.Patients and Methods: From the DNPR we extracted data on all patients given an UP diagnosis in the period 1977 to 2012. We selected all patients diagnosed with a primary UP diagnosis before age 40 at a department of neurology, neurophysiology, clinical genetics or pediatrics, and excluded all patients with a specified polyneuropathy diagnosis or with diagnostic codes related to alcohol and diabetes mellitus. To assess the proportion of possible CMT patients, we performed medical record review in a random sample of patients diagnosed in the Central Denmark Region. To further investigate the possible overlap between UP and CMT in the DNPR, we performed a series of searches for ICD-8 and ICD-10 codes related to CMT.Results: Between 1977 and 2012, 30.903 patients were diagnosed with UP without also being diagnosed with CMT. A total of 940 patients fulfilled the selection criteria. We found that 21.5% (95% CI 13.1%– 32.2%) of the cases in the random sample fulfilled our criteria for CMT. This estimate increases the prevalence of CMT in Denmark with 3.6 per 100,000 (95% CI 2.4%– 5.5%).Conclusion: This study illustrates how hitherto undiagnosed CMT patients may be identified in the DNPR and further reports the number of possible CMT cases. Our results support the hypothesis that the true prevalence of CMT is higher than recently reported.Keywords: registries, International Classification of Disease codes, epidemiology, hereditary neuropathy
Published: 2021

2. Validation of diagnostic codes for Charcot-Marie-Tooth disease in the Danish National Patient Registry

Author: Vaeth S, Jensen UB, Christensen R, and Andersen H
Subjects: Registries, positive predictive value, International Classification of Disease Codes, epidemiology, Infectious and parasitic diseases, RC109-216
Abstract: Signe Vaeth,1 Uffe Birk Jensen,1 Rikke Christensen,1 Henning Andersen2 1Department of Clinical Genetics, Aarhus University Hospital, Aarhus N, 2Department of Neurology, Aarhus University Hospital, Aarhus C, Denmark Purpose: To validate the diagnostic codes for Charcot–Marie–Tooth disease (CMT) in the Danish National Patient Registry (DNPR) using positive predictive value (PPV) as a measure of validity. Patients and methods: We used the DNPR to identify all patients diagnosed with at least one primary CMT diagnosis at a specialized department in the Central Denmark Region during the period 1977–2012. From this population, we randomly selected 123 patients for the validation study. Medical files were reviewed and used as reference standard. We estimated the PPV of the CMT diagnoses and stratified the analysis according to age at diagnosis, gender, and calendar time. Results: In the DNPR, 275 patients were identified. We were able to retrieve 96 medical files from the random sample of 123 patients, and 85 CMT diagnoses were confirmed. The average age at diagnosis was 42.5 years, and 34% were female. The PPV was 88.5% (95% confidence interval: 80.4–94.1). Conclusion: The CMT diagnoses in the DNPR have high validity. The DNPR can be used as a data source for epidemiologic research on CMT. Keywords: registries, positive predictive value, International Classification of Disease codes, epidemiology
Published: 2016

3. Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores

Author: Barnes, DR, Silvestri, V, Leslie, G, McGuffog, L, Dennis, J, Yang, X, Adlard, J, Agnarsson, BA, Ahmed, M, Aittomaki, K, Andrulis, IL, Arason, A, Arnold, N, Auber, B, Azzollini, J, Balmana, J, Barkardottir, RB, Barrowdale, D, Barwell, J, Belotti, M, Benitez, J, Berthet, P, Boonen, SE, Borg, A, Bozsik, A, Brady, AF, Brennan, P, Brewer, C, Brunet, J, Bucalo, A, Buys, SS, Caldes, T, Caligo, MA, Campbell, I, Cassingham, H, Christensen, LL, Cini, G, Claes, KBM, Cook, J, Coppa, A, Cortesi, L, Damante, G, Darder, E, Davidson, R, de la Hoya, M, De Leeneer, K, de Putter, R, Del Valle, J, Diez, O, Ding, YC, Domchek, SM, Donaldson, A, Eason, J, Eeles, R, Engel, C, Evans, DG, Feliubadalo, L, Fostira, F, Frone, M, Frost, D, Gallagher, D, Gehrig, A, Giraud, S, Glendon, G, Godwin, AK, Goldgar, DE, Greene, MH, Gregory, H, Gross, E, Hahnen, E, Hamann, U, Hansen, TVO, Hanson, H, Hentschel, J, Horvath, J, Izatt, L, Izquierdo, A, James, PA, Janavicius, R, Jensen, UB, Johannsson, OT, John, EM, Kramer, G, Kroeldrup, L, Kruse, TA, Lautrup, C, Lazaro, C, Lesueur, F, Lopez-Fernandez, A, Mai, PL, Manoukian, S, Matrai, Z, Matricardi, L, Maxwell, KN, Mebirouk, N, Meindl, A, Montagna, M, Monteiro, AN, Morrison, PJ, Muranen, TA, Murray, A, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Tu, N-D, Niederacher, D, Olah, E, Olopade, O, Palli, D, Parsons, MT, Pedersen, IS, Peissel, B, Perez-Segura, P, Peterlongo, P, Petersen, AH, Pinto, P, Porteous, ME, Pottinger, C, Pujana, MA, Radice, P, Ramser, J, Rantala, J, Robson, M, Rogers, MT, Ronlund, K, Rump, A, Sanchez de Abajo, AM, Shah, PD, Sharif, S, Side, LE, Singer, CF, Stadler, Z, Steele, L, Stoppa-Lyonnet, D, Sutter, C, Tan, YY, Teixeira, MR, Teule, A, Thull, DL, Tischkowitz, M, Toland, AE, Tommasi, S, Toss, A, Trainer, AH, Tripathi, V, Valentini, V, van Asperen, CJ, Venturelli, M, Viel, A, Vijai, J, Walker, L, Wang-Gohrke, S, Wappenschmidt, B, Whaite, A, Zanna, I, Offit, K, Thomassen, M, Couch, FJ, Schmutzler, RK, Simard, J, Easton, DF, Chenevix-Trench, G, Antoniou, AC, Ottini, L, Barnes, DR, Silvestri, V, Leslie, G, McGuffog, L, Dennis, J, Yang, X, Adlard, J, Agnarsson, BA, Ahmed, M, Aittomaki, K, Andrulis, IL, Arason, A, Arnold, N, Auber, B, Azzollini, J, Balmana, J, Barkardottir, RB, Barrowdale, D, Barwell, J, Belotti, M, Benitez, J, Berthet, P, Boonen, SE, Borg, A, Bozsik, A, Brady, AF, Brennan, P, Brewer, C, Brunet, J, Bucalo, A, Buys, SS, Caldes, T, Caligo, MA, Campbell, I, Cassingham, H, Christensen, LL, Cini, G, Claes, KBM, Cook, J, Coppa, A, Cortesi, L, Damante, G, Darder, E, Davidson, R, de la Hoya, M, De Leeneer, K, de Putter, R, Del Valle, J, Diez, O, Ding, YC, Domchek, SM, Donaldson, A, Eason, J, Eeles, R, Engel, C, Evans, DG, Feliubadalo, L, Fostira, F, Frone, M, Frost, D, Gallagher, D, Gehrig, A, Giraud, S, Glendon, G, Godwin, AK, Goldgar, DE, Greene, MH, Gregory, H, Gross, E, Hahnen, E, Hamann, U, Hansen, TVO, Hanson, H, Hentschel, J, Horvath, J, Izatt, L, Izquierdo, A, James, PA, Janavicius, R, Jensen, UB, Johannsson, OT, John, EM, Kramer, G, Kroeldrup, L, Kruse, TA, Lautrup, C, Lazaro, C, Lesueur, F, Lopez-Fernandez, A, Mai, PL, Manoukian, S, Matrai, Z, Matricardi, L, Maxwell, KN, Mebirouk, N, Meindl, A, Montagna, M, Monteiro, AN, Morrison, PJ, Muranen, TA, Murray, A, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Tu, N-D, Niederacher, D, Olah, E, Olopade, O, Palli, D, Parsons, MT, Pedersen, IS, Peissel, B, Perez-Segura, P, Peterlongo, P, Petersen, AH, Pinto, P, Porteous, ME, Pottinger, C, Pujana, MA, Radice, P, Ramser, J, Rantala, J, Robson, M, Rogers, MT, Ronlund, K, Rump, A, Sanchez de Abajo, AM, Shah, PD, Sharif, S, Side, LE, Singer, CF, Stadler, Z, Steele, L, Stoppa-Lyonnet, D, Sutter, C, Tan, YY, Teixeira, MR, Teule, A, Thull, DL, Tischkowitz, M, Toland, AE, Tommasi, S, Toss, A, Trainer, AH, Tripathi, V, Valentini, V, van Asperen, CJ, Venturelli, M, Viel, A, Vijai, J, Walker, L, Wang-Gohrke, S, Wappenschmidt, B, Whaite, A, Zanna, I, Offit, K, Thomassen, M, Couch, FJ, Schmutzler, RK, Simard, J, Easton, DF, Chenevix-Trench, G, Antoniou, AC, and Ottini, L
Abstract: BACKGROUND: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers. METHODS: 483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)-negative (PRSER-), or ER-positive (PRSER+) breast cancer risk. RESULTS: PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions. CONCLUSIONS: Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management.
Published: 2022

4. The predictive ability of the 313 variant-based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant

Author: Lakeman, IMM, van den Broek, AJ, Vos, JAM, Barnes, DR, Adlard, J, Andrulis, IL, Arason, A, Arnold, N, Arun, BK, Balmana, J, Barrowdale, D, Benitez, J, Borg, A, Caldes, T, Caligo, MA, Chung, WK, Claes, KBM, Collee, JM, Couch, FJ, Daly, MB, Dennis, J, Dhawan, M, Domchek, SM, Eeles, R, Engel, C, Evans, DG, Feliubadalo, L, Foretova, L, Friedman, E, Frost, D, Ganz, PA, Garber, J, Gayther, SA, Gerdes, A-M, Godwin, AK, Goldgar, DE, Hahnen, E, Hake, CR, Hamann, U, Hogervorst, FBL, Hooning, MJ, Hopper, JL, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Jakubowska, A, James, PA, Janavicius, R, Jensen, UB, Jiao, Y, John, EM, Joseph, V, Karlan, BY, Kets, CM, Konstantopoulou, I, Kwong, A, Legrand, C, Leslie, G, Lesueur, F, Loud, JT, Lubinski, J, Manoukian, S, McGuffog, L, Miller, A, Gomes, DM, Montagna, M, Mouret-Fourme, E, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Yie, JNY, Olah, E, Olopade, OI, Park, SK, Parsons, MT, Peterlongo, P, Piedmonte, M, Radice, P, Rantala, J, Rennert, G, Risch, HA, Schmutzler, RK, Sharma, P, Simard, J, Singer, CF, Stadler, Z, Stoppa-Lyonnet, D, Sutter, C, Tan, YY, Teixeira, MR, Teo, SH, Teule, A, Thomassen, M, Thull, DL, Tischkowitz, M, Toland, AE, Tung, N, van Rensburg, EJ, Vega, A, Wappenschmidt, B, Devilee, P, van Asperen, CJ, Bernstein, JL, Offit, K, Easton, DF, Rookus, MA, Chenevix-Trench, G, Antoniou, AC, Robson, M, Schmidt, MK, Lakeman, IMM, van den Broek, AJ, Vos, JAM, Barnes, DR, Adlard, J, Andrulis, IL, Arason, A, Arnold, N, Arun, BK, Balmana, J, Barrowdale, D, Benitez, J, Borg, A, Caldes, T, Caligo, MA, Chung, WK, Claes, KBM, Collee, JM, Couch, FJ, Daly, MB, Dennis, J, Dhawan, M, Domchek, SM, Eeles, R, Engel, C, Evans, DG, Feliubadalo, L, Foretova, L, Friedman, E, Frost, D, Ganz, PA, Garber, J, Gayther, SA, Gerdes, A-M, Godwin, AK, Goldgar, DE, Hahnen, E, Hake, CR, Hamann, U, Hogervorst, FBL, Hooning, MJ, Hopper, JL, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Jakubowska, A, James, PA, Janavicius, R, Jensen, UB, Jiao, Y, John, EM, Joseph, V, Karlan, BY, Kets, CM, Konstantopoulou, I, Kwong, A, Legrand, C, Leslie, G, Lesueur, F, Loud, JT, Lubinski, J, Manoukian, S, McGuffog, L, Miller, A, Gomes, DM, Montagna, M, Mouret-Fourme, E, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Yie, JNY, Olah, E, Olopade, OI, Park, SK, Parsons, MT, Peterlongo, P, Piedmonte, M, Radice, P, Rantala, J, Rennert, G, Risch, HA, Schmutzler, RK, Sharma, P, Simard, J, Singer, CF, Stadler, Z, Stoppa-Lyonnet, D, Sutter, C, Tan, YY, Teixeira, MR, Teo, SH, Teule, A, Thomassen, M, Thull, DL, Tischkowitz, M, Toland, AE, Tung, N, van Rensburg, EJ, Vega, A, Wappenschmidt, B, Devilee, P, van Asperen, CJ, Bernstein, JL, Offit, K, Easton, DF, Rookus, MA, Chenevix-Trench, G, Antoniou, AC, Robson, M, and Schmidt, MK
Abstract: PURPOSE: To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes. METHODS: We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk. RESULTS: For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06-1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR = 1.15, 95% CI (1.07-1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS313 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively. CONCLUSION: The PRS313 can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS313 needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making.
Published: 2021

5. A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers (vol 12, 1078, 2021)

Author: Coignard, J, Lush, M, Beesley, J, O'Mara, TA, Dennis, J, Tyrer, JP, Barnes, DR, McGuffog, L, Leslie, G, Bolla, MK, Adank, MA, Agata, S, Ahearn, T, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Arnold, N, Aronson, KJ, Arun, BK, Augustinsson, A, Azzollini, J, Barrowdale, D, Baynes, C, Becher, H, Bermisheva, M, Bernstein, L, Bialkowska, K, Blomqvist, C, Bojesen, SE, Bonanni, B, Borg, A, Brauch, H, Brenner, H, Burwinkel, B, Buys, SS, Caldes, T, Caligo, MA, Campa, D, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chung, WK, Claes, KBM, Clarke, CL, Collee, JM, Conroy, DM, Czene, K, Daly, MB, Devilee, P, Diez, O, Ding, YC, Domchek, SM, Doerk, T, dos-Santos-Silva, I, Dunning, AM, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Flyger, H, Fostira, F, Friedman, E, Fritschi, L, Frost, D, Gago-Dominguez, M, Gapstur, SM, Garber, J, Garcia-Barberan, V, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Gayther, SA, Gehrig, A, Georgoulias, V, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Guenel, P, Haeberle, L, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Harrington, PA, Hart, SN, He, W, Hogervorst, FBL, Hollestelle, A, Hopper, JL, Horcasitas, DJ, Hulick, PJ, Hunter, DJ, Imyanitov, EN, Fox, S, van der Hout, AH, Clarke, C, Jager, A, Jakubowska, A, James, PA, Jensen, UB, John, EM, Jones, ME, Kaaks, R, Kapoor, PM, Karlan, BY, Keeman, R, Khusnutdinova, E, Kiiski, JI, Ko, Y-D, Kosma, V-M, Kraft, P, Kurian, AW, Laitman, Y, Lambrechts, D, Le Marchand, L, Lester, J, Lesueur, F, Lindstrom, T, Lopez-Fernandez, A, Loud, JT, Luccarini, C, Mannermaa, A, Manoukian, S, Margolin, S, Martens, JWM, Mebirouk, N, Meindl, A, Miller, A, Milne, RL, Montagna, M, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nielsen, FC, O'Brien, KM, Olopade, OI, Olson, JE, Olsson, H, Osorio, A, Ottini, L, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peshkin, B, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, Polley, EC, Poppe, B, Presneau, N, Pujana, MA, Punie, K, Radice, P, Rantala, J, Rashid, MU, Rennert, G, Rennert, HS, Robson, M, Romero, A, Rossing, M, Saloustros, E, Sandler, DP, Santella, R, Scheuner, MT, Schmidt, MK, Schmidt, G, Scott, C, Sharma, P, Soucy, P, Southey, MC, Spinelli, JJ, Steinsnyder, Z, Stone, J, Stoppa-Lyonnet, D, Swerdlow, A, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Teule, A, Thull, DL, Tischkowitz, M, Toland, AE, Torres, D, Trainer, AH, Truong, T, Tung, N, Vachon, CM, Vega, A, Vijai, J, Wang, Q, Wappenschmidt, B, Weinberg, CR, Weitzel, JN, Wendt, C, Wolk, A, Yadav, S, Yang, XR, Yannoukakos, D, Zheng, W, Ziogas, A, Zorn, KK, Park, SK, Thomassen, M, Offit, K, Schmutzler, RK, Couch, FJ, Simard, J, Chenevix-Trench, G, Easton, DF, Andrieu, N, Antoniou, AC, Coignard, J, Lush, M, Beesley, J, O'Mara, TA, Dennis, J, Tyrer, JP, Barnes, DR, McGuffog, L, Leslie, G, Bolla, MK, Adank, MA, Agata, S, Ahearn, T, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Arnold, N, Aronson, KJ, Arun, BK, Augustinsson, A, Azzollini, J, Barrowdale, D, Baynes, C, Becher, H, Bermisheva, M, Bernstein, L, Bialkowska, K, Blomqvist, C, Bojesen, SE, Bonanni, B, Borg, A, Brauch, H, Brenner, H, Burwinkel, B, Buys, SS, Caldes, T, Caligo, MA, Campa, D, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chung, WK, Claes, KBM, Clarke, CL, Collee, JM, Conroy, DM, Czene, K, Daly, MB, Devilee, P, Diez, O, Ding, YC, Domchek, SM, Doerk, T, dos-Santos-Silva, I, Dunning, AM, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Flyger, H, Fostira, F, Friedman, E, Fritschi, L, Frost, D, Gago-Dominguez, M, Gapstur, SM, Garber, J, Garcia-Barberan, V, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Gayther, SA, Gehrig, A, Georgoulias, V, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Guenel, P, Haeberle, L, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Harrington, PA, Hart, SN, He, W, Hogervorst, FBL, Hollestelle, A, Hopper, JL, Horcasitas, DJ, Hulick, PJ, Hunter, DJ, Imyanitov, EN, Fox, S, van der Hout, AH, Clarke, C, Jager, A, Jakubowska, A, James, PA, Jensen, UB, John, EM, Jones, ME, Kaaks, R, Kapoor, PM, Karlan, BY, Keeman, R, Khusnutdinova, E, Kiiski, JI, Ko, Y-D, Kosma, V-M, Kraft, P, Kurian, AW, Laitman, Y, Lambrechts, D, Le Marchand, L, Lester, J, Lesueur, F, Lindstrom, T, Lopez-Fernandez, A, Loud, JT, Luccarini, C, Mannermaa, A, Manoukian, S, Margolin, S, Martens, JWM, Mebirouk, N, Meindl, A, Miller, A, Milne, RL, Montagna, M, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nielsen, FC, O'Brien, KM, Olopade, OI, Olson, JE, Olsson, H, Osorio, A, Ottini, L, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peshkin, B, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, Polley, EC, Poppe, B, Presneau, N, Pujana, MA, Punie, K, Radice, P, Rantala, J, Rashid, MU, Rennert, G, Rennert, HS, Robson, M, Romero, A, Rossing, M, Saloustros, E, Sandler, DP, Santella, R, Scheuner, MT, Schmidt, MK, Schmidt, G, Scott, C, Sharma, P, Soucy, P, Southey, MC, Spinelli, JJ, Steinsnyder, Z, Stone, J, Stoppa-Lyonnet, D, Swerdlow, A, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Teule, A, Thull, DL, Tischkowitz, M, Toland, AE, Torres, D, Trainer, AH, Truong, T, Tung, N, Vachon, CM, Vega, A, Vijai, J, Wang, Q, Wappenschmidt, B, Weinberg, CR, Weitzel, JN, Wendt, C, Wolk, A, Yadav, S, Yang, XR, Yannoukakos, D, Zheng, W, Ziogas, A, Zorn, KK, Park, SK, Thomassen, M, Offit, K, Schmutzler, RK, Couch, FJ, Simard, J, Chenevix-Trench, G, Easton, DF, Andrieu, N, and Antoniou, AC
Abstract: Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10-8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.
Published: 2021

6. A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers.

Author: Coignard, J, Lush, M, Beesley, J, O'Mara, TA, Dennis, J, Tyrer, JP, Barnes, DR, McGuffog, L, Leslie, G, Bolla, MK, Adank, MA, Agata, S, Ahearn, T, Aittomäki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Arnold, N, Aronson, KJ, Arun, BK, Augustinsson, A, Azzollini, J, Barrowdale, D, Baynes, C, Becher, H, Bermisheva, M, Bernstein, L, Białkowska, K, Blomqvist, C, Bojesen, SE, Bonanni, B, Borg, A, Brauch, H, Brenner, H, Burwinkel, B, Buys, SS, Caldés, T, Caligo, MA, Campa, D, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chung, WK, Claes, KBM, Clarke, CL, GEMO Study Collaborators, EMBRACE Collaborators, Collée, JM, Conroy, DM, Czene, K, Daly, MB, Devilee, P, Diez, O, Ding, YC, Domchek, SM, Dörk, T, Dos-Santos-Silva, I, Dunning, AM, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Flyger, H, Fostira, F, Friedman, E, Fritschi, L, Frost, D, Gago-Dominguez, M, Gapstur, SM, Garber, J, Garcia-Barberan, V, García-Closas, M, García-Sáenz, JA, Gaudet, MM, Gayther, SA, Gehrig, A, Georgoulias, V, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, González-Neira, A, Greene, MH, Guénel, P, Haeberle, L, Hahnen, E, Haiman, CA, Håkansson, N, Hall, P, Hamann, U, Harrington, PA, Hart, SN, He, W, Hogervorst, FBL, Hollestelle, A, Hopper, JL, Horcasitas, DJ, Hulick, PJ, Hunter, DJ, Imyanitov, EN, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Jager, A, Jakubowska, A, James, PA, Jensen, UB, John, EM, Jones, ME, Kaaks, R, Kapoor, PM, Karlan, BY, Keeman, R, Khusnutdinova, E, Kiiski, JI, Ko, Y-D, Kosma, V-M, Kraft, P, Kurian, AW, Laitman, Y, Lambrechts, D, Le Marchand, L, Lester, J, Lesueur, F, Lindstrom, T, Lopez-Fernández, A, Loud, JT, Luccarini, C, Mannermaa, A, Manoukian, S, Margolin, S, Martens, JWM, Mebirouk, N, Meindl, A, Miller, A, Milne, RL, Montagna, M, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nielsen, FC, O'Brien, KM, Olopade, OI, Olson, JE, Olsson, H, Osorio, A, Ottini, L, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peshkin, B, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, Polley, EC, Poppe, B, Presneau, N, Pujana, MA, Punie, K, Radice, P, Rantala, J, Rashid, MU, Rennert, G, Rennert, HS, Robson, M, Romero, A, Rossing, M, Saloustros, E, Sandler, DP, Santella, R, Scheuner, MT, Schmidt, MK, Schmidt, G, Scott, C, Sharma, P, Soucy, P, Southey, MC, Spinelli, JJ, Steinsnyder, Z, Stone, J, Stoppa-Lyonnet, D, Swerdlow, A, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Teulé, A, Thull, DL, Tischkowitz, M, Toland, AE, Torres, D, Trainer, AH, Truong, T, Tung, N, Vachon, CM, Vega, A, Vijai, J, Wang, Q, Wappenschmidt, B, Weinberg, CR, Weitzel, JN, Wendt, C, Wolk, A, Yadav, S, Yang, XR, Yannoukakos, D, Zheng, W, Ziogas, A, Zorn, KK, Park, SK, Thomassen, M, Offit, K, Schmutzler, RK, Couch, FJ, Simard, J, Chenevix-Trench, G, Easton, DF, Andrieu, N, Antoniou, AC, Coignard, J, Lush, M, Beesley, J, O'Mara, TA, Dennis, J, Tyrer, JP, Barnes, DR, McGuffog, L, Leslie, G, Bolla, MK, Adank, MA, Agata, S, Ahearn, T, Aittomäki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Arnold, N, Aronson, KJ, Arun, BK, Augustinsson, A, Azzollini, J, Barrowdale, D, Baynes, C, Becher, H, Bermisheva, M, Bernstein, L, Białkowska, K, Blomqvist, C, Bojesen, SE, Bonanni, B, Borg, A, Brauch, H, Brenner, H, Burwinkel, B, Buys, SS, Caldés, T, Caligo, MA, Campa, D, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chung, WK, Claes, KBM, Clarke, CL, GEMO Study Collaborators, EMBRACE Collaborators, Collée, JM, Conroy, DM, Czene, K, Daly, MB, Devilee, P, Diez, O, Ding, YC, Domchek, SM, Dörk, T, Dos-Santos-Silva, I, Dunning, AM, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Flyger, H, Fostira, F, Friedman, E, Fritschi, L, Frost, D, Gago-Dominguez, M, Gapstur, SM, Garber, J, Garcia-Barberan, V, García-Closas, M, García-Sáenz, JA, Gaudet, MM, Gayther, SA, Gehrig, A, Georgoulias, V, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, González-Neira, A, Greene, MH, Guénel, P, Haeberle, L, Hahnen, E, Haiman, CA, Håkansson, N, Hall, P, Hamann, U, Harrington, PA, Hart, SN, He, W, Hogervorst, FBL, Hollestelle, A, Hopper, JL, Horcasitas, DJ, Hulick, PJ, Hunter, DJ, Imyanitov, EN, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Jager, A, Jakubowska, A, James, PA, Jensen, UB, John, EM, Jones, ME, Kaaks, R, Kapoor, PM, Karlan, BY, Keeman, R, Khusnutdinova, E, Kiiski, JI, Ko, Y-D, Kosma, V-M, Kraft, P, Kurian, AW, Laitman, Y, Lambrechts, D, Le Marchand, L, Lester, J, Lesueur, F, Lindstrom, T, Lopez-Fernández, A, Loud, JT, Luccarini, C, Mannermaa, A, Manoukian, S, Margolin, S, Martens, JWM, Mebirouk, N, Meindl, A, Miller, A, Milne, RL, Montagna, M, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nielsen, FC, O'Brien, KM, Olopade, OI, Olson, JE, Olsson, H, Osorio, A, Ottini, L, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peshkin, B, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, Polley, EC, Poppe, B, Presneau, N, Pujana, MA, Punie, K, Radice, P, Rantala, J, Rashid, MU, Rennert, G, Rennert, HS, Robson, M, Romero, A, Rossing, M, Saloustros, E, Sandler, DP, Santella, R, Scheuner, MT, Schmidt, MK, Schmidt, G, Scott, C, Sharma, P, Soucy, P, Southey, MC, Spinelli, JJ, Steinsnyder, Z, Stone, J, Stoppa-Lyonnet, D, Swerdlow, A, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Teulé, A, Thull, DL, Tischkowitz, M, Toland, AE, Torres, D, Trainer, AH, Truong, T, Tung, N, Vachon, CM, Vega, A, Vijai, J, Wang, Q, Wappenschmidt, B, Weinberg, CR, Weitzel, JN, Wendt, C, Wolk, A, Yadav, S, Yang, XR, Yannoukakos, D, Zheng, W, Ziogas, A, Zorn, KK, Park, SK, Thomassen, M, Offit, K, Schmutzler, RK, Couch, FJ, Simard, J, Chenevix-Trench, G, Easton, DF, Andrieu, N, and Antoniou, AC
Abstract: Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10-8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.
Published: 2021

7. Author Correction: A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers.

Author: Coignard, J, Lush, M, Beesley, J, O'Mara, TA, Dennis, J, Tyrer, JP, Barnes, DR, McGuffog, L, Leslie, G, Bolla, MK, Adank, MA, Agata, S, Ahearn, T, Aittomäki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Arnold, N, Aronson, KJ, Arun, BK, Augustinsson, A, Azzollini, J, Barrowdale, D, Baynes, C, Becher, H, Bermisheva, M, Bernstein, L, Białkowska, K, Blomqvist, C, Bojesen, SE, Bonanni, B, Borg, A, Brauch, H, Brenner, H, Burwinkel, B, Buys, SS, Caldés, T, Caligo, MA, Campa, D, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chung, WK, Claes, KBM, Clarke, CL, GEMO Study Collaborators, EMBRACE Collaborators, Collée, JM, Conroy, DM, Czene, K, Daly, MB, Devilee, P, Diez, O, Ding, YC, Domchek, SM, Dörk, T, Dos-Santos-Silva, I, Dunning, AM, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Flyger, H, Fostira, F, Friedman, E, Fritschi, L, Frost, D, Gago-Dominguez, M, Gapstur, SM, Garber, J, Garcia-Barberan, V, García-Closas, M, García-Sáenz, JA, Gaudet, MM, Gayther, SA, Gehrig, A, Georgoulias, V, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, González-Neira, A, Greene, MH, Guénel, P, Haeberle, L, Hahnen, E, Haiman, CA, Håkansson, N, Hall, P, Hamann, U, Harrington, PA, Hart, SN, He, W, Hogervorst, FBL, Hollestelle, A, Hopper, JL, Horcasitas, DJ, Hulick, PJ, Hunter, DJ, Imyanitov, EN, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Jager, A, Jakubowska, A, James, PA, Jensen, UB, John, EM, Jones, ME, Kaaks, R, Kapoor, PM, Karlan, BY, Keeman, R, Khusnutdinova, E, Kiiski, JI, Ko, Y-D, Kosma, V-M, Kraft, P, Kurian, AW, Laitman, Y, Lambrechts, D, Le Marchand, L, Lester, J, Lesueur, F, Lindstrom, T, Lopez-Fernández, A, Loud, JT, Luccarini, C, Mannermaa, A, Manoukian, S, Margolin, S, Martens, JWM, Mebirouk, N, Meindl, A, Miller, A, Milne, RL, Montagna, M, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nielsen, FC, O'Brien, KM, Olopade, OI, Olson, JE, Olsson, H, Osorio, A, Ottini, L, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peshkin, B, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, Polley, EC, Poppe, B, Presneau, N, Pujana, MA, Punie, K, Radice, P, Rantala, J, Rashid, MU, Rennert, G, Rennert, HS, Robson, M, Romero, A, Rossing, M, Saloustros, E, Sandler, DP, Santella, R, Scheuner, MT, Schmidt, MK, Schmidt, G, Scott, C, Sharma, P, Soucy, P, Southey, MC, Spinelli, JJ, Steinsnyder, Z, Stone, J, Stoppa-Lyonnet, D, Swerdlow, A, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Teulé, A, Thull, DL, Tischkowitz, M, Toland, AE, Torres, D, Trainer, AH, Truong, T, Tung, N, Vachon, CM, Vega, A, Vijai, J, Wang, Q, Wappenschmidt, B, Weinberg, CR, Weitzel, JN, Wendt, C, Wolk, A, Yadav, S, Yang, XR, Yannoukakos, D, Zheng, W, Ziogas, A, Zorn, KK, Park, SK, Thomassen, M, Offit, K, Schmutzler, RK, Couch, FJ, Simard, J, Chenevix-Trench, G, Easton, DF, Andrieu, N, Antoniou, AC, Coignard, J, Lush, M, Beesley, J, O'Mara, TA, Dennis, J, Tyrer, JP, Barnes, DR, McGuffog, L, Leslie, G, Bolla, MK, Adank, MA, Agata, S, Ahearn, T, Aittomäki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Arnold, N, Aronson, KJ, Arun, BK, Augustinsson, A, Azzollini, J, Barrowdale, D, Baynes, C, Becher, H, Bermisheva, M, Bernstein, L, Białkowska, K, Blomqvist, C, Bojesen, SE, Bonanni, B, Borg, A, Brauch, H, Brenner, H, Burwinkel, B, Buys, SS, Caldés, T, Caligo, MA, Campa, D, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chung, WK, Claes, KBM, Clarke, CL, GEMO Study Collaborators, EMBRACE Collaborators, Collée, JM, Conroy, DM, Czene, K, Daly, MB, Devilee, P, Diez, O, Ding, YC, Domchek, SM, Dörk, T, Dos-Santos-Silva, I, Dunning, AM, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Flyger, H, Fostira, F, Friedman, E, Fritschi, L, Frost, D, Gago-Dominguez, M, Gapstur, SM, Garber, J, Garcia-Barberan, V, García-Closas, M, García-Sáenz, JA, Gaudet, MM, Gayther, SA, Gehrig, A, Georgoulias, V, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, González-Neira, A, Greene, MH, Guénel, P, Haeberle, L, Hahnen, E, Haiman, CA, Håkansson, N, Hall, P, Hamann, U, Harrington, PA, Hart, SN, He, W, Hogervorst, FBL, Hollestelle, A, Hopper, JL, Horcasitas, DJ, Hulick, PJ, Hunter, DJ, Imyanitov, EN, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Jager, A, Jakubowska, A, James, PA, Jensen, UB, John, EM, Jones, ME, Kaaks, R, Kapoor, PM, Karlan, BY, Keeman, R, Khusnutdinova, E, Kiiski, JI, Ko, Y-D, Kosma, V-M, Kraft, P, Kurian, AW, Laitman, Y, Lambrechts, D, Le Marchand, L, Lester, J, Lesueur, F, Lindstrom, T, Lopez-Fernández, A, Loud, JT, Luccarini, C, Mannermaa, A, Manoukian, S, Margolin, S, Martens, JWM, Mebirouk, N, Meindl, A, Miller, A, Milne, RL, Montagna, M, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nielsen, FC, O'Brien, KM, Olopade, OI, Olson, JE, Olsson, H, Osorio, A, Ottini, L, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peshkin, B, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, Polley, EC, Poppe, B, Presneau, N, Pujana, MA, Punie, K, Radice, P, Rantala, J, Rashid, MU, Rennert, G, Rennert, HS, Robson, M, Romero, A, Rossing, M, Saloustros, E, Sandler, DP, Santella, R, Scheuner, MT, Schmidt, MK, Schmidt, G, Scott, C, Sharma, P, Soucy, P, Southey, MC, Spinelli, JJ, Steinsnyder, Z, Stone, J, Stoppa-Lyonnet, D, Swerdlow, A, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Teulé, A, Thull, DL, Tischkowitz, M, Toland, AE, Torres, D, Trainer, AH, Truong, T, Tung, N, Vachon, CM, Vega, A, Vijai, J, Wang, Q, Wappenschmidt, B, Weinberg, CR, Weitzel, JN, Wendt, C, Wolk, A, Yadav, S, Yang, XR, Yannoukakos, D, Zheng, W, Ziogas, A, Zorn, KK, Park, SK, Thomassen, M, Offit, K, Schmutzler, RK, Couch, FJ, Simard, J, Chenevix-Trench, G, Easton, DF, Andrieu, N, and Antoniou, AC
Abstract: A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-23162-4.
Published: 2021

8. Association of Genomic Domains in BRCA1 and BRCA2 with Prostate Cancer Risk and Aggressiveness

Author: Patel, VL, Busch, EL, Friebel, TM, Cronin, A, Leslie, G, McGuffog, L, Adlard, J, Agata, S, Agnarsson, BA, Ahmed, M, Aittomaki, K, Alducci, E, Andrulis, IL, Arason, A, Arnold, N, Artioli, G, Arver, B, Auber, B, Azzollini, J, Balmana, J, Barkardottir, RB, Barnes, DR, Barroso, A, Barrowdale, D, Belotti, M, Benitez, J, Bertelsen, B, Blok, MJ, Bodrogi, I, Bonadona, V, Bonanni, B, Bondavalli, D, Boonen, SE, Borde, J, Borg, A, Bradbury, AR, Brady, A, Brewer, C, Brunet, J, Buecher, B, Buys, SS, Cabezas-Camarero, S, Caldes, T, Caliebe, A, Caligo, MA, Calvello, M, Campbell, IG, Carnevali, I, Carrasco, E, Chan, TL, Chu, ATW, Chung, WK, Claes, KBM, Cook, J, Cortesi, L, Couch, FJ, Daly, MB, Damante, G, Darder, E, Davidson, R, de la Hoya, M, Della Puppa, L, Dennis, J, Diez, O, Ding, YC, Ditsch, N, Domchek, SM, Donaldson, A, Dworniczak, B, Easton, DF, Eccles, DM, Eeles, RA, Ehrencrona, H, Ejlertsen, B, Engel, C, Evans, DG, Faivre, L, Faust, U, Feliubadalo, L, Foretova, L, Fostira, F, Fountzilas, G, Frost, D, Garcia-Barberan, V, Garre, P, Gauthier-Villars, M, Geczi, L, Gehrig, A, Gerdes, A-M, Gesta, P, Giannini, G, Glendon, G, Godwin, AK, Goldgar, DE, Greene, MH, Gutierrez-Barrera, AM, Hahnen, E, Hamann, U, Hauke, J, Herold, N, Hogervorst, FBL, Honisch, E, Hopper, JL, Hulick, PJ, Izatt, L, Jager, A, James, P, Janavicius, R, Jensen, UB, Jensen, TD, Johannsson, OT, John, EM, Joseph, V, Kang, E, Kast, K, Kiiski, J, Kim, S-W, Kim, Z, Ko, K-P, Konstantopoulou, I, Kramer, G, Krogh, L, Kruse, TA, Kwong, A, Larsen, M, Lasset, C, Lautrup, C, Lazaro, C, Lee, J, Lee, JW, Lee, MH, Lemke, J, Lesueur, F, Liljegren, A, Lindblom, A, Llovet, P, Lopez-Fernandez, A, Lopez-Perolio, I, Lorca, V, Loud, JT, Ma, ESK, Mai, PL, Manoukian, S, Mari, V, Martin, L, Matricardi, L, Mebirouk, N, Medici, V, Meijers-Heijboer, HEJ, Meindl, A, Mensenkamp, AR, Miller, C, Gomes, DM, Montagna, M, Mooij, TM, Moserle, L, Mouret-Fourme, E, Mulligan, AM, Nathanson, KL, Navratilova, M, Nevanlinna, H, Niederacher, D, Nielsen, FCC, Nikitina-Zake, L, Offit, K, Olah, E, Olopade, O, Ong, K-R, Osorio, A, Ott, C-E, Palli, D, Park, SK, Parsons, MT, Pedersen, IS, Peissel, B, Peixoto, A, Perez-Segura, P, Peterlongo, P, Petersen, AH, Porteous, ME, Angel Pujana, M, Radice, P, Ramser, J, Rantala, J, Rashid, MU, Rhiem, K, Rizzolo, P, Robson, ME, Rookus, MA, Rossing, CM, Ruddy, KJ, Santos, C, Saule, C, Scarpitta, R, Schmutzler, RK, Schuster, H, Senter, L, Seynaeve, CM, Shah, PD, Sharma, P, Shin, VY, Silvestri, V, Simard, J, Singer, CF, Skytte, A-B, Snape, K, Solano, AR, Soucy, P, Southey, MC, Spurdle, AB, Steele, L, Steinemann, D, Stoppa-Lyonnet, D, Stradella, A, Sunde, L, Sutter, C, Tan, YY, Teixeira, MR, Teo, SH, Thomassen, M, Tibiletti, MG, Tischkowitz, M, Tognazzo, S, Toland, AE, Tommasi, S, Torres, D, Toss, A, Trainer, AH, Tung, N, van Asperen, CJ, van der Baan, FH, van der Kolk, LE, van der Luijt, RB, van Hest, LP, Varesco, L, Varon-Mateeva, R, Viel, A, Vierstraete, J, Villa, R, von Wachenfeldt, A, Wagner, P, Wang-Gohrke, S, Wappenschmidt, B, Weitzel, JN, Wieme, G, Yadav, S, Yannoukakos, D, Yoon, S-Y, Zanzottera, C, Zorn, KK, D'Amico, A, Freedman, ML, Pomerantz, MM, Chenevix-Trench, G, Antoniou, AC, Neuhausen, SL, Ottini, L, Nielsen, HR, Rebbeck, TR, Patel, VL, Busch, EL, Friebel, TM, Cronin, A, Leslie, G, McGuffog, L, Adlard, J, Agata, S, Agnarsson, BA, Ahmed, M, Aittomaki, K, Alducci, E, Andrulis, IL, Arason, A, Arnold, N, Artioli, G, Arver, B, Auber, B, Azzollini, J, Balmana, J, Barkardottir, RB, Barnes, DR, Barroso, A, Barrowdale, D, Belotti, M, Benitez, J, Bertelsen, B, Blok, MJ, Bodrogi, I, Bonadona, V, Bonanni, B, Bondavalli, D, Boonen, SE, Borde, J, Borg, A, Bradbury, AR, Brady, A, Brewer, C, Brunet, J, Buecher, B, Buys, SS, Cabezas-Camarero, S, Caldes, T, Caliebe, A, Caligo, MA, Calvello, M, Campbell, IG, Carnevali, I, Carrasco, E, Chan, TL, Chu, ATW, Chung, WK, Claes, KBM, Cook, J, Cortesi, L, Couch, FJ, Daly, MB, Damante, G, Darder, E, Davidson, R, de la Hoya, M, Della Puppa, L, Dennis, J, Diez, O, Ding, YC, Ditsch, N, Domchek, SM, Donaldson, A, Dworniczak, B, Easton, DF, Eccles, DM, Eeles, RA, Ehrencrona, H, Ejlertsen, B, Engel, C, Evans, DG, Faivre, L, Faust, U, Feliubadalo, L, Foretova, L, Fostira, F, Fountzilas, G, Frost, D, Garcia-Barberan, V, Garre, P, Gauthier-Villars, M, Geczi, L, Gehrig, A, Gerdes, A-M, Gesta, P, Giannini, G, Glendon, G, Godwin, AK, Goldgar, DE, Greene, MH, Gutierrez-Barrera, AM, Hahnen, E, Hamann, U, Hauke, J, Herold, N, Hogervorst, FBL, Honisch, E, Hopper, JL, Hulick, PJ, Izatt, L, Jager, A, James, P, Janavicius, R, Jensen, UB, Jensen, TD, Johannsson, OT, John, EM, Joseph, V, Kang, E, Kast, K, Kiiski, J, Kim, S-W, Kim, Z, Ko, K-P, Konstantopoulou, I, Kramer, G, Krogh, L, Kruse, TA, Kwong, A, Larsen, M, Lasset, C, Lautrup, C, Lazaro, C, Lee, J, Lee, JW, Lee, MH, Lemke, J, Lesueur, F, Liljegren, A, Lindblom, A, Llovet, P, Lopez-Fernandez, A, Lopez-Perolio, I, Lorca, V, Loud, JT, Ma, ESK, Mai, PL, Manoukian, S, Mari, V, Martin, L, Matricardi, L, Mebirouk, N, Medici, V, Meijers-Heijboer, HEJ, Meindl, A, Mensenkamp, AR, Miller, C, Gomes, DM, Montagna, M, Mooij, TM, Moserle, L, Mouret-Fourme, E, Mulligan, AM, Nathanson, KL, Navratilova, M, Nevanlinna, H, Niederacher, D, Nielsen, FCC, Nikitina-Zake, L, Offit, K, Olah, E, Olopade, O, Ong, K-R, Osorio, A, Ott, C-E, Palli, D, Park, SK, Parsons, MT, Pedersen, IS, Peissel, B, Peixoto, A, Perez-Segura, P, Peterlongo, P, Petersen, AH, Porteous, ME, Angel Pujana, M, Radice, P, Ramser, J, Rantala, J, Rashid, MU, Rhiem, K, Rizzolo, P, Robson, ME, Rookus, MA, Rossing, CM, Ruddy, KJ, Santos, C, Saule, C, Scarpitta, R, Schmutzler, RK, Schuster, H, Senter, L, Seynaeve, CM, Shah, PD, Sharma, P, Shin, VY, Silvestri, V, Simard, J, Singer, CF, Skytte, A-B, Snape, K, Solano, AR, Soucy, P, Southey, MC, Spurdle, AB, Steele, L, Steinemann, D, Stoppa-Lyonnet, D, Stradella, A, Sunde, L, Sutter, C, Tan, YY, Teixeira, MR, Teo, SH, Thomassen, M, Tibiletti, MG, Tischkowitz, M, Tognazzo, S, Toland, AE, Tommasi, S, Torres, D, Toss, A, Trainer, AH, Tung, N, van Asperen, CJ, van der Baan, FH, van der Kolk, LE, van der Luijt, RB, van Hest, LP, Varesco, L, Varon-Mateeva, R, Viel, A, Vierstraete, J, Villa, R, von Wachenfeldt, A, Wagner, P, Wang-Gohrke, S, Wappenschmidt, B, Weitzel, JN, Wieme, G, Yadav, S, Yannoukakos, D, Yoon, S-Y, Zanzottera, C, Zorn, KK, D'Amico, A, Freedman, ML, Pomerantz, MM, Chenevix-Trench, G, Antoniou, AC, Neuhausen, SL, Ottini, L, Nielsen, HR, and Rebbeck, TR
Abstract: Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3' region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25-2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12-11.54; P = 0.0002). No genotype-phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. SIGNIFICANCE: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.
Published: 2020

9. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations

Author: Rebbeck, TR, Friebel, TM, Friedman, E, Hamann, U, Huo, D, Kwong, A, Olah, E, Olopade, OI, Solano, AR, Teo, S-H, Thomassen, M, Weitzel, JN, Chan, TL, Couch, FJ, Goldgar, DE, Kruse, TA, Palmero, EI, Park, SK, Torres, D, van Rensburg, EJ, McGuffog, L, Parsons, MT, Leslie, G, Aalfs, CM, Abugattas, J, Adlard, J, Agata, S, Aittomaki, K, Andrews, L, Andrulis, IL, Arason, A, Arnold, N, Arun, BK, Asseryanis, E, Auerbach, L, Azzollini, J, Balmana, J, Barile, M, Barkardottir, RB, Barrowdale, D, Benitez, J, Berger, A, Berger, R, Blanco, AM, Blazer, KR, Blok, MJ, Bonadona, V, Bonanni, B, Bradbury, AR, Brewer, C, Buecher, B, Buys, SS, Caldes, T, Caliebe, A, Caligo, MA, Campbell, I, Caputo, SM, Chiquette, J, Chung, WK, Claes, KBM, Collee, JM, Cook, J, Davidson, R, de la Hoya, M, De Leeneer, K, de Pauw, A, Delnatte, C, Diez, O, Ding, YC, Ditsch, N, Domchek, S, Dorfling, CM, Velazquez, C, Dworniczak, B, Eason, J, Easton, DF, Eeles, R, Ehrencrona, H, Ejlertsen, B, Engel, C, Engert, S, Evans, DG, Faivre, L, Feliubadalo, L, Ferrer, SF, Foretova, L, Fowler, J, Frost, D, Galvao, HCR, Ganz, PA, Garber, J, Gauthier-Villars, M, Gehrig, A, Gerdes, A-M, Gesta, P, Giannini, G, Giraud, S, Glendon, G, Godwin, AK, Greene, MH, Gronwald, J, Gutierrez-Barrera, A, Hahnen, E, Hauke, J, Henderson, A, Hentschel, J, Hogervorst, FBL, Honisch, E, Imyanitov, EN, Isaacs, C, Izatt, L, Izquierdo, A, Jakubowska, A, James, P, Janavicius, R, Jensen, UB, John, EM, Vijai, J, Kaczmarek, K, Karlan, BY, Kast, K, Kim, S-W, Konstantopoulou, I, Korach, J, Laitman, Y, Lasa, A, Lasset, C, Lazaro, C, Lee, A, Lee, MH, Lester, J, Lesueur, F, Liljegren, A, Lindor, NM, Longy, M, Loud, JT, Lu, KH, Lubinski, J, Machackova, E, Manoukian, S, Mari, V, Martinez-Bouzas, C, Matrai, Z, Mebirouk, N, Meijers-Heijboer, HEJ, Meindl, A, Mensenkamp, AR, Mickys, U, Miller, A, Montagna, M, Moysich, KB, Mulligan, AM, Musinsky, J, Neuhausen, SL, Nevanlinna, H, Ngeow, J, Nguyen, HP, Niederacher, D, Nielsen, HR, Nielsen, FC, Nussbaum, RL, Offit, K, Ofverholm, A, Ong, K-R, Osorio, A, Papi, L, Papp, J, Pasini, B, Pedersen, IS, Peixoto, A, Peruga, N, Peterlongo, P, Pohl, E, Pradhan, N, Prajzendanc, K, Prieur, F, Pujol, P, Radice, P, Ramus, SJ, Rantala, J, Rashid, MU, Rhiem, K, Robson, M, Rodriguez, GC, Rogers, MT, Rudaitis, V, Schmidt, AY, Schmutzler, RK, Senter, L, Shah, PD, Sharma, P, Side, LE, Simard, J, Singer, CF, Skytte, A-B, Slavin, TP, Snape, K, Sobol, H, Southey, M, Steele, L, Steinemann, D, Sukiennicki, G, Sutter, C, Szabo, CI, Tan, YY, Teixeira, MR, Terry, MB, Teule, A, Thomas, A, Thull, DL, Tischkowitz, M, Tognazzo, S, Toland, AE, Topka, S, Trainer, AH, Tung, N, van Asperen, CJ, van der Hout, AH, van der Kolk, LE, van der Luijt, RB, Van Heetvelde, M, Varesco, L, Varon-Mateeva, R, Vega, A, Villarreal-Garza, C, von Wachenfeldt, A, Walker, L, Wang-Gohrke, S, Wappenschmidt, B, Weber, BHF, Yannoukakos, D, Yoon, S-Y, Zanzottera, C, Zidan, J, Zorn, KK, Selkirk, CGH, Hulick, PJ, Chenevix-Trench, G, Spurdle, AB, Antoniou, AC, Nathanson, KL, Rebbeck, TR, Friebel, TM, Friedman, E, Hamann, U, Huo, D, Kwong, A, Olah, E, Olopade, OI, Solano, AR, Teo, S-H, Thomassen, M, Weitzel, JN, Chan, TL, Couch, FJ, Goldgar, DE, Kruse, TA, Palmero, EI, Park, SK, Torres, D, van Rensburg, EJ, McGuffog, L, Parsons, MT, Leslie, G, Aalfs, CM, Abugattas, J, Adlard, J, Agata, S, Aittomaki, K, Andrews, L, Andrulis, IL, Arason, A, Arnold, N, Arun, BK, Asseryanis, E, Auerbach, L, Azzollini, J, Balmana, J, Barile, M, Barkardottir, RB, Barrowdale, D, Benitez, J, Berger, A, Berger, R, Blanco, AM, Blazer, KR, Blok, MJ, Bonadona, V, Bonanni, B, Bradbury, AR, Brewer, C, Buecher, B, Buys, SS, Caldes, T, Caliebe, A, Caligo, MA, Campbell, I, Caputo, SM, Chiquette, J, Chung, WK, Claes, KBM, Collee, JM, Cook, J, Davidson, R, de la Hoya, M, De Leeneer, K, de Pauw, A, Delnatte, C, Diez, O, Ding, YC, Ditsch, N, Domchek, S, Dorfling, CM, Velazquez, C, Dworniczak, B, Eason, J, Easton, DF, Eeles, R, Ehrencrona, H, Ejlertsen, B, Engel, C, Engert, S, Evans, DG, Faivre, L, Feliubadalo, L, Ferrer, SF, Foretova, L, Fowler, J, Frost, D, Galvao, HCR, Ganz, PA, Garber, J, Gauthier-Villars, M, Gehrig, A, Gerdes, A-M, Gesta, P, Giannini, G, Giraud, S, Glendon, G, Godwin, AK, Greene, MH, Gronwald, J, Gutierrez-Barrera, A, Hahnen, E, Hauke, J, Henderson, A, Hentschel, J, Hogervorst, FBL, Honisch, E, Imyanitov, EN, Isaacs, C, Izatt, L, Izquierdo, A, Jakubowska, A, James, P, Janavicius, R, Jensen, UB, John, EM, Vijai, J, Kaczmarek, K, Karlan, BY, Kast, K, Kim, S-W, Konstantopoulou, I, Korach, J, Laitman, Y, Lasa, A, Lasset, C, Lazaro, C, Lee, A, Lee, MH, Lester, J, Lesueur, F, Liljegren, A, Lindor, NM, Longy, M, Loud, JT, Lu, KH, Lubinski, J, Machackova, E, Manoukian, S, Mari, V, Martinez-Bouzas, C, Matrai, Z, Mebirouk, N, Meijers-Heijboer, HEJ, Meindl, A, Mensenkamp, AR, Mickys, U, Miller, A, Montagna, M, Moysich, KB, Mulligan, AM, Musinsky, J, Neuhausen, SL, Nevanlinna, H, Ngeow, J, Nguyen, HP, Niederacher, D, Nielsen, HR, Nielsen, FC, Nussbaum, RL, Offit, K, Ofverholm, A, Ong, K-R, Osorio, A, Papi, L, Papp, J, Pasini, B, Pedersen, IS, Peixoto, A, Peruga, N, Peterlongo, P, Pohl, E, Pradhan, N, Prajzendanc, K, Prieur, F, Pujol, P, Radice, P, Ramus, SJ, Rantala, J, Rashid, MU, Rhiem, K, Robson, M, Rodriguez, GC, Rogers, MT, Rudaitis, V, Schmidt, AY, Schmutzler, RK, Senter, L, Shah, PD, Sharma, P, Side, LE, Simard, J, Singer, CF, Skytte, A-B, Slavin, TP, Snape, K, Sobol, H, Southey, M, Steele, L, Steinemann, D, Sukiennicki, G, Sutter, C, Szabo, CI, Tan, YY, Teixeira, MR, Terry, MB, Teule, A, Thomas, A, Thull, DL, Tischkowitz, M, Tognazzo, S, Toland, AE, Topka, S, Trainer, AH, Tung, N, van Asperen, CJ, van der Hout, AH, van der Kolk, LE, van der Luijt, RB, Van Heetvelde, M, Varesco, L, Varon-Mateeva, R, Vega, A, Villarreal-Garza, C, von Wachenfeldt, A, Walker, L, Wang-Gohrke, S, Wappenschmidt, B, Weber, BHF, Yannoukakos, D, Yoon, S-Y, Zanzottera, C, Zidan, J, Zorn, KK, Selkirk, CGH, Hulick, PJ, Chenevix-Trench, G, Spurdle, AB, Antoniou, AC, and Nathanson, KL
Abstract: The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.
Published: 2018

10. GRIN2B encephalopathy: Novel findings on phenotype, variant clustering, functional consequences and treatment aspects

Author: Platzer, K, Yuan, H, Schütz, H, Winschel, A, Chen, W, Hu, C, Kusumoto, H, Heyne, HO, Helbig, KL, Tang, S, Willing, MC, Tinkle, BT, Adams, DJ, Depienne, C, Keren, B, Mignot, C, Frengen, E, Strømme, P, Biskup, S, Döcker, D, Strom, TM, Mefford, HC, Myers, CT, Muir, AM, LaCroix, A, Sadleir, L, Scheffer, IE, Brilstra, E, van Haelst, MM, van der Smagt, JJ, Bok, LA, Møller, RS, Jensen, UB, Millichap, JJ, Berg, AT, Goldberg, EM, De Bie, I, Fox, S, Major, P, Jones, JR, Zackai, EH, Abou Jamra, R, Rolfs, A, Leventer, RJ, Lawson, JA, Roscioli, T, Jansen, FE, Ranza, E, Korff, CM, Lehesjoki, AE, Courage, C, Linnankivi, T, Smith, DR, Stanley, C, Mintz, M, McKnight, D, Decker, A, Tan, WH, Tarnopolsky, MA, Brady, LI, Wolff, M, Dondit, L, Pedro, HF, Parisotto, SE, Jones, KL, Patel, AD, Franz, DN, Vanzo, R, Marco, E, Ranells, JD, Di Donato, N, Dobyns, WB, Laube, B, Traynelis, SF, Lemke, JR, Platzer, K, Yuan, H, Schütz, H, Winschel, A, Chen, W, Hu, C, Kusumoto, H, Heyne, HO, Helbig, KL, Tang, S, Willing, MC, Tinkle, BT, Adams, DJ, Depienne, C, Keren, B, Mignot, C, Frengen, E, Strømme, P, Biskup, S, Döcker, D, Strom, TM, Mefford, HC, Myers, CT, Muir, AM, LaCroix, A, Sadleir, L, Scheffer, IE, Brilstra, E, van Haelst, MM, van der Smagt, JJ, Bok, LA, Møller, RS, Jensen, UB, Millichap, JJ, Berg, AT, Goldberg, EM, De Bie, I, Fox, S, Major, P, Jones, JR, Zackai, EH, Abou Jamra, R, Rolfs, A, Leventer, RJ, Lawson, JA, Roscioli, T, Jansen, FE, Ranza, E, Korff, CM, Lehesjoki, AE, Courage, C, Linnankivi, T, Smith, DR, Stanley, C, Mintz, M, McKnight, D, Decker, A, Tan, WH, Tarnopolsky, MA, Brady, LI, Wolff, M, Dondit, L, Pedro, HF, Parisotto, SE, Jones, KL, Patel, AD, Franz, DN, Vanzo, R, Marco, E, Ranells, JD, Di Donato, N, Dobyns, WB, Laube, B, Traynelis, SF, and Lemke, JR
Abstract: Background: We aimed for a comprehensive delineation of genetic, functional and phenotypic aspects of GRIN2B encephalopathy and explored potential prospects of personalised medicine. Methods: Data of 48 individuals with de novo GRIN2B variants were collected from several diagnostic and research cohorts, as well as from 43 patients from the literature. Functional consequences and response to memantine treatment were investigated in vitro and eventually translated into patient care. Results: Overall, de novo variants in 86 patients were classified as pathogenic/likely pathogenic. Patients presented with neurodevelopmental disorders and a spectrum of hypotonia, movement disorder, cortical visual impairment, cerebral volume loss and epilepsy. Six patients presented with a consistent malformation of cortical development (MCD) intermediate between tubulinopathies and polymicrogyria. Missense variants cluster in transmembrane segments and ligand-binding sites. Functional consequences of variants were diverse, revealing various potential gain-of-function and loss-of-function mechanisms and a retained sensitivity to the use-dependent blocker memantine. However, an objectifiable beneficial treatment response in the respective patients still remains to be demonstrated. Conclusions: In addition to previously known features of intellectual disability, epilepsy and autism, we found evidence that GRIN2B encephalopathy is also frequently associated with movement disorder, cortical visual impairment and MCD revealing novel phenotypic consequences of channelopathies.
Published: 2017

11. Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3

Author: Hamdi, Y, Soucy, P, Kuchenbaeker, KB, Pastinen, T, Droit, A, Lemacon, A, Adlard, J, Aittomaki, K, Andrulis, IL, Arason, A, Arnold, N, Arun, BK, Azzollini, J, Bane, A, Barjhoux, L, Barrowdale, D, Benitez, J, Berthet, P, Blok, MJ, Bobolis, K, Bonadona, V, Bonanni, B, Bradbury, AR, Brewer, C, Buecher, B, Buys, SS, Caligo, MA, Chiquette, J, Chung, WK, Claes, KBM, Daly, MB, Damiola, F, Davidson, R, De la Hoya, M, De Leeneer, K, Diez, O, Ding, YC, Dolcetti, R, Domchek, SM, Dorfling, CM, Eccles, D, Eeles, R, Einbeigi, Z, Ejlertsen, B, Engel, C, Evans, DG, Feliubadalo, L, Foretova, L, Fostira, F, Foulkes, WD, Fountzilas, G, Friedman, E, Frost, D, Ganschow, P, Ganz, PA, Garber, J, Gayther, SA, Gerdes, A-M, Glendon, G, Godwin, AK, Goldgar, DE, Greene, MH, Gronwald, J, Hahnen, E, Hamann, U, Hansen, TVO, Hart, S, Hays, JL, Hogervorst, FBL, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Jakubowska, A, James, P, Janavicius, R, Jensen, UB, John, EM, Joseph, V, Just, W, Kaczmarek, K, Karlan, BY, Kets, CM, Kirk, J, Kriege, M, Laitman, Y, Laurent, M, Lazaro, C, Leslie, G, Lester, J, Lesueur, F, Liljegren, A, Loman, N, Loud, JT, Manoukian, S, Mariani, M, Mazoyer, S, McGuffog, L, Meijers-Heijboer, HEJ, Meindl, A, Miller, A, Montagna, M, Mulligan, AM, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nussbaum, RL, Olah, E, Olopade, OI, Ong, K-R, Oosterwijk, JC, Osorio, A, Papi, L, Park, SK, Pedersen, IS, Peissel, B, Segura, PP, Peterlongo, P, Phelan, CM, Radice, P, Rantala, J, Rappaport-Fuerhauser, C, Rennert, G, Richardson, A, Robson, M, Rodriguez, GC, Rookus, MA, Schmutzler, RK, Sevenet, N, Shah, PD, Singer, CF, Slavin, TP, Snape, K, Sokolowska, J, Sonderstrup, IMH, Southey, M, Spurdle, AB, Stadler, Z, Stoppa-Lyonnet, D, Sukiennicki, G, Sutter, C, Tan, Y, Tea, M-K, Teixeira, MR, Teule, A, Teo, S-H, Terry, MB, Thomassen, M, Tihomirova, L, Tischkowitz, M, Tognazzo, S, Toland, AE, Tung, N, van den Ouweland, AMW, van der Luijt, RB, van Engelen, K, van Rensburg, EJ, Varon-Mateeva, R, Wappenschmidt, B, Wijnen, JT, Rebbeck, T, Chenevix-Trench, G, Offit, K, Couch, FJ, Nord, S, Easton, DF, Antoniou, AC, Simard, J, Hamdi, Y, Soucy, P, Kuchenbaeker, KB, Pastinen, T, Droit, A, Lemacon, A, Adlard, J, Aittomaki, K, Andrulis, IL, Arason, A, Arnold, N, Arun, BK, Azzollini, J, Bane, A, Barjhoux, L, Barrowdale, D, Benitez, J, Berthet, P, Blok, MJ, Bobolis, K, Bonadona, V, Bonanni, B, Bradbury, AR, Brewer, C, Buecher, B, Buys, SS, Caligo, MA, Chiquette, J, Chung, WK, Claes, KBM, Daly, MB, Damiola, F, Davidson, R, De la Hoya, M, De Leeneer, K, Diez, O, Ding, YC, Dolcetti, R, Domchek, SM, Dorfling, CM, Eccles, D, Eeles, R, Einbeigi, Z, Ejlertsen, B, Engel, C, Evans, DG, Feliubadalo, L, Foretova, L, Fostira, F, Foulkes, WD, Fountzilas, G, Friedman, E, Frost, D, Ganschow, P, Ganz, PA, Garber, J, Gayther, SA, Gerdes, A-M, Glendon, G, Godwin, AK, Goldgar, DE, Greene, MH, Gronwald, J, Hahnen, E, Hamann, U, Hansen, TVO, Hart, S, Hays, JL, Hogervorst, FBL, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Jakubowska, A, James, P, Janavicius, R, Jensen, UB, John, EM, Joseph, V, Just, W, Kaczmarek, K, Karlan, BY, Kets, CM, Kirk, J, Kriege, M, Laitman, Y, Laurent, M, Lazaro, C, Leslie, G, Lester, J, Lesueur, F, Liljegren, A, Loman, N, Loud, JT, Manoukian, S, Mariani, M, Mazoyer, S, McGuffog, L, Meijers-Heijboer, HEJ, Meindl, A, Miller, A, Montagna, M, Mulligan, AM, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nussbaum, RL, Olah, E, Olopade, OI, Ong, K-R, Oosterwijk, JC, Osorio, A, Papi, L, Park, SK, Pedersen, IS, Peissel, B, Segura, PP, Peterlongo, P, Phelan, CM, Radice, P, Rantala, J, Rappaport-Fuerhauser, C, Rennert, G, Richardson, A, Robson, M, Rodriguez, GC, Rookus, MA, Schmutzler, RK, Sevenet, N, Shah, PD, Singer, CF, Slavin, TP, Snape, K, Sokolowska, J, Sonderstrup, IMH, Southey, M, Spurdle, AB, Stadler, Z, Stoppa-Lyonnet, D, Sukiennicki, G, Sutter, C, Tan, Y, Tea, M-K, Teixeira, MR, Teule, A, Teo, S-H, Terry, MB, Thomassen, M, Tihomirova, L, Tischkowitz, M, Tognazzo, S, Toland, AE, Tung, N, van den Ouweland, AMW, van der Luijt, RB, van Engelen, K, van Rensburg, EJ, Varon-Mateeva, R, Wappenschmidt, B, Wijnen, JT, Rebbeck, T, Chenevix-Trench, G, Offit, K, Couch, FJ, Nord, S, Easton, DF, Antoniou, AC, and Simard, J
Abstract: PURPOSE: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways. METHODS: Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2. RESULTS: We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10-6). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance. CONCLUSION: We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.
Published: 2017

12. Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores

Author: Lecarpentier, J, Silvestri, V, Kuchenbaecker, KB, Barrowdale, D, Dennis, J, McGuffog, L, Soucy, P, Leslie, G, Rizzolo, P, Navazio, AS, Valentini, V, Zelli, V, Lee, A, Al Olama, AA, Tyrer, JP, Southey, M, John, EM, Conner, TA, Goldgar, DE, Buys, SS, Janavicius, R, Steele, L, Ding, YC, Neuhausen, SL, Hansen, TVO, Osorio, A, Weitzel, JN, Toss, A, Medici, V, Cortesi, L, Zanna, I, Palli, D, Radice, P, Manoukian, S, Peissel, B, Azzollini, J, Viel, A, Cini, G, Damante, G, Tommasi, S, Peterlongo, P, Fostira, F, Hamann, U, Evans, DG, Henderson, A, Brewer, C, Eccles, D, Cook, J, Ong, K-R, Walker, L, Side, LE, Porteous, ME, Davidson, R, Hodgson, S, Frost, D, Adlard, J, Izatt, L, Eeles, R, Ellis, S, Tischkowitz, M, Godwin, AK, Meindl, A, Gehrig, A, Dworniczak, B, Sutter, C, Engel, C, Niederacher, D, Steinemann, D, Hahnen, E, Hauke, J, Rhiem, K, Kast, K, Arnold, N, Ditsch, N, Wang-Gohrke, S, Wappenschmidt, B, Wand, D, Lasset, C, Stoppa-Lyonnet, D, Belotti, M, Damiola, F, Barjhoux, L, Mazoyer, S, Van Heetvelde, M, Poppe, B, De Leeneer, K, Claes, KBM, de la Hoya, M, Garcia-Barberan, V, Caldes, T, Perez Segura, P, Kiiski, JI, Aittomaeki, K, Khan, S, Nevanlinna, H, van Asperen, CJ, Vaszko, T, Kasler, M, Olah, E, Balmana, J, Gutierrez-Enriquez, S, Diez, O, Teule, A, Izquierdo, A, Darder, E, Brunet, J, Del Valle, J, Feliubadalo, L, Pujana, MA, Lazaro, C, Arason, A, Agnarsson, BA, Johannsson, OT, Barkardottir, RB, Alducci, E, Tognazzo, S, Montagna, M, Teixeira, MR, Pinto, P, Spurdle, AB, Holland, H, Lee, JW, Lee, MH, Lee, J, Kim, S-W, Kang, E, Kim, Z, Sharma, P, Rebbeck, TR, Vijai, J, Robson, M, Lincoln, A, Musinsky, J, Gaddam, P, Tan, YY, Berger, A, Singer, CF, Loud, JT, Greene, MH, Mulligan, AM, Glendon, G, Andrulis, IL, Toland, AE, Senter, L, Bojesen, A, Nielsen, HR, Skytte, A-B, Sunde, L, Jensen, UB, Pedersen, IS, Krogh, L, Kruse, TA, Caligo, MA, Yoon, S-Y, Teo, S-H, von Wachenfeldt, A, Huo, D, Nielsen, SM, Olopade, OI, Nathanson, KL, Domchek, SM, Lorenchick, C, Jankowitz, RC, Campbell, I, James, P, Mitchell, G, Orr, N, Park, SK, Thomassen, M, Offit, K, Couch, FJ, Simard, J, Easton, DF, Chenevix-Trench, G, Schmutzler, RK, Antoniou, AC, Ottini, L, Lecarpentier, J, Silvestri, V, Kuchenbaecker, KB, Barrowdale, D, Dennis, J, McGuffog, L, Soucy, P, Leslie, G, Rizzolo, P, Navazio, AS, Valentini, V, Zelli, V, Lee, A, Al Olama, AA, Tyrer, JP, Southey, M, John, EM, Conner, TA, Goldgar, DE, Buys, SS, Janavicius, R, Steele, L, Ding, YC, Neuhausen, SL, Hansen, TVO, Osorio, A, Weitzel, JN, Toss, A, Medici, V, Cortesi, L, Zanna, I, Palli, D, Radice, P, Manoukian, S, Peissel, B, Azzollini, J, Viel, A, Cini, G, Damante, G, Tommasi, S, Peterlongo, P, Fostira, F, Hamann, U, Evans, DG, Henderson, A, Brewer, C, Eccles, D, Cook, J, Ong, K-R, Walker, L, Side, LE, Porteous, ME, Davidson, R, Hodgson, S, Frost, D, Adlard, J, Izatt, L, Eeles, R, Ellis, S, Tischkowitz, M, Godwin, AK, Meindl, A, Gehrig, A, Dworniczak, B, Sutter, C, Engel, C, Niederacher, D, Steinemann, D, Hahnen, E, Hauke, J, Rhiem, K, Kast, K, Arnold, N, Ditsch, N, Wang-Gohrke, S, Wappenschmidt, B, Wand, D, Lasset, C, Stoppa-Lyonnet, D, Belotti, M, Damiola, F, Barjhoux, L, Mazoyer, S, Van Heetvelde, M, Poppe, B, De Leeneer, K, Claes, KBM, de la Hoya, M, Garcia-Barberan, V, Caldes, T, Perez Segura, P, Kiiski, JI, Aittomaeki, K, Khan, S, Nevanlinna, H, van Asperen, CJ, Vaszko, T, Kasler, M, Olah, E, Balmana, J, Gutierrez-Enriquez, S, Diez, O, Teule, A, Izquierdo, A, Darder, E, Brunet, J, Del Valle, J, Feliubadalo, L, Pujana, MA, Lazaro, C, Arason, A, Agnarsson, BA, Johannsson, OT, Barkardottir, RB, Alducci, E, Tognazzo, S, Montagna, M, Teixeira, MR, Pinto, P, Spurdle, AB, Holland, H, Lee, JW, Lee, MH, Lee, J, Kim, S-W, Kang, E, Kim, Z, Sharma, P, Rebbeck, TR, Vijai, J, Robson, M, Lincoln, A, Musinsky, J, Gaddam, P, Tan, YY, Berger, A, Singer, CF, Loud, JT, Greene, MH, Mulligan, AM, Glendon, G, Andrulis, IL, Toland, AE, Senter, L, Bojesen, A, Nielsen, HR, Skytte, A-B, Sunde, L, Jensen, UB, Pedersen, IS, Krogh, L, Kruse, TA, Caligo, MA, Yoon, S-Y, Teo, S-H, von Wachenfeldt, A, Huo, D, Nielsen, SM, Olopade, OI, Nathanson, KL, Domchek, SM, Lorenchick, C, Jankowitz, RC, Campbell, I, James, P, Mitchell, G, Orr, N, Park, SK, Thomassen, M, Offit, K, Couch, FJ, Simard, J, Easton, DF, Chenevix-Trench, G, Schmutzler, RK, Antoniou, AC, and Ottini, L
Abstract: Purpose BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigated-for the first time to our knowledge-associations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/ 2 mutations and implications for cancer risk prediction. Materials and Methods We genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights. Results In male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 × 10-6). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; P = 3.2 × 10-9). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of BRCA1 mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively. Conclusion PRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.
Published: 2017

13. The Majority of Plakophilin-2 Mutations in Arrhythmogenic Cardiomyopathy are Associated with Haploinsufficiency in the Myocardium and Epidermis

Author: Rasmussen, TB, Nissen, PH, Palmfeldt, J, Gehmlich, K, Dalager, S, Jensen, UB, Kim, WY, Heickendorff, L, Molgaard, H, Jensen, HK, Baandrup, UT, Bross, P, and Mogensen, J
Published: 2016

14. Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Author: Pfeiler, G, Vigorito, E, Kuchenbaecker, KB, Beesley, J, Adlard, J, Agnarsson, BA, Andrulis, IL, Arun, BK, Barjhoux, L, Belotti, M, Benitez, J, Berger, A, Phelan, CM, Piedmonte, M, Poppe, B, Pujana, MA, Radice, P, Rennert, G, Rodriguez, GC, Rookus, MA, Ross, EA, Bojesen, A, Schmutzler, RK, Simard, J, Singer, CF, Slavin, TP, Soucy, P, Southey, M, Steinemann, D, Stoppa-Lyonnet, D, Sukiennicki, G, Sutter, C, Bonanni, B, Szabo, CI, Tea, MK, Teixeira, MR, Teo, SH, Terry, MB, Thomassen, M, Tibiletti, MG, Tihomirova, L, Tognazzo, S, van Rensburg, EJ, Brewer, C, Varesco, L, Varon-Mateeva, R, Vratimos, A, Weitzel, JN, McGuffog, L, Kirk, J, Toland, AE, Hamann, U, Lindor, N, Ramus, SJ, Caldes, T, Greene, MH, Couch, FJ, Offit, K, Pharoah, PDP, Chenevix-Trench, G, Antoniou, AC, Prokunina-Olsson, L, Caligo, MA, Campbell, I, Chan, SB, Claes, KBM, Cohn, DE, Cook, J, Daly, MB, Damiola, F, Davidson, R, Pauw, AD, Delnatte, C, Diez, O, Domchek, SM, Dumont, M, Durda, K, Dworniczak, B, Easton, DF, Eccles, D, Edwinsdotter Ardnor, C, Eeles, R, Ejlertsen, B, Ellis, S, Evans, G, Feliubadalo, L, Fostira, F, Foulkes, WD, Friedman, E, Frost, D, Gaddam, P, Ganz, PA, Garber, J, Garcia-Barberan, V, Gauthier-Villars, M, Gehrig, A, Gerdes, AM, Giraud, S, Godwin, AK, Goldgar, DE, Hake, CR, Hansen, TVO, Healey, S, Hodgson, S, Hogervorst, FBL, Houdayer, C, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Izquierdo, A, Jacobs, L, Jakubowska, A, Janavicius, R, Jaworska-Bieniek, K, Jensen, UB, John, EM, Vijai, J, Karlan, BY, Kast, K, Investigators, K, Khan, S, Kwong, A, Laitman, Y, Lester, J, Lesueur, F, Liljegren, A, Lubinski, J, Mai, PL, Manoukian, S, Mazoyer, S, Meindl, A, Mensenkamp, AR, Montagna, M, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Niederacher, D, Olah, E, Olopade, OI, Ong, KR, Osorio, A, Park, SK, Paulsson-Karlsson, Y, Pedersen, IS, Peissel, B, and Peterlongo, P
Subjects: endocrine system diseases, skin and connective tissue diseases
Abstract: Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA 1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10−16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10−6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population
Published: 2016

15. Refined histopathological predictors of BRCA1 and BRCA2 mutation status: A large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia

Author: Spurdle, AB, Couch, FJ, Parsons, MT, McGuffog, L, Barrowdale, D, Bolla, MK, Wang, Q, Healey, S, Schmutzler, RK, Wappenschmidt, B, Rhiem, K, Hahnen, E, Engel, C, Meindl, A, Ditsch, N, Arnold, N, Plendl, H, Niederacher, D, Sutter, C, Wang-Gohrke, S, Steinemann, D, Preisler-Adams, S, Kast, K, Varon-Mateeva, R, Ellis, S, Frost, D, Platte, R, Perkins, J, Gareth Evans, D, Izatt, L, Eeles, R, Adlard, J, Davidson, R, Cole, T, Scuvera, G, Manoukian, S, Bonanni, B, Mariette, F, Fortuzzi, S, Viel, A, Pasini, B, Papi, L, Varesco, L, Balleine, R, Nathanson, KL, Domchek, SM, Offitt, K, Jakubowska, A, Lindor, N, Thomassen, M, Jensen, UB, Rantala, J, Borg, Å, Andrulis, IL, Miron, A, Hansen, TVO, Caldes, T, Neuhausen, SL, Toland, AE, Nevanlinna, H, Montagna, M, Garber, J, Godwin, AK, Osorio, A, Factor, RE, Terry, MB, Rebbeck, TR, Karlan, BY, Southey, M, Rashid, MU, Tung, N, Pharoah, PDP, Blows, FM, Dunning, AM, Provenzano, E, Hall, P, Czene, K, Schmidt, MK, Broeks, A, Cornelissen, S, Verhoef, S, Fasching, PA, Beckmann, MW, Ekici, AB, Slamon, DJ, Bojesen, SE, and Nordestgaard, BG
Subjects: endocrine system diseases, skin and connective tissue diseases
Abstract: © 2014 Spurdle et al. Introduction: The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling. Methods: Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of mutation status by histopathological markers were derived using a Mantel-Haenszel approach. Results: ER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years or older (LR = 4.13 (3.70 to 4.62)) versus younger than 50 years (LR = 3.16 (2.96 to 3.37)). For BRCA2, ER-positive grade 3 phenotype modestly predicted positive mutation status irrespective of age (LR = 1.7-fold), whereas ER-negative grade 3 features modestly predicted positive mutation status at 50 years or older (LR = 1.54 (1.27 to 1.88)). Triple-negative tumor status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR = 3.73 (3.43 to 4.05)) and 50 years or older (LR = 4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years or older (LR = 1.79 (1.42 to 2.24)). Conclusions: These results refine likelihood-ratio estimates for predicting BRCA1 and BRCA2 mutation status by using commonly measured histopathological features. Age at diagnosis is an important variable for most analyses, and grade is more informative than ER status for BRCA2 mutation carrier prediction. The estimates will improve BRCA1 and BRCA2 variant classification and inform patient mutation testing and clinical management.
Published: 2014

16. Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2

Author: Silvestri, V, Barrowdale, D, Mulligan, AM, Neuhausen, SL, Fox, S, Karlan, BY, Mitchell, G, James, P, Thull, DL, Zorn, KK, Carter, NJ, Nathanson, KL, Dornchek, SM, Rebbeck, TR, Ramus, SJ, Nussbaum, RL, Olopade, OI, Rantala, J, Yoon, S-Y, Caligo, MA, Spugnesi, L, Bojesen, A, Pedersen, IS, Thomassen, M, Jensen, UB, Toland, AE, Senter, L, Andrulis, IL, Glendon, G, Hulick, PJ, Irnyanitov, EN, Greene, MH, Mai, PL, Singer, CF, Rappaport-Fuerhauser, C, Kramer, G, Vijai, J, Offit, K, Robson, M, Lincoln, A, Jacobs, L, Machackova, E, Foretova, L, Navratilova, M, Vasickova, P, Couch, FJ, Hallberg, E, Ruddy, KJ, Sharma, P, Kim, S-W, Teixeira, MR, Pinte, P, Montagna, M, Matricardi, L, Arason, A, Johannsson, OT, Barkardottir, RB, Jakubowska, A, Lubinski, J, Izquierdo, A, Angel Pujana, M, Balmana, J, Diez, O, Ivady, G, Papp, J, Olah, E, Kwong, A, Nevanlinna, H, Aittomaki, K, Perez Segura, P, Caldes, T, Van Maerken, T, Poppe, B, Claes, KBM, Isaacs, C, Elan, C, Lasset, C, Stoppa-Lyonnet, D, Barjhoux, L, Belotti, M, Meindl, A, Gehrig, A, Sutter, C, Enger, C, Niederacher, D, Steinemann, D, Hahnen, E, Kast, K, Arnold, N, Varon-Mateeva, R, Wand, D, Godwin, AK, Evans, DG, Frost, D, Perkins, J, Adlard, J, Izatt, L, Platte, R, Eeles, R, Ellis, S, Hamann, U, Garber, J, Fostira, F, Fountzilas, G, Pasini, B, Giannini, G, Rizzolo, P, Russo, A, Cortesi, L, Papi, L, Varesco, L, Palli, D, Zanna, I, Savarese, A, Radice, P, Manoukian, S, Peissel, B, Barile, M, Bonanni, B, Viel, A, Pensotti, V, Tommasi, S, Peterlongo, P, Weitzel, JN, Osorio, A, Benitez, J, McGuffog, L, Healey, S, Gerdes, A-M, Ejlertsen, B, Hansen, TVO, Steele, L, Ding, YC, Tung, N, Janavicius, R, Goldgar, DE, Buys, SS, Daly, MB, Bane, A, Terry, MB, John, EM, Southey, M, Easton, DF, Chenevix-Trench, G, Antoniou, AC, Ottini, L, Silvestri, V, Barrowdale, D, Mulligan, AM, Neuhausen, SL, Fox, S, Karlan, BY, Mitchell, G, James, P, Thull, DL, Zorn, KK, Carter, NJ, Nathanson, KL, Dornchek, SM, Rebbeck, TR, Ramus, SJ, Nussbaum, RL, Olopade, OI, Rantala, J, Yoon, S-Y, Caligo, MA, Spugnesi, L, Bojesen, A, Pedersen, IS, Thomassen, M, Jensen, UB, Toland, AE, Senter, L, Andrulis, IL, Glendon, G, Hulick, PJ, Irnyanitov, EN, Greene, MH, Mai, PL, Singer, CF, Rappaport-Fuerhauser, C, Kramer, G, Vijai, J, Offit, K, Robson, M, Lincoln, A, Jacobs, L, Machackova, E, Foretova, L, Navratilova, M, Vasickova, P, Couch, FJ, Hallberg, E, Ruddy, KJ, Sharma, P, Kim, S-W, Teixeira, MR, Pinte, P, Montagna, M, Matricardi, L, Arason, A, Johannsson, OT, Barkardottir, RB, Jakubowska, A, Lubinski, J, Izquierdo, A, Angel Pujana, M, Balmana, J, Diez, O, Ivady, G, Papp, J, Olah, E, Kwong, A, Nevanlinna, H, Aittomaki, K, Perez Segura, P, Caldes, T, Van Maerken, T, Poppe, B, Claes, KBM, Isaacs, C, Elan, C, Lasset, C, Stoppa-Lyonnet, D, Barjhoux, L, Belotti, M, Meindl, A, Gehrig, A, Sutter, C, Enger, C, Niederacher, D, Steinemann, D, Hahnen, E, Kast, K, Arnold, N, Varon-Mateeva, R, Wand, D, Godwin, AK, Evans, DG, Frost, D, Perkins, J, Adlard, J, Izatt, L, Platte, R, Eeles, R, Ellis, S, Hamann, U, Garber, J, Fostira, F, Fountzilas, G, Pasini, B, Giannini, G, Rizzolo, P, Russo, A, Cortesi, L, Papi, L, Varesco, L, Palli, D, Zanna, I, Savarese, A, Radice, P, Manoukian, S, Peissel, B, Barile, M, Bonanni, B, Viel, A, Pensotti, V, Tommasi, S, Peterlongo, P, Weitzel, JN, Osorio, A, Benitez, J, McGuffog, L, Healey, S, Gerdes, A-M, Ejlertsen, B, Hansen, TVO, Steele, L, Ding, YC, Tung, N, Janavicius, R, Goldgar, DE, Buys, SS, Daly, MB, Bane, A, Terry, MB, John, EM, Southey, M, Easton, DF, Chenevix-Trench, G, Antoniou, AC, and Ottini, L
Abstract: BACKGROUND: BRCA1 and, more commonly, BRCA2 mutations are associated with increased risk of male breast cancer (MBC). However, only a paucity of data exists on the pathology of breast cancers (BCs) in men with BRCA1/2 mutations. Using the largest available dataset, we determined whether MBCs arising in BRCA1/2 mutation carriers display specific pathologic features and whether these features differ from those of BRCA1/2 female BCs (FBCs). METHODS: We characterised the pathologic features of 419 BRCA1/2 MBCs and, using logistic regression analysis, contrasted those with data from 9675 BRCA1/2 FBCs and with population-based data from 6351 MBCs in the Surveillance, Epidemiology, and End Results (SEER) database. RESULTS: Among BRCA2 MBCs, grade significantly decreased with increasing age at diagnosis (P = 0.005). Compared with BRCA2 FBCs, BRCA2 MBCs were of significantly higher stage (P for trend = 2 × 10(-5)) and higher grade (P for trend = 0.005) and were more likely to be oestrogen receptor-positive [odds ratio (OR) 10.59; 95 % confidence interval (CI) 5.15-21.80] and progesterone receptor-positive (OR 5.04; 95 % CI 3.17-8.04). With the exception of grade, similar patterns of associations emerged when we compared BRCA1 MBCs and FBCs. BRCA2 MBCs also presented with higher grade than MBCs from the SEER database (P for trend = 4 × 10(-12)). CONCLUSIONS: On the basis of the largest series analysed to date, our results show that BRCA1/2 MBCs display distinct pathologic characteristics compared with BRCA1/2 FBCs, and we identified a specific BRCA2-associated MBC phenotype characterised by a variable suggesting greater biological aggressiveness (i.e., high histologic grade). These findings could lead to the development of gender-specific risk prediction models and guide clinical strategies appropriate for MBC management.
Published: 2016

17. Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer

Author: Couch, FJ, Kuchenbaecker, KB, Michailidou, K, Mendoza-Fandino, GA, Nord, S, Lilyquist, J, Olswold, C, Hallberg, E, Agata, S, Ahsan, H, Aittomaeki, K, Ambrosone, C, Andrulis, IL, Anton-Culver, H, Arndt, V, Arun, BK, Arver, B, Barile, M, Barkardottir, RB, Barrowdale, D, Beckmann, L, Beckmann, MW, Benitez, J, Blank, SV, Blomqvist, C, Bogdanova, NV, Bojesen, SE, Bolla, MK, Bonanni, B, Brauch, H, Brenner, H, Burwinkel, B, Buys, SS, Caldes, T, Caligo, MA, Canzian, F, Carpenter, J, Chang-Claude, J, Chanock, SJ, Chung, WK, Claes, KBM, Cox, A, Cross, SS, Cunningham, JM, Czene, K, Daly, MB, Damiola, F, Darabi, H, de la Hoya, M, Devilee, P, Diez, O, Ding, YC, Dolcetti, R, Domchek, SM, Dorfling, CM, dos-Santos-Silva, I, Dumont, M, Dunning, AM, Eccles, DM, Ehrencrona, H, Ekici, AB, Eliassen, H, Ellis, S, Fasching, PA, Figueroa, J, Flesch-Janys, D, Foersti, A, Fostira, F, Foulkes, WD, Friebel, T, Friedman, E, Frost, D, Gabrielson, M, Gammon, MD, Ganz, PA, Gapstur, SM, Garber, J, Gaudet, MM, Gayther, SA, Gerdes, A-M, Ghoussaini, M, Giles, GG, Glendon, G, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Gronwald, J, Guenel, P, Gunter, M, Haeberle, L, Haiman, CA, Hamann, U, Hansen, TVO, Hart, S, Healey, S, Heikkinen, T, Henderson, BE, Herzog, J, Hogervorst, FBL, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Humphreys, K, Hunter, DJ, Huzarski, T, Imyanitov, EN, Isaacs, C, Jakubowska, A, James, P, Janavicius, R, Jensen, UB, John, EM, Jones, M, Kabisch, M, Kar, S, Karlan, BY, Khan, S, Khaw, K-T, Kibriya, MG, Knight, JA, Ko, Y-D, Konstantopoulou, I, Kosma, V-M, Kristensen, V, Kwong, A, Laitman, Y, Lambrechts, D, Lazaro, C, Lee, E, Le Marchand, L, Lester, J, Lindblom, A, Lindor, N, Lindstrom, S, Liu, J, Long, J, Lubinski, J, Mai, PL, Makalic, E, Malone, KE, Mannermaa, A, Manoukian, S, Margolin, S, Marme, F, Martens, JWM, McGuffog, L, Meindl, A, Miller, A, Milne, RL, Miron, P, Montagna, M, Mazoyer, S, Mulligan, AM, Muranen, TA, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nordestgaard, BG, Nussbaum, RL, Offit, K, Olah, E, Olopade, OI, Olson, JE, Osorio, A, Park, SK, Peeters, PH, Peissel, B, Peterlongo, P, Peto, J, Phelan, CM, Pilarski, R, Poppe, B, Pylkaes, K, Radice, P, Rahman, N, Rantala, J, Rappaport, C, Rennert, G, Richardson, A, Robson, M, Romieu, I, Rudolph, A, Rutgers, EJ, Sanchez, M-J, Santella, RM, Sawyer, EJ, Schmidt, DF, Schmidt, MK, Schmutzler, RK, Schumacher, F, Scott, R, Senter, L, Sharma, P, Simard, J, Singer, CF, Sinilnikova, OM, Soucy, P, Southey, M, Steinemann, D, Stenmark-Askmalm, M, Stoppa-Lyonnet, D, Swerdlow, A, Szabo, CI, Tamimi, R, Tapper, W, Teixeira, MR, Teo, S-H, Terry, MB, Thomassen, M, Thompson, D, Tihomirova, L, Toland, AE, Tollenaar, RAEM, Tomlinson, I, Truong, T, Tsimiklis, H, Teule, A, Tumino, R, Tung, N, Turnbull, C, Ursin, G, van Deurzen, CHM, van Rensburg, EJ, Varon-Mateeva, R, Wang, Z, Wang-Gohrke, S, Weiderpass, E, Weitzel, JN, Whittemore, A, Wildiers, H, Winqvist, R, Yang, XR, Yannoukakos, D, Yao, S, Zamora, MP, Zheng, W, Hall, P, Kraft, P, Vachon, C, Slager, S, Chenevix-Trench, G, Pharoah, PDP, Monteiro, AAN, Garcia-Closas, M, Easton, DF, Antoniou, AC, Couch, FJ, Kuchenbaecker, KB, Michailidou, K, Mendoza-Fandino, GA, Nord, S, Lilyquist, J, Olswold, C, Hallberg, E, Agata, S, Ahsan, H, Aittomaeki, K, Ambrosone, C, Andrulis, IL, Anton-Culver, H, Arndt, V, Arun, BK, Arver, B, Barile, M, Barkardottir, RB, Barrowdale, D, Beckmann, L, Beckmann, MW, Benitez, J, Blank, SV, Blomqvist, C, Bogdanova, NV, Bojesen, SE, Bolla, MK, Bonanni, B, Brauch, H, Brenner, H, Burwinkel, B, Buys, SS, Caldes, T, Caligo, MA, Canzian, F, Carpenter, J, Chang-Claude, J, Chanock, SJ, Chung, WK, Claes, KBM, Cox, A, Cross, SS, Cunningham, JM, Czene, K, Daly, MB, Damiola, F, Darabi, H, de la Hoya, M, Devilee, P, Diez, O, Ding, YC, Dolcetti, R, Domchek, SM, Dorfling, CM, dos-Santos-Silva, I, Dumont, M, Dunning, AM, Eccles, DM, Ehrencrona, H, Ekici, AB, Eliassen, H, Ellis, S, Fasching, PA, Figueroa, J, Flesch-Janys, D, Foersti, A, Fostira, F, Foulkes, WD, Friebel, T, Friedman, E, Frost, D, Gabrielson, M, Gammon, MD, Ganz, PA, Gapstur, SM, Garber, J, Gaudet, MM, Gayther, SA, Gerdes, A-M, Ghoussaini, M, Giles, GG, Glendon, G, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Gronwald, J, Guenel, P, Gunter, M, Haeberle, L, Haiman, CA, Hamann, U, Hansen, TVO, Hart, S, Healey, S, Heikkinen, T, Henderson, BE, Herzog, J, Hogervorst, FBL, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Humphreys, K, Hunter, DJ, Huzarski, T, Imyanitov, EN, Isaacs, C, Jakubowska, A, James, P, Janavicius, R, Jensen, UB, John, EM, Jones, M, Kabisch, M, Kar, S, Karlan, BY, Khan, S, Khaw, K-T, Kibriya, MG, Knight, JA, Ko, Y-D, Konstantopoulou, I, Kosma, V-M, Kristensen, V, Kwong, A, Laitman, Y, Lambrechts, D, Lazaro, C, Lee, E, Le Marchand, L, Lester, J, Lindblom, A, Lindor, N, Lindstrom, S, Liu, J, Long, J, Lubinski, J, Mai, PL, Makalic, E, Malone, KE, Mannermaa, A, Manoukian, S, Margolin, S, Marme, F, Martens, JWM, McGuffog, L, Meindl, A, Miller, A, Milne, RL, Miron, P, Montagna, M, Mazoyer, S, Mulligan, AM, Muranen, TA, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nordestgaard, BG, Nussbaum, RL, Offit, K, Olah, E, Olopade, OI, Olson, JE, Osorio, A, Park, SK, Peeters, PH, Peissel, B, Peterlongo, P, Peto, J, Phelan, CM, Pilarski, R, Poppe, B, Pylkaes, K, Radice, P, Rahman, N, Rantala, J, Rappaport, C, Rennert, G, Richardson, A, Robson, M, Romieu, I, Rudolph, A, Rutgers, EJ, Sanchez, M-J, Santella, RM, Sawyer, EJ, Schmidt, DF, Schmidt, MK, Schmutzler, RK, Schumacher, F, Scott, R, Senter, L, Sharma, P, Simard, J, Singer, CF, Sinilnikova, OM, Soucy, P, Southey, M, Steinemann, D, Stenmark-Askmalm, M, Stoppa-Lyonnet, D, Swerdlow, A, Szabo, CI, Tamimi, R, Tapper, W, Teixeira, MR, Teo, S-H, Terry, MB, Thomassen, M, Thompson, D, Tihomirova, L, Toland, AE, Tollenaar, RAEM, Tomlinson, I, Truong, T, Tsimiklis, H, Teule, A, Tumino, R, Tung, N, Turnbull, C, Ursin, G, van Deurzen, CHM, van Rensburg, EJ, Varon-Mateeva, R, Wang, Z, Wang-Gohrke, S, Weiderpass, E, Weitzel, JN, Whittemore, A, Wildiers, H, Winqvist, R, Yang, XR, Yannoukakos, D, Yao, S, Zamora, MP, Zheng, W, Hall, P, Kraft, P, Vachon, C, Slager, S, Chenevix-Trench, G, Pharoah, PDP, Monteiro, AAN, Garcia-Closas, M, Easton, DF, and Antoniou, AC
Abstract: Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.
Published: 2016

18. Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus

Author: Zeng, C, Guo, X, Long, J, Kuchenbaecker, KB, Droit, A, Michailidou, K, Ghoussaini, M, Kar, S, Freeman, A, Hopper, JL, Milne, RL, Bolla, MK, Wang, Q, Dennis, J, Agata, S, Ahmed, S, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arason, A, Arndt, V, Arun, BK, Arver, B, Bacot, F, Barrowdale, D, Baynes, C, Beeghly-Fadiel, A, Benitez, J, Bermisheva, M, Blomqvist, C, Blot, WJ, Bogdanova, NV, Bojesen, SE, Bonanni, B, Borresen-Dale, A-L, Brand, JS, Brauch, H, Brennan, P, Brenner, H, Broeks, A, Bruening, T, Burwinkel, B, Buys, SS, Cai, Q, Caldes, T, Campbell, I, Carpenter, J, Chang-Claude, J, Choi, J-Y, Claes, KBM, Clarke, C, Cox, A, Cross, SS, Czene, K, Daly, MB, de la Hoya, M, De Leeneer, K, Devilee, P, Diez, O, Domchek, SM, Doody, M, Dorfling, CM, Doerk, T, dos-Santos-Silva, I, Dumont, M, Dwek, M, Dworniczak, B, Egan, K, Eilber, U, Einbeigi, Z, Ejlertsen, B, Ellis, S, Frost, D, Lalloo, F, Fasching, PA, Figueroa, J, Flyger, H, Friedlander, M, Friedman, E, Gambino, G, Gao, Y-T, Garber, J, Garcia-Closas, M, Gehrig, A, Damiola, F, Lesueur, F, Mazoyer, S, Stoppa-Lyonnet, D, Giles, GG, Godwin, AK, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Guenel, P, Haeberle, L, Haiman, CA, Hallberg, E, Hamann, U, Hansen, TVO, Hart, S, Hartikainen, JM, Hartman, M, Hassan, N, Healey, S, Hogervorst, FBL, Verhoef, S, Hendricks, CB, Hillemanns, P, Hollestelle, A, Hulick, PJ, Hunter, DJ, Imyanitov, EN, Isaacs, C, Ito, H, Jakubowska, A, Janavicius, R, Jaworska-Bieniek, K, Jensen, UB, John, EM, Beauparlant, CJ, Jones, M, Kabisch, M, Kang, D, Karlan, BY, Kauppila, S, Kerin, MJ, Khan, S, Khusnutdinova, E, Knight, JA, Konstantopoulou, I, Kraft, P, Kwong, A, Laitman, Y, Lambrechts, D, Lazaro, C, Le Marchand, L, Lee, CN, Lee, MH, Lester, J, Li, J, Liljegren, A, Lindblom, A, Lophatananon, A, Lubinski, J, Mai, PL, Mannermaa, A, Manoukian, S, Margolin, S, Marme, F, Matsuo, K, McGuffog, L, Meindl, A, Menegaux, F, Montagna, M, Muir, K, Mulligan, AM, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Newcomb, PA, Nord, S, Nussbaum, RL, Offit, K, Olah, E, Olopade, OI, Olswold, C, Osorio, A, Papi, L, Park-Simon, T-W, Paulsson-Karlsson, Y, Peeters, S, Peissel, B, Peterlongo, P, Peto, J, Pfeiler, G, Phelan, CM, Presneau, N, Radice, P, Rahman, N, Ramus, SJ, Rashid, MU, Rennert, G, Rhiem, K, Rudolph, A, Salani, R, Sangrajrang, S, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Schoemaker, MJ, Schuermann, P, Seynaeve, C, Shen, C-Y, Shrubsole, MJ, Shu, X-O, Sigurdson, A, Singer, CF, Slager, S, Soucy, P, Southey, M, Steinemann, D, Swerdlow, A, Szabo, CI, Tchatchou, S, Teixeira, MR, Teo, SH, Terry, MB, Tessier, DC, Teule, A, Thomassen, M, Tihomirova, L, Tischkowitz, M, Toland, AE, Tung, N, Turnbull, C, van den Ouweland, AMW, van Rensburg, EJ, ven den Berg, D, Vijai, J, Wang-Gohrke, S, Weitzel, JN, Whittemore, AS, Winqvist, R, Wong, TY, Wu, AH, Yannoukakos, D, Yu, J-C, Pharoah, PDP, Hall, P, Chenevix-Trench, G, Dunning, AM, Simard, J, Couch, FJ, Antoniou, AC, Easton, DF, Zheng, W, Zeng, C, Guo, X, Long, J, Kuchenbaecker, KB, Droit, A, Michailidou, K, Ghoussaini, M, Kar, S, Freeman, A, Hopper, JL, Milne, RL, Bolla, MK, Wang, Q, Dennis, J, Agata, S, Ahmed, S, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arason, A, Arndt, V, Arun, BK, Arver, B, Bacot, F, Barrowdale, D, Baynes, C, Beeghly-Fadiel, A, Benitez, J, Bermisheva, M, Blomqvist, C, Blot, WJ, Bogdanova, NV, Bojesen, SE, Bonanni, B, Borresen-Dale, A-L, Brand, JS, Brauch, H, Brennan, P, Brenner, H, Broeks, A, Bruening, T, Burwinkel, B, Buys, SS, Cai, Q, Caldes, T, Campbell, I, Carpenter, J, Chang-Claude, J, Choi, J-Y, Claes, KBM, Clarke, C, Cox, A, Cross, SS, Czene, K, Daly, MB, de la Hoya, M, De Leeneer, K, Devilee, P, Diez, O, Domchek, SM, Doody, M, Dorfling, CM, Doerk, T, dos-Santos-Silva, I, Dumont, M, Dwek, M, Dworniczak, B, Egan, K, Eilber, U, Einbeigi, Z, Ejlertsen, B, Ellis, S, Frost, D, Lalloo, F, Fasching, PA, Figueroa, J, Flyger, H, Friedlander, M, Friedman, E, Gambino, G, Gao, Y-T, Garber, J, Garcia-Closas, M, Gehrig, A, Damiola, F, Lesueur, F, Mazoyer, S, Stoppa-Lyonnet, D, Giles, GG, Godwin, AK, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Guenel, P, Haeberle, L, Haiman, CA, Hallberg, E, Hamann, U, Hansen, TVO, Hart, S, Hartikainen, JM, Hartman, M, Hassan, N, Healey, S, Hogervorst, FBL, Verhoef, S, Hendricks, CB, Hillemanns, P, Hollestelle, A, Hulick, PJ, Hunter, DJ, Imyanitov, EN, Isaacs, C, Ito, H, Jakubowska, A, Janavicius, R, Jaworska-Bieniek, K, Jensen, UB, John, EM, Beauparlant, CJ, Jones, M, Kabisch, M, Kang, D, Karlan, BY, Kauppila, S, Kerin, MJ, Khan, S, Khusnutdinova, E, Knight, JA, Konstantopoulou, I, Kraft, P, Kwong, A, Laitman, Y, Lambrechts, D, Lazaro, C, Le Marchand, L, Lee, CN, Lee, MH, Lester, J, Li, J, Liljegren, A, Lindblom, A, Lophatananon, A, Lubinski, J, Mai, PL, Mannermaa, A, Manoukian, S, Margolin, S, Marme, F, Matsuo, K, McGuffog, L, Meindl, A, Menegaux, F, Montagna, M, Muir, K, Mulligan, AM, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Newcomb, PA, Nord, S, Nussbaum, RL, Offit, K, Olah, E, Olopade, OI, Olswold, C, Osorio, A, Papi, L, Park-Simon, T-W, Paulsson-Karlsson, Y, Peeters, S, Peissel, B, Peterlongo, P, Peto, J, Pfeiler, G, Phelan, CM, Presneau, N, Radice, P, Rahman, N, Ramus, SJ, Rashid, MU, Rennert, G, Rhiem, K, Rudolph, A, Salani, R, Sangrajrang, S, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Schoemaker, MJ, Schuermann, P, Seynaeve, C, Shen, C-Y, Shrubsole, MJ, Shu, X-O, Sigurdson, A, Singer, CF, Slager, S, Soucy, P, Southey, M, Steinemann, D, Swerdlow, A, Szabo, CI, Tchatchou, S, Teixeira, MR, Teo, SH, Terry, MB, Tessier, DC, Teule, A, Thomassen, M, Tihomirova, L, Tischkowitz, M, Toland, AE, Tung, N, Turnbull, C, van den Ouweland, AMW, van Rensburg, EJ, ven den Berg, D, Vijai, J, Wang-Gohrke, S, Weitzel, JN, Whittemore, AS, Winqvist, R, Wong, TY, Wu, AH, Yannoukakos, D, Yu, J-C, Pharoah, PDP, Hall, P, Chenevix-Trench, G, Dunning, AM, Simard, J, Couch, FJ, Antoniou, AC, Easton, DF, and Zheng, W
Abstract: BACKGROUND: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. METHOD: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/ ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. RESULTS: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 × 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 × 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 × 10(-4)) identified in the general populations, and rs113824616 (P = 7 × 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. CONCLUSION: This
Published: 2016

19. Identification of six new susceptibility loci for invasive epithelial ovarian cancer

Author: Kuchenbaecker, KB, Ramus, SJ, Tyrer, J, Lee, A, Shen, HC, Beesley, J, Lawrenson, K, McGuffog, L, Healey, S, Lee, JM, Spindler, TJ, Lin, YG, Pejovic, T, Bean, Y, Li, Q, Coetzee, S, Hazelett, D, Miron, A, Southey, M, Terry, MB, Goldgar, DE, Buys, SS, Janavicius, R, Dorfling, CM, van Rensburg, EJ, Neuhausen, SL, Ding, YC, Hansen, TVO, Jonson, L, Gerdes, A-M, Ejlertsen, B, Barrowdale, D, Dennis, J, Benitez, J, Osorio, A, Garcia, MJ, Komenaka, I, Weitzel, JN, Ganschow, P, Peterlongo, P, Bernard, L, Viel, A, Bonanni, B, Peissel, B, Manoukian, S, Radice, P, Papi, L, Ottini, L, Fostira, F, Konstantopoulou, I, Garber, J, Frost, D, Perkins, J, Platte, R, Ellis, S, Godwin, AK, Schmutzler, RK, Meindl, A, Engel, C, Sutter, C, Sinilnikova, OM, Damiola, F, Mazoyer, S, Stoppa-Lyonnet, D, Claes, K, De Leeneer, K, Kirk, J, Rodriguez, GC, Piedmonte, M, O'Malley, DM, de la Hoya, M, Caldes, T, Aittomaeki, K, Nevanlinna, H, Collee, JM, Rookus, MA, Oosterwijk, JC, Tihomirova, L, Tung, N, Hamann, U, Isaccs, C, Tischkowitz, M, Imyanitov, EN, Caligo, MA, Campbell, IG, Hogervorst, FBL, Olah, E, Diez, O, Blanco, I, Brunet, J, Lazaroso, C, Angel Pujana, M, Jakubowska, A, Gronwald, J, Lubinski, J, Sukiennicki, G, Barkardottir, RB, Plante, M, Simard, J, Soucy, P, Montagna, M, Tognazzo, S, Teixeira, MR, Pankratz, VS, Wang, X, Lindor, N, Szabo, CI, Kauff, N, Vijai, J, Aghajanian, CA, Pfeiler, G, Berger, A, Singer, CF, Tea, M-K, Phelan, CM, Greene, MH, Mai, PL, Rennert, G, Mulligan, AM, Tchatchou, S, Andrulis, IL, Glendon, G, Toland, AE, Jensen, UB, Kruse, TA, Thomassen, M, Bojesen, A, Zidan, J, Friedman, E, Laitman, Y, Soller, M, Liljegren, A, Arver, B, Einbeigi, Z, Stenmark-Askmalm, M, Olopade, OI, Nussbaum, RL, Rebbeck, TR, Nathanson, KL, Domchek, SM, Lu, KH, Karlan, BY, Walsh, C, Lester, J, Hein, A, Ekici, AB, Beckmann, MW, Fasching, PA, Lambrechts, D, Van Nieuwenhuysen, E, Vergote, I, Lambrechts, S, Dicks, E, Doherty, JA, Wicklund, KG, Rossing, MA, Rudolph, A, Chang-Claude, J, Wang-Gohrke, S, Eilber, U, Moysich, KB, Odunsi, K, Sucheston, L, Lele, S, Wilkens, LR, Goodman, MT, Thompson, PJ, Shvetsov, YB, Runnebaum, IB, Duerst, M, Hillemanns, P, Doerk, T, Antonenkova, N, Bogdanova, N, Leminen, A, Pelttari, LM, Butzow, R, Modugno, F, Kelley, JL, Edwards, RP, Ness, RB, du Bois, A, Heitz, F, Schwaab, I, Harter, P, Matsuo, K, Hosono, S, Orsulic, S, Jensen, A, Kjaer, SK, Hogdall, E, Hasmad, HN, Azmi, MAN, Teo, S-H, Woo, Y-L, Fridley, BL, Goode, EL, Cunningham, JM, Vierkant, RA, Bruinsma, F, Giles, GG, Liang, D, Hildebrandt, MAT, Wu, X, Levine, DA, Bisogna, M, Berchuck, A, Iversen, ES, Schildkraut, JM, Concannon, P, Weber, RP, Cramer, DW, Terry, KL, Poole, EM, Tworoger, SS, Bandera, EV, Orlow, I, Olson, SH, Krakstad, C, Salvesen, HB, Tangen, IL, Bjorge, L, van Altena, AM, Aben, KKH, Kiemeney, LA, Massuger, LFAG, Kellar, M, Brooks-Wilson, A, Kelemen, LE, Cook, LS, Le, ND, Cybulski, C, Yang, H, Lissowska, J, Brinton, LA, Wentzensen, N, Hogdall, C, Lundvall, L, Nedergaard, L, Baker, H, Song, H, Eccles, D, McNeish, I, Paul, J, Carty, K, Siddiqui, N, Glasspool, R, Whittemore, AS, Rothstein, JH, McGuire, V, Sieh, W, Ji, B-T, Zheng, W, Shu, X-O, Gao, Y-T, Rosen, B, Risch, HA, McLaughlin, JR, Narod, SA, Monteiro, AN, Chen, A, Lin, H-Y, Permuth-Wey, J, Sellers, TA, Tsai, Y-Y, Chen, Z, Ziogas, A, Anton-Culver, H, Gentry-Maharaj, A, Menon, U, Harrington, P, Lee, AW, Wu, AH, Pearce, CL, Coetzee, G, Pike, MC, Dansonka-Mieszkowska, A, Timorek, A, Rzepecka, IK, Kupryjanczyk, J, Freedman, M, Noushmehr, H, Easton, DF, Offit, K, Couch, FJ, Gayther, S, Pharoah, PP, Antoniou, AC, Chenevix-Trench, G, Kuchenbaecker, KB, Ramus, SJ, Tyrer, J, Lee, A, Shen, HC, Beesley, J, Lawrenson, K, McGuffog, L, Healey, S, Lee, JM, Spindler, TJ, Lin, YG, Pejovic, T, Bean, Y, Li, Q, Coetzee, S, Hazelett, D, Miron, A, Southey, M, Terry, MB, Goldgar, DE, Buys, SS, Janavicius, R, Dorfling, CM, van Rensburg, EJ, Neuhausen, SL, Ding, YC, Hansen, TVO, Jonson, L, Gerdes, A-M, Ejlertsen, B, Barrowdale, D, Dennis, J, Benitez, J, Osorio, A, Garcia, MJ, Komenaka, I, Weitzel, JN, Ganschow, P, Peterlongo, P, Bernard, L, Viel, A, Bonanni, B, Peissel, B, Manoukian, S, Radice, P, Papi, L, Ottini, L, Fostira, F, Konstantopoulou, I, Garber, J, Frost, D, Perkins, J, Platte, R, Ellis, S, Godwin, AK, Schmutzler, RK, Meindl, A, Engel, C, Sutter, C, Sinilnikova, OM, Damiola, F, Mazoyer, S, Stoppa-Lyonnet, D, Claes, K, De Leeneer, K, Kirk, J, Rodriguez, GC, Piedmonte, M, O'Malley, DM, de la Hoya, M, Caldes, T, Aittomaeki, K, Nevanlinna, H, Collee, JM, Rookus, MA, Oosterwijk, JC, Tihomirova, L, Tung, N, Hamann, U, Isaccs, C, Tischkowitz, M, Imyanitov, EN, Caligo, MA, Campbell, IG, Hogervorst, FBL, Olah, E, Diez, O, Blanco, I, Brunet, J, Lazaroso, C, Angel Pujana, M, Jakubowska, A, Gronwald, J, Lubinski, J, Sukiennicki, G, Barkardottir, RB, Plante, M, Simard, J, Soucy, P, Montagna, M, Tognazzo, S, Teixeira, MR, Pankratz, VS, Wang, X, Lindor, N, Szabo, CI, Kauff, N, Vijai, J, Aghajanian, CA, Pfeiler, G, Berger, A, Singer, CF, Tea, M-K, Phelan, CM, Greene, MH, Mai, PL, Rennert, G, Mulligan, AM, Tchatchou, S, Andrulis, IL, Glendon, G, Toland, AE, Jensen, UB, Kruse, TA, Thomassen, M, Bojesen, A, Zidan, J, Friedman, E, Laitman, Y, Soller, M, Liljegren, A, Arver, B, Einbeigi, Z, Stenmark-Askmalm, M, Olopade, OI, Nussbaum, RL, Rebbeck, TR, Nathanson, KL, Domchek, SM, Lu, KH, Karlan, BY, Walsh, C, Lester, J, Hein, A, Ekici, AB, Beckmann, MW, Fasching, PA, Lambrechts, D, Van Nieuwenhuysen, E, Vergote, I, Lambrechts, S, Dicks, E, Doherty, JA, Wicklund, KG, Rossing, MA, Rudolph, A, Chang-Claude, J, Wang-Gohrke, S, Eilber, U, Moysich, KB, Odunsi, K, Sucheston, L, Lele, S, Wilkens, LR, Goodman, MT, Thompson, PJ, Shvetsov, YB, Runnebaum, IB, Duerst, M, Hillemanns, P, Doerk, T, Antonenkova, N, Bogdanova, N, Leminen, A, Pelttari, LM, Butzow, R, Modugno, F, Kelley, JL, Edwards, RP, Ness, RB, du Bois, A, Heitz, F, Schwaab, I, Harter, P, Matsuo, K, Hosono, S, Orsulic, S, Jensen, A, Kjaer, SK, Hogdall, E, Hasmad, HN, Azmi, MAN, Teo, S-H, Woo, Y-L, Fridley, BL, Goode, EL, Cunningham, JM, Vierkant, RA, Bruinsma, F, Giles, GG, Liang, D, Hildebrandt, MAT, Wu, X, Levine, DA, Bisogna, M, Berchuck, A, Iversen, ES, Schildkraut, JM, Concannon, P, Weber, RP, Cramer, DW, Terry, KL, Poole, EM, Tworoger, SS, Bandera, EV, Orlow, I, Olson, SH, Krakstad, C, Salvesen, HB, Tangen, IL, Bjorge, L, van Altena, AM, Aben, KKH, Kiemeney, LA, Massuger, LFAG, Kellar, M, Brooks-Wilson, A, Kelemen, LE, Cook, LS, Le, ND, Cybulski, C, Yang, H, Lissowska, J, Brinton, LA, Wentzensen, N, Hogdall, C, Lundvall, L, Nedergaard, L, Baker, H, Song, H, Eccles, D, McNeish, I, Paul, J, Carty, K, Siddiqui, N, Glasspool, R, Whittemore, AS, Rothstein, JH, McGuire, V, Sieh, W, Ji, B-T, Zheng, W, Shu, X-O, Gao, Y-T, Rosen, B, Risch, HA, McLaughlin, JR, Narod, SA, Monteiro, AN, Chen, A, Lin, H-Y, Permuth-Wey, J, Sellers, TA, Tsai, Y-Y, Chen, Z, Ziogas, A, Anton-Culver, H, Gentry-Maharaj, A, Menon, U, Harrington, P, Lee, AW, Wu, AH, Pearce, CL, Coetzee, G, Pike, MC, Dansonka-Mieszkowska, A, Timorek, A, Rzepecka, IK, Kupryjanczyk, J, Freedman, M, Noushmehr, H, Easton, DF, Offit, K, Couch, FJ, Gayther, S, Pharoah, PP, Antoniou, AC, and Chenevix-Trench, G
Abstract: Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.
Published: 2015

20. An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Author: Blein, S, Bardel, C, Danjean, V, McGuffog, L, Healey, S, Barrowdale, D, Lee, A, Dennis, J, Kuchenbaecker, KB, Soucy, P, Terry, MB, Chung, WK, Goldgar, DE, Buys, SS, Janavicius, R, Tihomirova, L, Tung, N, Dorfling, CM, van Rensburg, EJ, Neuhausen, SL, Ding, YC, Gerdes, A-M, Ejlertsen, B, Nielsen, FC, Hansen, TVO, Osorio, A, Benitez, J, Andres Conejero, R, Segota, E, Weitzel, JN, Thelander, M, Peterlongo, P, Radice, P, Pensotti, V, Dolcetti, R, Bonanni, B, Peissel, B, Zaffaroni, D, Scuvera, G, Manoukian, S, Varesco, L, Capone, GL, Papi, L, Ottini, L, Yannoukakos, D, Konstantopoulou, I, Garber, J, Hamann, U, Donaldson, A, Brady, A, Brewer, C, Foo, C, Evans, DG, Frost, D, Eccles, D, Douglas, F, Cook, J, Adlard, J, Barwell, J, Walker, L, Izatt, L, Side, LE, Kennedy, MJ, Tischkowitz, M, Rogers, MT, Porteous, ME, Morrison, PJ, Platte, R, Eeles, R, Davidson, R, Hodgson, S, Cole, T, Godwin, AK, Isaacs, C, Claes, K, De Leeneer, K, Meindl, A, Gehrig, A, Wappenschmidt, B, Sutter, C, Engel, C, Niederacher, D, Steinemann, D, Plendl, H, Kast, K, Rhiem, K, Ditsch, N, Arnold, N, Varon-Mateeva, R, Schmutzler, RK, Preisler-Adams, S, Markov, NB, Wang-Gohrke, S, de Pauw, A, Lefol, C, Lasset, C, Leroux, D, Rouleau, E, Damiola, F, Dreyfus, H, Barjhoux, L, Golmard, L, Uhrhammer, N, Bonadona, V, Sornin, V, Bignon, Y-J, Carter, J, Van Le, L, Piedmonte, M, DiSilvestro, PA, de la Hoya, M, Caldes, T, Nevanlinna, H, Aittomaki, K, Jager, A, van den Ouweland, AMW, Kets, CM, Aalfs, CM, van Leeuwen, FE, Hogervorst, FBL, Meijers-Heijboer, HEJ, Oosterwijk, JC, van Roozendaal, KEP, Rookus, MA, Devilee, P, van der Luijt, RB, Olah, E, Diez, O, Teule, A, Lazaro, C, Blanco, I, Del Valle, J, Jakubowska, A, Sukiennicki, G, Gronwald, J, Lubinski, J, Durda, K, Jaworska-Bieniek, K, Agnarsson, BA, Maugard, C, Amadori, A, Montagna, M, Teixeira, MR, Spurdle, AB, Foulkes, W, Olswold, C, Lindor, NM, Pankratz, VS, Szabo, CI, Lincoln, A, Jacobs, L, Corines, M, Robson, M, Vijai, J, Berger, A, Fink-Retter, A, Singer, CF, Rappaport, C, Kaulich, DG, Pfeiler, G, Tea, M-K, Greene, MH, Mai, PL, Rennert, G, Imyanitov, EN, Mulligan, AM, Glendon, G, Andrulis, IL, Tchatchou, S, Toland, AE, Pedersen, IS, Thomassen, M, Kruse, TA, Jensen, UB, Caligo, MA, Friedman, E, Zidan, J, Laitman, Y, Lindblom, A, Melin, B, Arver, B, Loman, N, Rosenquist, R, Olopade, OI, Nussbaum, RL, Ramus, SJ, Nathanson, KL, Domchek, SM, Rebbeck, TR, Arun, BK, Mitchell, G, Karlan, BY, Lester, J, Orsulic, S, Stoppa-Lyonnet, D, Thomas, G, Simard, J, Couch, FJ, Offit, K, Easton, DF, Chenevix-Trench, G, Antoniou, AC, Mazoyer, S, Phelan, CM, Sinilnikova, OM, Cox, DG, Blein, S, Bardel, C, Danjean, V, McGuffog, L, Healey, S, Barrowdale, D, Lee, A, Dennis, J, Kuchenbaecker, KB, Soucy, P, Terry, MB, Chung, WK, Goldgar, DE, Buys, SS, Janavicius, R, Tihomirova, L, Tung, N, Dorfling, CM, van Rensburg, EJ, Neuhausen, SL, Ding, YC, Gerdes, A-M, Ejlertsen, B, Nielsen, FC, Hansen, TVO, Osorio, A, Benitez, J, Andres Conejero, R, Segota, E, Weitzel, JN, Thelander, M, Peterlongo, P, Radice, P, Pensotti, V, Dolcetti, R, Bonanni, B, Peissel, B, Zaffaroni, D, Scuvera, G, Manoukian, S, Varesco, L, Capone, GL, Papi, L, Ottini, L, Yannoukakos, D, Konstantopoulou, I, Garber, J, Hamann, U, Donaldson, A, Brady, A, Brewer, C, Foo, C, Evans, DG, Frost, D, Eccles, D, Douglas, F, Cook, J, Adlard, J, Barwell, J, Walker, L, Izatt, L, Side, LE, Kennedy, MJ, Tischkowitz, M, Rogers, MT, Porteous, ME, Morrison, PJ, Platte, R, Eeles, R, Davidson, R, Hodgson, S, Cole, T, Godwin, AK, Isaacs, C, Claes, K, De Leeneer, K, Meindl, A, Gehrig, A, Wappenschmidt, B, Sutter, C, Engel, C, Niederacher, D, Steinemann, D, Plendl, H, Kast, K, Rhiem, K, Ditsch, N, Arnold, N, Varon-Mateeva, R, Schmutzler, RK, Preisler-Adams, S, Markov, NB, Wang-Gohrke, S, de Pauw, A, Lefol, C, Lasset, C, Leroux, D, Rouleau, E, Damiola, F, Dreyfus, H, Barjhoux, L, Golmard, L, Uhrhammer, N, Bonadona, V, Sornin, V, Bignon, Y-J, Carter, J, Van Le, L, Piedmonte, M, DiSilvestro, PA, de la Hoya, M, Caldes, T, Nevanlinna, H, Aittomaki, K, Jager, A, van den Ouweland, AMW, Kets, CM, Aalfs, CM, van Leeuwen, FE, Hogervorst, FBL, Meijers-Heijboer, HEJ, Oosterwijk, JC, van Roozendaal, KEP, Rookus, MA, Devilee, P, van der Luijt, RB, Olah, E, Diez, O, Teule, A, Lazaro, C, Blanco, I, Del Valle, J, Jakubowska, A, Sukiennicki, G, Gronwald, J, Lubinski, J, Durda, K, Jaworska-Bieniek, K, Agnarsson, BA, Maugard, C, Amadori, A, Montagna, M, Teixeira, MR, Spurdle, AB, Foulkes, W, Olswold, C, Lindor, NM, Pankratz, VS, Szabo, CI, Lincoln, A, Jacobs, L, Corines, M, Robson, M, Vijai, J, Berger, A, Fink-Retter, A, Singer, CF, Rappaport, C, Kaulich, DG, Pfeiler, G, Tea, M-K, Greene, MH, Mai, PL, Rennert, G, Imyanitov, EN, Mulligan, AM, Glendon, G, Andrulis, IL, Tchatchou, S, Toland, AE, Pedersen, IS, Thomassen, M, Kruse, TA, Jensen, UB, Caligo, MA, Friedman, E, Zidan, J, Laitman, Y, Lindblom, A, Melin, B, Arver, B, Loman, N, Rosenquist, R, Olopade, OI, Nussbaum, RL, Ramus, SJ, Nathanson, KL, Domchek, SM, Rebbeck, TR, Arun, BK, Mitchell, G, Karlan, BY, Lester, J, Orsulic, S, Stoppa-Lyonnet, D, Thomas, G, Simard, J, Couch, FJ, Offit, K, Easton, DF, Chenevix-Trench, G, Antoniou, AC, Mazoyer, S, Phelan, CM, Sinilnikova, OM, and Cox, DG
Abstract: INTRODUCTION: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. METHODS: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. RESULTS: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. CONCLUSIONS: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effe
Published: 2015

21. Assessing Associations between the AURKA-HMMR-TPX2-TUBG1 Functional Module and Breast Cancer Risk in BRCA1/2 Mutation Carriers

Author: Blanco, I, Kuchenbaecker, K, Cuadras, D, Wang, XS, Barrowdale, D, Garibay, GR, Librado, P, Sanchez-Gracia, A, Rozas, J, Bonifaci, N, McGuffog, L, Pankratz, VS, Islam, A, Mateo, F, Berenguer, A, Petit, A, Catala, I, Brunet, J, Feliubadalo, L, Tornero, E, Benitez, J, Osorio, A, Cajal, TRY, Nevanlinna, H, Aittomaki, K, Arun, BK, Toland, AE, Karlan, BY, Walsh, C, Lester, J, Greene, MH, Mai, PL, Nussbaum, RL, Andrulis, IL, Domchek, SM, Nathanson, KL, Rebbeck, TR, Barkardottir, RB, Jakubowska, A, Lubinski, J, Durda, K, Jaworska-Bieniek, K, Claes, K, Van Maerken, T, Diez, O, Hansen, TV, Jonson, L, Gerdes, AM, Ejlertsen, B, de la Hoya, M, Caldees, T, Dunning, AM, Oliver, C, Fineberg, E, Cook, M, Peock, S, McCann, E, Murray, A, Jacobs, C, Pichert, G, Lalloo, F, Chu, C, Dorkins, H, Paterson, J, Ong, KR, Teixeira, MR, Teixeira, Hogervorst, FBL, van der Hout, AH, Seynaeve, Caroline, van der Luijt, RB, Ligtenberg, MJL, Devilee, P, Wijnen, JT, Rookus, MA, Meijers-Heijboer, HEJ, Blok, MJ, van den Ouweland, Ans, Aalfs, CM, Rodriguez, GC, Phillips, KAA, Piedmonte, M, Nerenstone, SR, Bae-Jump, VL, O'Malley, DM, Ratner, ES, Schmutzler, RK, Wappenschmidt, B, Rhiem, K, Engel, C, Meindl, A, Ditsch, N, Arnold, N, Plendl, HJ, Niederacher, D, Sutter, C, Wang-Gohrke, S, Steinemann, D, Preisler-Adams, S, Kast, K, Varon-Mateeva, R, Gehrig, A, Bojesen, A, Pedersen, IS, Sunde, L, Jensen, UB, Thomassen, Marga, Kruse, TA, Foretova, L, Peterlongo, P, Bernard, L, Peissel, B, Scuvera, G, Manoukian, S, Radice, P, Ottini, L, Montagna, M, Agata, S, Maugard, C, Simard, J, Soucy, P, Berger, A, Fink-Retter, A, Singer, CF, Rappaport, C, Geschwantler-Kaulich, D, Tea, MK, Pfeiler, G, John, EM, Miron, A, Neuhausen, SL, Terry, MB, Chung, WK, Daly, MB, Goldgar, DE, Janavicius, R, Dorfling, CM, van Rensburg, EJ, Fostira, F, Konstantopoulou, I, Garber, J, Godwin, AK, Olah, E, Narod, SA, Rennert, G, Paluch, SS, Laitman, Y, Friedman, E, Liljegren, A, Rantala, J, Stenmark-Askmalm, M, Loman, N, Imyanitov, EN, Hamann, U, Spurdle, AB, Healey, S, Weitzel, JN, Herzog, J, Margileth, D, Gorrini, C, Esteller, M, Gomez, A, Sayols, S, Vidal, E, Heyn, H, Stoppa-Lyonnet, Leone, M, Barjhoux, L, Fassy-Colcombet, M, de Pauw, A, Lasset, C, Ferrer, SF, Castera, L, Berthet, P, Cornelis, F, Bignon, YJ, Damiola, F, Mazoyer, S, Sinilnikova, OM, Maxwell, CA, Vijai, J, Robson, M, Kauff, N, Corines, MJ, Villano, D, Cunningham, J, van der Lee, A, Lindor, N, Lazaro, C (Conxi), Easton, DF, Offit, K, Chenevix-Trench, G, Couch, FJ, Antoniou, AC, Pujana, MA, Blanco, I, Kuchenbaecker, K, Cuadras, D, Wang, XS, Barrowdale, D, Garibay, GR, Librado, P, Sanchez-Gracia, A, Rozas, J, Bonifaci, N, McGuffog, L, Pankratz, VS, Islam, A, Mateo, F, Berenguer, A, Petit, A, Catala, I, Brunet, J, Feliubadalo, L, Tornero, E, Benitez, J, Osorio, A, Cajal, TRY, Nevanlinna, H, Aittomaki, K, Arun, BK, Toland, AE, Karlan, BY, Walsh, C, Lester, J, Greene, MH, Mai, PL, Nussbaum, RL, Andrulis, IL, Domchek, SM, Nathanson, KL, Rebbeck, TR, Barkardottir, RB, Jakubowska, A, Lubinski, J, Durda, K, Jaworska-Bieniek, K, Claes, K, Van Maerken, T, Diez, O, Hansen, TV, Jonson, L, Gerdes, AM, Ejlertsen, B, de la Hoya, M, Caldees, T, Dunning, AM, Oliver, C, Fineberg, E, Cook, M, Peock, S, McCann, E, Murray, A, Jacobs, C, Pichert, G, Lalloo, F, Chu, C, Dorkins, H, Paterson, J, Ong, KR, Teixeira, MR, Teixeira, Hogervorst, FBL, van der Hout, AH, Seynaeve, Caroline, van der Luijt, RB, Ligtenberg, MJL, Devilee, P, Wijnen, JT, Rookus, MA, Meijers-Heijboer, HEJ, Blok, MJ, van den Ouweland, Ans, Aalfs, CM, Rodriguez, GC, Phillips, KAA, Piedmonte, M, Nerenstone, SR, Bae-Jump, VL, O'Malley, DM, Ratner, ES, Schmutzler, RK, Wappenschmidt, B, Rhiem, K, Engel, C, Meindl, A, Ditsch, N, Arnold, N, Plendl, HJ, Niederacher, D, Sutter, C, Wang-Gohrke, S, Steinemann, D, Preisler-Adams, S, Kast, K, Varon-Mateeva, R, Gehrig, A, Bojesen, A, Pedersen, IS, Sunde, L, Jensen, UB, Thomassen, Marga, Kruse, TA, Foretova, L, Peterlongo, P, Bernard, L, Peissel, B, Scuvera, G, Manoukian, S, Radice, P, Ottini, L, Montagna, M, Agata, S, Maugard, C, Simard, J, Soucy, P, Berger, A, Fink-Retter, A, Singer, CF, Rappaport, C, Geschwantler-Kaulich, D, Tea, MK, Pfeiler, G, John, EM, Miron, A, Neuhausen, SL, Terry, MB, Chung, WK, Daly, MB, Goldgar, DE, Janavicius, R, Dorfling, CM, van Rensburg, EJ, Fostira, F, Konstantopoulou, I, Garber, J, Godwin, AK, Olah, E, Narod, SA, Rennert, G, Paluch, SS, Laitman, Y, Friedman, E, Liljegren, A, Rantala, J, Stenmark-Askmalm, M, Loman, N, Imyanitov, EN, Hamann, U, Spurdle, AB, Healey, S, Weitzel, JN, Herzog, J, Margileth, D, Gorrini, C, Esteller, M, Gomez, A, Sayols, S, Vidal, E, Heyn, H, Stoppa-Lyonnet, Leone, M, Barjhoux, L, Fassy-Colcombet, M, de Pauw, A, Lasset, C, Ferrer, SF, Castera, L, Berthet, P, Cornelis, F, Bignon, YJ, Damiola, F, Mazoyer, S, Sinilnikova, OM, Maxwell, CA, Vijai, J, Robson, M, Kauff, N, Corines, MJ, Villano, D, Cunningham, J, van der Lee, A, Lindor, N, Lazaro, C (Conxi), Easton, DF, Offit, K, Chenevix-Trench, G, Couch, FJ, Antoniou, AC, and Pujana, MA
Abstract: While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04 - 1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03 - 1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted p(interaction) values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.
Published: 2015

22. Protein expression studies of desmoplakin mutations in cardiomyopathy patients reveal different molecular disease mechanisms

Author: Rasmussen, Tb, Hansen, J., Nissen, Ph, Palmfeldt, J., Dalager, S., Jensen, Ub, Kim, Wy, Heickendorff, L., Mølgaard, H., Jensen, Hk, Sørensen, Ke, Baandrup, Ulrik, Bross, P., and Mogensen, J.
Subjects: Keratinocytes, integumentary system, stomatognathic system, Arrhythmogenic cardiomyopathy, Genetics, Protein expression, Desmoplakin, Desmosomes, arrhythmogenic cardiomyopathy desmoplakin desmosomes genetics keratinocytes protein expression RIGHT-VENTRICULAR CARDIOMYOPATHY TASK-FORCE CRITERIA DILATED CARDIOMYOPATHY GENE-MUTATIONS WOOLLY HAIR DYSPLASIA/CARDIOMYOPATHY KERATODERMA FAMILIES CELLS
Abstract: Mutations in the gene for desmoplakin (DSP) may cause arrhythmogenic right ventricular cardiomyopathy (ARVC) and Carvajal syndrome (CS). Desmoplakin is part of all desmosomes, which are abundantly expressed in both myocardial and epidermal tissue and serve as intercellular mechanical junctions. This study aimed to investigate protein expression in myocardial and epidermal tissue of ARVC and CS patients carrying DSP mutations in order to elucidate potential molecular disease mechanisms. Genetic investigations identified three ARVC patients carrying different heterozygous DSP mutations in addition to a homozygous DSP mutation in a CS patient. The protein expression of DSP in mutation carriers was evaluated in biopsies from myocardial and epidermal tissue by immunohistochemistry. Keratinocyte cultures were established from skin biopsies of mutation carriers and characterized by reverse transcriptase polymerase chain reaction, western blotting, and protein mass spectrometry. The results showed that the mutation carriers had abnormal DSP expression in both myocardial and epidermal tissue. The investigations revealed that the disease mechanisms varied accordingly to the specific types of DSP mutation identified and included haploinsufficiency, dominant-negative effects, or a combination hereof. Furthermore, the results suggest that the keratinocytes cultured from patients are a valuable and easily accessible resource to elucidate the effects of desmosomal gene mutations in humans.
Published: 2013

23. Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers

Author: Antoniou, AC, Kuchenbaecker, KB, Soucy, P, Beesley, J, Chen, X, McGuffog, L, Lee, A, Barrowdale, D, Healey, S, Sinilnikova, OM, Caligo, MA, Loman, N, Harbst, K, Lindblom, A, Arver, B, Rosenquist, R, Karlsson, P, Nathanson, K, Domchek, S, Rebbeck, T, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Złowowcka-Perłowska, E, Osorio, A, Durán, M, Andrés, R, Benítez, J, Hamann, U, Hogervorst, FB, van Os, TA, Verhoef, S, Meijers-Heijboer, HE, Wijnen, J, Gómez Garcia, EB, Ligtenberg, MJ, Kriege, M, Collée, JM, Ausems, MG, Oosterwijk, JC, Peock, S, Frost, D, Ellis, SD, Platte, R, Fineberg, E, Evans, DG, Lalloo, F, Jacobs, C, Eeles, R, Adlard, J, Davidson, R, Cole, T, Cook, J, Paterson, J, Douglas, F, Brewer, C, Hodgson, S, Morrison, PJ, Walker, L, Rogers, MT, Donaldson, A, Dorkins, H, Godwin, AK, Bove, B, Stoppa-Lyonnet, D, Houdayer, C, Buecher, B, de Pauw, A, Mazoyer, S, Calender, A, Léoné, M, Bressac-de Paillerets, B, Caron, O, Sobol, H, Frenay, M, Prieur, F, Ferrer, SU, Mortemousque, I, Buys, S, Daly, M, Miron, A, Terry, MU, Hopper, JL, John, EM, Southey, M, Goldgar, D, Singer, CF, Fink-Retter, A, Tea, MK, Kaulich, DU, Hansen, TV, Nielsen, FC, Barkardottir, RB, Gaudet, M, Kirchhoff, T, Joseph, V, Dutra-Clarke, A, Offit, K, Piedmonte, M, Kirk, J, Cohn, D, Hurteau, J, Byron, J, Fiorica, J, Toland, AE, Montagna, M, Oliani, C, Imyanitov, E, Isaacs, C, Tihomirova, L, Blanco, I, Lazaro, C, Teulé, A, Valle, JD, Gayther, SA, Odunsi, K, Gross, J, Karlan, BY, Olah, E, Teo, SH, Ganz, PA, Beattie, MS, Dorfling, CM, van Rensburg, EU, Diez, O, Kwong, A, Schmutzler, RK, Wappenschmidt, B, Engel, C, Meindl, A, Ditsch, N, Arnold, N, Heidemann, S, Niederacher, D, Preisler-Adams, S, Gadzicki, D, Varon-Mateeva, R, Deissler, H, Gehrig, A, Sutter, C, Kast, K, Fiebig, B, Schäfer, D, Caldes, T, de la Hoya, M, Nevanlinna, H, Muranen, TA, Lespérance, B, Spurdle, AB, Neuhausen, SL, Ding, YC, Wang, X, Fredericksen, Z, Pankratz, VS, Lindor, NM, Peterlongo, P, Manoukian, S, Peissel, B, Zaffaroni, D, Bonanni, B, Bernard, L, Dolcetti, R, Papi, L, Ottini, L, Radice, P, Greene, MH, Loud, JT, Andrulis, IL, Ozcelik, H, Mulligan, AU, Glendon, G, Thomassen, M, Gerdes, AM, Jensen, UB, Skytte, AB, Kruse, TA, Chenevix-Trench, G, Couch, FJ, Simard, J, Easton, DF, CIMBA, SWE-BRCA, HEBON, EMBRACE, GEMO Collaborators Study, and kConFab Investigators
Subjects: skin and connective tissue diseases
Abstract: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2).
Published: 2012

24. Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers

Author: Kuchenbaecker, KB, Neuhausen, SL, Robson, M, Barrowdale, D, McGuffog, L, Mulligan, AM, Andrulis, IL, Spurdle, AB, Schmidt, MK, Schmutzler, RK, Engel, C, Wappenschmidt, B, Nevanlinna, H, Thomassen, M, Southey, M, Radice, P, Ramus, SJ, Domchek, SM, Nathanson, KL, Lee, A, Healey, S, Nussbaum, RL, Rebbeck, TR, Arun, BK, James, P, Karlan, BY, Lester, J, Cass, I, Terry, MB, Daly, MB, Goldgar, DE, Buys, SS, Janavicius, R, Tihomirova, L, Tung, N, Dorfling, CM, van Rensburg, EJ, Steele, L, Hansen, TVO, Ejlertsen, B, Gerdes, A-M, Nielsen, FC, Dennis, J, Cunningham, J, Hart, S, Slager, S, Osorio, A, Benitez, J, Duran, M, Weitzel, JN, Tafur, I, Hander, M, Peterlongo, P, Manoukian, S, Peissel, B, Roversi, G, Scuvera, G, Bonanni, B, Mariani, P, Volorio, S, Dolcetti, R, Varesco, L, Papi, L, Tibiletti, MG, Giannini, G, Fostira, F, Konstantopoulou, I, Garber, J, Hamann, U, Donaldson, A, Brewer, C, Foo, C, Evans, DG, Frost, D, Eccles, D, Douglas, F, Brady, A, Cook, J, Tischkowitz, M, Adlard, J, Barwell, J, Ong, K-R, Walker, L, Izatt, L, Side, LE, Kennedy, MJ, Rogers, MT, Porteous, ME, Morrison, PJ, Platte, R, Eeles, R, Davidson, R, Hodgson, S, Ellis, S, Godwin, AK, Rhiem, K, Meindl, A, Ditsch, N, Arnold, N, Plendl, H, Niederacher, D, Sutter, C, Steinemann, D, Bogdanova-Markov, N, Kast, K, Varon-Mateeva, R, Wang-Gohrke, S, Gehrig, A, Markiefka, B, Buecher, B, Lefol, C, Stoppa-Lyonnet, D, Rouleau, E, Prieur, F, Damiola, F, Barjhoux, L, Faivre, L, Longy, M, Sevenet, N, Sinilnikova, OM, Mazoyer, S, Bonadona, V, Caux-Moncoutier, V, Isaacs, C, Van Maerken, T, Claes, K, Piedmonte, M, Andrews, L, Hays, J, Rodriguez, GC, Caldes, T, de la Hoya, M, Khan, S, Hogervorst, FBL, Aalfs, CM, de lange, JL, Meijers-Heijboer, HEJ, van der Hout, AH, Wijnen, JT, van Roozendaal, KEP, Mensenkamp, AR, van den Ouweland, AMW, van Deurzen, CHM, van der Luijt, RB, Olah, E, Diez, O, Lazaro, C, Blanco, I, Teule, A, Menendez, M, Jakubowska, A, Lubinski, J, Cybulski, C, Gronwald, J, Jaworska-Bieniek, K, Durda, K, Arason, A, Maugard, C, Soucy, P, Montagna, M, Agata, S, Teixeira, MR, Olswold, C, Lindor, N, Pankratz, VS, Hallberg, E, Wang, X, Szabo, CI, Vijai, J, Jacobs, L, Corines, M, Lincoln, A, Berger, A, Fink-Retter, A, Singer, CF, Rappaport, C, Kaulich, DG, Pfeiler, G, Tea, M-K, Phelan, CM, Mai, PL, Greene, MH, Rennert, G, Imyanitov, EN, Glendon, G, Toland, AE, Bojesen, A, Pedersen, IS, Jensen, UB, Caligo, MA, Friedman, E, Berger, R, Laitman, Y, Rantala, J, Arver, B, Loman, N, Borg, A, Ehrencrona, H, Olopade, OI, Simard, J, Easton, DF, Chenevix-Trench, G, Offit, K, Couch, FJ, Antoniou, AC, Kuchenbaecker, KB, Neuhausen, SL, Robson, M, Barrowdale, D, McGuffog, L, Mulligan, AM, Andrulis, IL, Spurdle, AB, Schmidt, MK, Schmutzler, RK, Engel, C, Wappenschmidt, B, Nevanlinna, H, Thomassen, M, Southey, M, Radice, P, Ramus, SJ, Domchek, SM, Nathanson, KL, Lee, A, Healey, S, Nussbaum, RL, Rebbeck, TR, Arun, BK, James, P, Karlan, BY, Lester, J, Cass, I, Terry, MB, Daly, MB, Goldgar, DE, Buys, SS, Janavicius, R, Tihomirova, L, Tung, N, Dorfling, CM, van Rensburg, EJ, Steele, L, Hansen, TVO, Ejlertsen, B, Gerdes, A-M, Nielsen, FC, Dennis, J, Cunningham, J, Hart, S, Slager, S, Osorio, A, Benitez, J, Duran, M, Weitzel, JN, Tafur, I, Hander, M, Peterlongo, P, Manoukian, S, Peissel, B, Roversi, G, Scuvera, G, Bonanni, B, Mariani, P, Volorio, S, Dolcetti, R, Varesco, L, Papi, L, Tibiletti, MG, Giannini, G, Fostira, F, Konstantopoulou, I, Garber, J, Hamann, U, Donaldson, A, Brewer, C, Foo, C, Evans, DG, Frost, D, Eccles, D, Douglas, F, Brady, A, Cook, J, Tischkowitz, M, Adlard, J, Barwell, J, Ong, K-R, Walker, L, Izatt, L, Side, LE, Kennedy, MJ, Rogers, MT, Porteous, ME, Morrison, PJ, Platte, R, Eeles, R, Davidson, R, Hodgson, S, Ellis, S, Godwin, AK, Rhiem, K, Meindl, A, Ditsch, N, Arnold, N, Plendl, H, Niederacher, D, Sutter, C, Steinemann, D, Bogdanova-Markov, N, Kast, K, Varon-Mateeva, R, Wang-Gohrke, S, Gehrig, A, Markiefka, B, Buecher, B, Lefol, C, Stoppa-Lyonnet, D, Rouleau, E, Prieur, F, Damiola, F, Barjhoux, L, Faivre, L, Longy, M, Sevenet, N, Sinilnikova, OM, Mazoyer, S, Bonadona, V, Caux-Moncoutier, V, Isaacs, C, Van Maerken, T, Claes, K, Piedmonte, M, Andrews, L, Hays, J, Rodriguez, GC, Caldes, T, de la Hoya, M, Khan, S, Hogervorst, FBL, Aalfs, CM, de lange, JL, Meijers-Heijboer, HEJ, van der Hout, AH, Wijnen, JT, van Roozendaal, KEP, Mensenkamp, AR, van den Ouweland, AMW, van Deurzen, CHM, van der Luijt, RB, Olah, E, Diez, O, Lazaro, C, Blanco, I, Teule, A, Menendez, M, Jakubowska, A, Lubinski, J, Cybulski, C, Gronwald, J, Jaworska-Bieniek, K, Durda, K, Arason, A, Maugard, C, Soucy, P, Montagna, M, Agata, S, Teixeira, MR, Olswold, C, Lindor, N, Pankratz, VS, Hallberg, E, Wang, X, Szabo, CI, Vijai, J, Jacobs, L, Corines, M, Lincoln, A, Berger, A, Fink-Retter, A, Singer, CF, Rappaport, C, Kaulich, DG, Pfeiler, G, Tea, M-K, Phelan, CM, Mai, PL, Greene, MH, Rennert, G, Imyanitov, EN, Glendon, G, Toland, AE, Bojesen, A, Pedersen, IS, Jensen, UB, Caligo, MA, Friedman, E, Berger, R, Laitman, Y, Rantala, J, Arver, B, Loman, N, Borg, A, Ehrencrona, H, Olopade, OI, Simard, J, Easton, DF, Chenevix-Trench, G, Offit, K, Couch, FJ, and Antoniou, AC
Abstract: INTRODUCTION: More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. METHODS: We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement. RESULTS: The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC) = 0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC = 0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC = 0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P <10(-6) in the analyses by PR status, HER2 status, TN phenotype, morphologic subtypes, histological grade and nodal involvement
Published: 2014

25. Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers

Author: Kuchenbaecker, K, Neuhausen, S, Robson, M, Barrowdale, D, Mcguffog, L, Mulligan, A, Andrulis, I, Spurdle, A, Schmidt, M, Schmutzler, R, Engel, C, Wappenschmidt, B, Nevanlinna, H, Thomassen, M, Southey, M, Radice, P, Ramus, S, Domchek, S, Nathanson, K, Lee, A, Healey, S, Nussbaum, R, Rebbeck, T, Arun, B, James, P, Karlan, B, Lester, J, Cass, I, Breast Cancer Family, R, Terry, M, Daly, M, Goldgar, D, Buys, S, Janavicius, R, Tihomirova, L, Tung, N, Dorfling, C, van Rensburg, E, Steele, L, v. O. Hansen, T, Ejlertsen, B, Gerdes, A, Nielsen, F, Dennis, J, Cunningham, J, Hart, S, Slager, S, Osorio, A, Benitez, J, Duran, M, Weitzel, J, Tafur, I, Hander, M, Peterlongo, P, Manoukian, S, Peissel, B, Roversi, G, Scuvera, G, Bonanni, B, Mariani, P, Volorio, S, Dolcetti, R, Varesco, L, Papi, L, Tibiletti, M, Giannini, G, Fostira, F, Konstantopoulou, I, Garber, J, Hamann, U, Donaldson, A, Brewer, C, Foo, C, Evans, D, Frost, D, Eccles, D, Embrace, S, Douglas, F, Brady, A, Cook, J, Tischkowitz, M, Adlard, J, Barwell, J, Ong, K, Walker, L, Izatt, L, Side, L, Kennedy, M, Rogers, M, Porteous, M, Morrison, P, Platte, R, Eeles, R, Davidson, R, Hodgson, S, Ellis, S, Godwin, A, Rhiem, K, Meindl, A, Ditsch, N, Arnold, N, Plendl, H, Niederacher, D, Sutter, C, Steinemann, D, Bogdanova Markov, N, Kast, K, Varon Mateeva, R, Wang Gohrke, S, Gehrig, A, Markiefka, B, Buecher, B, Lefol, C, Stoppa Lyonnet, D, Rouleau, E, Prieur, F, Damiola, F, GEMO Study, C, Barjhoux, L, Faivre, L, Longy, M, Sevenet, N, Sinilnikova, O, Mazoyer, S, Bonadona, V, Caux Moncoutier, V, Isaacs, C, Van Maerken, T, Claes, K, Piedmonte, M, Andrews, L, Hays, J, Rodriguez, G, Caldes, T, de la Hoya, M, Khan, S, Hogervorst, F, Aalfs, C, de Lange, J, Meijers Heijboer, H, van der Hout, A, Wijnen, J, van Roozendaal, K, Mensenkamp, A, van den Ouweland, A, van Deurzen, C, van der Luijt, R, Hebon, Olah, E, Diez, O, Lazaro, C, Blanco, I, Teulé, A, Menendez, M, Jakubowska, A, Lubinski, J, Cybulski, C, Gronwald, J, Jaworska Bieniek, K, Durda, K, Arason, A, Maugard, C, Soucy, P, Montagna, M, Agata, S, Teixeira, M, Kconfab, I, Olswold, C, Lindor, N, Pankratz, V, Hallberg, E, Wang, X, Szabo, C, Vijai, J, Jacobs, L, Corines, M, Lincoln, A, Berger, A, Fink Retter, A, Singer, C, Rappaport, C, Kaulich, D, Pfeiler, G, Tea, M, Phelan, C, Mai, P, Greene, M, Rennert, G, Imyanitov, E, Glendon, G, Toland, A, Bojesen, A, Pedersen, I, Jensen, U, Caligo, M, Friedman, E, Berger, R, Laitman, Y, Rantala, J, Arver, B, Loman, N, Borg, A, Ehrencrona, H, Olopade, O, Simard, J, Easton, D, Chenevix Trench, G, Offit, K, Couch, F, Antoniou, A, Cimba, Kuchenbaecker, KB, Neuhausen, SL, McGuffog, L, Mulligan, AM, Andrulis, IL, Spurdle, AB, Schmidt, MK, Schmutzler, RK, Ramus, SJ, Domchek, SM, Nathanson, KL, Nussbaum, RL, Rebbeck, TR, Arun, BK, Karlan, BY, Breast Cancer Family Registry, Terry, MB, Daly, MB, Goldgar, DE, Buys, SS, Dorfling, CM, van Rensburg, EJ, Gerdes, AM, Nielsen, FC, Weitzel, JN, ROVERSI, GAIA, Tibiletti, MG, Evans, DG, EMBRACE Study, Ong, KR, Side, LE, Kennedy, MJ, Rogers, MT, Porteous, ME, Morrison, PJ, Godwin, AK, GEMO Study Collaborators, Sinilnikova, OM, Rodriguez, GC, Hogervorst, FB, Aalfs, CM, de Lange, JL, Meijers Heijboer, HE, van der Hout, AH, Wijnen, JT, van Roozendaal, KE, Mensenkamp, AR, van den Ouweland, AM, van Deurzen, CH, van der Luijt, RB, HEBON, Teixeira, MR, KConFab, Investigators, Pankratz, VS, Szabo, CI, Singer, CF, Kaulich, DG, Tea, MK, Phelan, CM, Mai, PL, Greene, MH, Imyanitov, EN, Toland, AE, Pedersen, IS, Jensen, UB, Caligo, MA, Olopade, OI, Easton, DF, Couch, FJ, Antoniou, AC, CIMBA, Kuchenbaecker, K, Neuhausen, S, Robson, M, Barrowdale, D, Mcguffog, L, Mulligan, A, Andrulis, I, Spurdle, A, Schmidt, M, Schmutzler, R, Engel, C, Wappenschmidt, B, Nevanlinna, H, Thomassen, M, Southey, M, Radice, P, Ramus, S, Domchek, S, Nathanson, K, Lee, A, Healey, S, Nussbaum, R, Rebbeck, T, Arun, B, James, P, Karlan, B, Lester, J, Cass, I, Breast Cancer Family, R, Terry, M, Daly, M, Goldgar, D, Buys, S, Janavicius, R, Tihomirova, L, Tung, N, Dorfling, C, van Rensburg, E, Steele, L, v. O. Hansen, T, Ejlertsen, B, Gerdes, A, Nielsen, F, Dennis, J, Cunningham, J, Hart, S, Slager, S, Osorio, A, Benitez, J, Duran, M, Weitzel, J, Tafur, I, Hander, M, Peterlongo, P, Manoukian, S, Peissel, B, Roversi, G, Scuvera, G, Bonanni, B, Mariani, P, Volorio, S, Dolcetti, R, Varesco, L, Papi, L, Tibiletti, M, Giannini, G, Fostira, F, Konstantopoulou, I, Garber, J, Hamann, U, Donaldson, A, Brewer, C, Foo, C, Evans, D, Frost, D, Eccles, D, Embrace, S, Douglas, F, Brady, A, Cook, J, Tischkowitz, M, Adlard, J, Barwell, J, Ong, K, Walker, L, Izatt, L, Side, L, Kennedy, M, Rogers, M, Porteous, M, Morrison, P, Platte, R, Eeles, R, Davidson, R, Hodgson, S, Ellis, S, Godwin, A, Rhiem, K, Meindl, A, Ditsch, N, Arnold, N, Plendl, H, Niederacher, D, Sutter, C, Steinemann, D, Bogdanova Markov, N, Kast, K, Varon Mateeva, R, Wang Gohrke, S, Gehrig, A, Markiefka, B, Buecher, B, Lefol, C, Stoppa Lyonnet, D, Rouleau, E, Prieur, F, Damiola, F, GEMO Study, C, Barjhoux, L, Faivre, L, Longy, M, Sevenet, N, Sinilnikova, O, Mazoyer, S, Bonadona, V, Caux Moncoutier, V, Isaacs, C, Van Maerken, T, Claes, K, Piedmonte, M, Andrews, L, Hays, J, Rodriguez, G, Caldes, T, de la Hoya, M, Khan, S, Hogervorst, F, Aalfs, C, de Lange, J, Meijers Heijboer, H, van der Hout, A, Wijnen, J, van Roozendaal, K, Mensenkamp, A, van den Ouweland, A, van Deurzen, C, van der Luijt, R, Hebon, Olah, E, Diez, O, Lazaro, C, Blanco, I, Teulé, A, Menendez, M, Jakubowska, A, Lubinski, J, Cybulski, C, Gronwald, J, Jaworska Bieniek, K, Durda, K, Arason, A, Maugard, C, Soucy, P, Montagna, M, Agata, S, Teixeira, M, Kconfab, I, Olswold, C, Lindor, N, Pankratz, V, Hallberg, E, Wang, X, Szabo, C, Vijai, J, Jacobs, L, Corines, M, Lincoln, A, Berger, A, Fink Retter, A, Singer, C, Rappaport, C, Kaulich, D, Pfeiler, G, Tea, M, Phelan, C, Mai, P, Greene, M, Rennert, G, Imyanitov, E, Glendon, G, Toland, A, Bojesen, A, Pedersen, I, Jensen, U, Caligo, M, Friedman, E, Berger, R, Laitman, Y, Rantala, J, Arver, B, Loman, N, Borg, A, Ehrencrona, H, Olopade, O, Simard, J, Easton, D, Chenevix Trench, G, Offit, K, Couch, F, Antoniou, A, Cimba, Kuchenbaecker, KB, Neuhausen, SL, McGuffog, L, Mulligan, AM, Andrulis, IL, Spurdle, AB, Schmidt, MK, Schmutzler, RK, Ramus, SJ, Domchek, SM, Nathanson, KL, Nussbaum, RL, Rebbeck, TR, Arun, BK, Karlan, BY, Breast Cancer Family Registry, Terry, MB, Daly, MB, Goldgar, DE, Buys, SS, Dorfling, CM, van Rensburg, EJ, Gerdes, AM, Nielsen, FC, Weitzel, JN, ROVERSI, GAIA, Tibiletti, MG, Evans, DG, EMBRACE Study, Ong, KR, Side, LE, Kennedy, MJ, Rogers, MT, Porteous, ME, Morrison, PJ, Godwin, AK, GEMO Study Collaborators, Sinilnikova, OM, Rodriguez, GC, Hogervorst, FB, Aalfs, CM, de Lange, JL, Meijers Heijboer, HE, van der Hout, AH, Wijnen, JT, van Roozendaal, KE, Mensenkamp, AR, van den Ouweland, AM, van Deurzen, CH, van der Luijt, RB, HEBON, Teixeira, MR, KConFab, Investigators, Pankratz, VS, Szabo, CI, Singer, CF, Kaulich, DG, Tea, MK, Phelan, CM, Mai, PL, Greene, MH, Imyanitov, EN, Toland, AE, Pedersen, IS, Jensen, UB, Caligo, MA, Olopade, OI, Easton, DF, Couch, FJ, Antoniou, AC, and CIMBA
Abstract: Introduction: More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. Methods: We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement. Results: The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC)=0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC=0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC=0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P <10-6 in the analyses by PR status, HER2 status, TN phenotype, morphologic subtypes, histological grade and nodal involvement. Con
Published: 2014

26. Membrane partitioning of acyl-CoA esters and reversal by acyl-CoA binding protein studied by AFM

Author: Simonsen, Ac, Jensen, Ub, Nils Færgeman, Knudsen, J., and Mouritsen, Og
Published: 2003

27. Identification of a BRCA2-Specific Modifier Locus at 6p24 Related to Breast Cancer Risk

Author: Hunter, KW, Gaudet, MM, Kuchenbaecker, KB, Vijai, J, Klein, RJ, Kirchhoff, T, McGuffog, L, Barrowdale, D, Dunning, AM, Lee, A, Dennis, J, Healey, S, Dicks, E, Soucy, P, Sinilnikova, OM, Pankratz, VS, Wang, X, Eldridge, RC, Tessier, DC, Vincent, D, Bacot, F, Hogervorst, FBL, Peock, S, Stoppa-Lyonnet, D, Peterlongo, P, Schmutzler, RK, Nathanson, KL, Piedmonte, M, Singer, CF, Thomassen, M, Hansen, TVO, Neuhausen, SL, Blanco, I, Greene, MH, Garber, J, Weitzel, JN, Andrulis, IL, Goldgar, DE, D'Andrea, E, Caldes, T, Nevanlinna, H, Osorio, A, van Rensburg, EJ, Arason, A, Rennert, G, van den Ouweland, AMW, van der Hout, AH, Kets, CM, Aalfs, CM, Wijnen, JT, Ausems, MGEM, Frost, D, Ellis, S, Fineberg, E, Platte, R, Evans, DG, Jacobs, C, Adlard, J, Tischkowitz, M, Porteous, ME, Damiola, F, Golmard, L, Barjhoux, L, Longy, M, Belotti, M, Ferrer, SF, Mazoyer, S, Spurdle, AB, Manoukian, S, Barile, M, Genuardi, M, Arnold, N, Meindl, A, Sutter, C, Wappenschmidt, B, Domchek, SM, Pfeiler, G, Friedman, E, Jensen, UB, Robson, M, Shah, S, Lazaro, C, Mai, PL, Benitez, J, Southey, MC, Schmidt, MK, Fasching, PA, Peto, J, Humphreys, MK, Wang, Q, Michailidou, K, Sawyer, EJ, Burwinkel, B, Guenel, P, Bojesen, SE, Milne, RL, Brenner, H, Lochmann, M, Aittomaki, K, Doerk, T, Margolin, S, Mannermaa, A, Lambrechts, D, Chang-Claude, J, Radice, P, Giles, GG, Haiman, CA, Winqvist, R, Devillee, P, Garcia-Closas, M, Schoof, N, Hooning, MJ, Cox, A, Pharoah, PDP, Jakubowska, A, Orr, N, Gonzalez-Neira, A, Pita, G, Rosario Alonso, M, Hall, P, Couch, FJ, Simard, J, Altshuler, D, Easton, DF, Chenevix-Trench, G, Antoniou, AC, Offit, K, Hunter, KW, Gaudet, MM, Kuchenbaecker, KB, Vijai, J, Klein, RJ, Kirchhoff, T, McGuffog, L, Barrowdale, D, Dunning, AM, Lee, A, Dennis, J, Healey, S, Dicks, E, Soucy, P, Sinilnikova, OM, Pankratz, VS, Wang, X, Eldridge, RC, Tessier, DC, Vincent, D, Bacot, F, Hogervorst, FBL, Peock, S, Stoppa-Lyonnet, D, Peterlongo, P, Schmutzler, RK, Nathanson, KL, Piedmonte, M, Singer, CF, Thomassen, M, Hansen, TVO, Neuhausen, SL, Blanco, I, Greene, MH, Garber, J, Weitzel, JN, Andrulis, IL, Goldgar, DE, D'Andrea, E, Caldes, T, Nevanlinna, H, Osorio, A, van Rensburg, EJ, Arason, A, Rennert, G, van den Ouweland, AMW, van der Hout, AH, Kets, CM, Aalfs, CM, Wijnen, JT, Ausems, MGEM, Frost, D, Ellis, S, Fineberg, E, Platte, R, Evans, DG, Jacobs, C, Adlard, J, Tischkowitz, M, Porteous, ME, Damiola, F, Golmard, L, Barjhoux, L, Longy, M, Belotti, M, Ferrer, SF, Mazoyer, S, Spurdle, AB, Manoukian, S, Barile, M, Genuardi, M, Arnold, N, Meindl, A, Sutter, C, Wappenschmidt, B, Domchek, SM, Pfeiler, G, Friedman, E, Jensen, UB, Robson, M, Shah, S, Lazaro, C, Mai, PL, Benitez, J, Southey, MC, Schmidt, MK, Fasching, PA, Peto, J, Humphreys, MK, Wang, Q, Michailidou, K, Sawyer, EJ, Burwinkel, B, Guenel, P, Bojesen, SE, Milne, RL, Brenner, H, Lochmann, M, Aittomaki, K, Doerk, T, Margolin, S, Mannermaa, A, Lambrechts, D, Chang-Claude, J, Radice, P, Giles, GG, Haiman, CA, Winqvist, R, Devillee, P, Garcia-Closas, M, Schoof, N, Hooning, MJ, Cox, A, Pharoah, PDP, Jakubowska, A, Orr, N, Gonzalez-Neira, A, Pita, G, Rosario Alonso, M, Hall, P, Couch, FJ, Simard, J, Altshuler, D, Easton, DF, Chenevix-Trench, G, Antoniou, AC, and Offit, K
Abstract: Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9 × 10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of br
Published: 2013

28. Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

Author: Hunter, KW, Couch, FJ, Wang, X, McGuffog, L, Lee, A, Olswold, C, Kuchenbaecker, KB, Soucy, P, Fredericksen, Z, Barrowdale, D, Dennis, J, Gaudet, MM, Dicks, E, Kosel, M, Healey, S, Sinilnikova, OM, Bacot, F, Vincent, D, Hogervorst, FBL, Peock, S, Stoppa-Lyonnet, D, Jakubowska, A, Radice, P, Schmutzler, RK, Domchek, SM, Piedmonte, M, Singer, CF, Friedman, E, Thomassen, M, Hansen, TVO, Neuhausen, SL, Szabo, CI, Blanco, I, Greene, MH, Karlan, BY, Garber, J, Phelan, CM, Weitzel, JN, Montagna, M, Olah, E, Andrulis, IL, Godwin, AK, Yannoukakos, D, Goldgar, DE, Caldes, T, Nevanlinna, H, Osorio, A, Terry, MB, Daly, MB, van Rensburg, EJ, Hamann, U, Ramus, SJ, Toland, AE, Caligo, MA, Olopade, OI, Tung, N, Claes, K, Beattie, MS, Southey, MC, Imyanitov, EN, Tischkowitz, M, Janavicius, R, John, EM, Kwong, A, Diez, O, Balmana, J, Barkardottir, RB, Arun, BK, Rennert, G, Teo, S-H, Ganz, PA, Campbell, I, van der Hout, AH, van Deurzen, CHM, Seynaeve, C, Garcia, EBG, van Leeuwen, FE, Meijers-Heijboer, HEJ, Gille, JJP, Ausems, MGEM, Blok, MJ, Ligtenberg, MJL, Rookus, MA, Devilee, P, Verhoef, S, van Os, TAM, Wijnen, JT, Frost, D, Ellis, S, Fineberg, E, Platte, R, Evans, DG, Izatt, L, Eeles, RA, Adlard, J, Eccles, DM, Cook, J, Brewer, C, Douglas, F, Hodgson, S, Morrison, PJ, Side, LE, Donaldson, A, Houghton, C, Rogers, MT, Dorkins, H, Eason, J, Gregory, H, McCann, E, Murray, A, Calender, A, Hardouin, A, Berthet, P, Delnatte, C, Nogues, C, Lasset, C, Houdayer, C, Leroux, D, Rouleau, E, Prieur, F, Damiola, F, Sobol, H, Coupier, I, Venat-Bouvet, L, Castera, L, Gauthier-Villars, M, Leone, M, Pujol, P, Mazoyer, S, Bignon, Y-J, Zlowocka-Perlowska, E, Gronwald, J, Lubinski, J, Durda, K, Jaworska, K, Huzarski, T, Spurdle, AB, Viel, A, Peissel, B, Bonanni, B, Melloni, G, Ottini, L, Papi, L, Varesco, L, Tibiletti, MG, Peterlongo, P, Volorio, S, Manoukian, S, Pensotti, V, Arnold, N, Engel, C, Deissler, H, Gadzicki, D, Gehrig, A, Kast, K, Rhiem, K, Meindl, A, Niederacher, D, Ditsch, N, Plendl, H, Preisler-Adams, S, Engert, S, Sutter, C, Varon-Mateeva, R, Wappenschmidt, B, Weber, BHF, Arver, B, Stenmark-Askmalm, M, Loman, N, Rosenquist, R, Einbeigi, Z, Nathanson, KL, Rebbeck, TR, Blank, SV, Cohn, DE, Rodriguez, GC, Small, L, Friedlander, M, Bae-Jump, VL, Fink-Retter, A, Rappaport, C, Gschwantler-Kaulich, D, Pfeiler, G, Tea, M-K, Lindor, NM, Kaufman, B, Paluch, SS, Laitman, Y, Skytte, A-B, Gerdes, A-M, Pedersen, IS, Moeller, ST, Kruse, TA, Jensen, UB, Vijai, J, Sarrel, K, Robson, M, Kauff, N, Mulligan, AM, Glendon, G, Ozcelik, H, Ejlertsen, B, Nielsen, FC, Jonson, L, Andersen, MK, Ding, YC, Steele, L, Foretova, L, Teule, A, Lazaro, C, Brunet, J, Angel Pujana, M, Mai, PL, Loud, JT, Walsh, C, Lester, J, Orsulic, S, Narod, SA, Herzog, J, Sand, SR, Tognazzo, S, Agata, S, Vaszko, T, Weaver, J, Stavropoulou, AV, Buys, SS, Romero, A, de la Hoya, M, Aittomaki, K, Muranen, TA, Duran, M, Chung, WK, Lasa, A, Dorfling, CM, Miron, A, Benitez, J, Senter, L, Huo, D, Chan, SB, Sokolenko, AP, Chiquette, J, Tihomirova, L, Friebel, TM, Agnarsson, BA, Lu, KH, Lejbkowicz, F, James, PA, Hall, P, Dunning, AM, Tessier, D, Cunningham, J, Slager, SL, Wang, C, Hart, S, Stevens, K, Simard, J, Pastinen, T, Pankratz, VS, Offit, K, Easton, DF, Chenevix-Trench, G, Antoniou, AC, Hunter, KW, Couch, FJ, Wang, X, McGuffog, L, Lee, A, Olswold, C, Kuchenbaecker, KB, Soucy, P, Fredericksen, Z, Barrowdale, D, Dennis, J, Gaudet, MM, Dicks, E, Kosel, M, Healey, S, Sinilnikova, OM, Bacot, F, Vincent, D, Hogervorst, FBL, Peock, S, Stoppa-Lyonnet, D, Jakubowska, A, Radice, P, Schmutzler, RK, Domchek, SM, Piedmonte, M, Singer, CF, Friedman, E, Thomassen, M, Hansen, TVO, Neuhausen, SL, Szabo, CI, Blanco, I, Greene, MH, Karlan, BY, Garber, J, Phelan, CM, Weitzel, JN, Montagna, M, Olah, E, Andrulis, IL, Godwin, AK, Yannoukakos, D, Goldgar, DE, Caldes, T, Nevanlinna, H, Osorio, A, Terry, MB, Daly, MB, van Rensburg, EJ, Hamann, U, Ramus, SJ, Toland, AE, Caligo, MA, Olopade, OI, Tung, N, Claes, K, Beattie, MS, Southey, MC, Imyanitov, EN, Tischkowitz, M, Janavicius, R, John, EM, Kwong, A, Diez, O, Balmana, J, Barkardottir, RB, Arun, BK, Rennert, G, Teo, S-H, Ganz, PA, Campbell, I, van der Hout, AH, van Deurzen, CHM, Seynaeve, C, Garcia, EBG, van Leeuwen, FE, Meijers-Heijboer, HEJ, Gille, JJP, Ausems, MGEM, Blok, MJ, Ligtenberg, MJL, Rookus, MA, Devilee, P, Verhoef, S, van Os, TAM, Wijnen, JT, Frost, D, Ellis, S, Fineberg, E, Platte, R, Evans, DG, Izatt, L, Eeles, RA, Adlard, J, Eccles, DM, Cook, J, Brewer, C, Douglas, F, Hodgson, S, Morrison, PJ, Side, LE, Donaldson, A, Houghton, C, Rogers, MT, Dorkins, H, Eason, J, Gregory, H, McCann, E, Murray, A, Calender, A, Hardouin, A, Berthet, P, Delnatte, C, Nogues, C, Lasset, C, Houdayer, C, Leroux, D, Rouleau, E, Prieur, F, Damiola, F, Sobol, H, Coupier, I, Venat-Bouvet, L, Castera, L, Gauthier-Villars, M, Leone, M, Pujol, P, Mazoyer, S, Bignon, Y-J, Zlowocka-Perlowska, E, Gronwald, J, Lubinski, J, Durda, K, Jaworska, K, Huzarski, T, Spurdle, AB, Viel, A, Peissel, B, Bonanni, B, Melloni, G, Ottini, L, Papi, L, Varesco, L, Tibiletti, MG, Peterlongo, P, Volorio, S, Manoukian, S, Pensotti, V, Arnold, N, Engel, C, Deissler, H, Gadzicki, D, Gehrig, A, Kast, K, Rhiem, K, Meindl, A, Niederacher, D, Ditsch, N, Plendl, H, Preisler-Adams, S, Engert, S, Sutter, C, Varon-Mateeva, R, Wappenschmidt, B, Weber, BHF, Arver, B, Stenmark-Askmalm, M, Loman, N, Rosenquist, R, Einbeigi, Z, Nathanson, KL, Rebbeck, TR, Blank, SV, Cohn, DE, Rodriguez, GC, Small, L, Friedlander, M, Bae-Jump, VL, Fink-Retter, A, Rappaport, C, Gschwantler-Kaulich, D, Pfeiler, G, Tea, M-K, Lindor, NM, Kaufman, B, Paluch, SS, Laitman, Y, Skytte, A-B, Gerdes, A-M, Pedersen, IS, Moeller, ST, Kruse, TA, Jensen, UB, Vijai, J, Sarrel, K, Robson, M, Kauff, N, Mulligan, AM, Glendon, G, Ozcelik, H, Ejlertsen, B, Nielsen, FC, Jonson, L, Andersen, MK, Ding, YC, Steele, L, Foretova, L, Teule, A, Lazaro, C, Brunet, J, Angel Pujana, M, Mai, PL, Loud, JT, Walsh, C, Lester, J, Orsulic, S, Narod, SA, Herzog, J, Sand, SR, Tognazzo, S, Agata, S, Vaszko, T, Weaver, J, Stavropoulou, AV, Buys, SS, Romero, A, de la Hoya, M, Aittomaki, K, Muranen, TA, Duran, M, Chung, WK, Lasa, A, Dorfling, CM, Miron, A, Benitez, J, Senter, L, Huo, D, Chan, SB, Sokolenko, AP, Chiquette, J, Tihomirova, L, Friebel, TM, Agnarsson, BA, Lu, KH, Lejbkowicz, F, James, PA, Hall, P, Dunning, AM, Tessier, D, Cunningham, J, Slager, SL, Wang, C, Hart, S, Stevens, K, Simard, J, Pastinen, T, Pankratz, VS, Offit, K, Easton, DF, Chenevix-Trench, G, and Antoniou, AC
Abstract: BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 × 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 × 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 × 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.
Published: 2013

29. Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

Author: Couch, FJ, Wang, XS, Olswold, C, Kuchenbaecker, KB, Soucy, P, Fredericksen, Z, Barrowdale, D, Dennis, J, Gaudet, MM, Dicks, E, Kosel, M, Healey, S, Sinilnikova, OM, van der Lee, A, Bacot, F, Vincent, D, Hogervorst, FBL, Peock, S, Stoppa-Lyonnet, D, Jakubowska, A, Radice, P, Schmutzler, RK, Domchek, SM, Piedmonte, M, Singer, CF, Friedman, E, Thomassen, Marga, Hansen, TVO, Neuhausen, SL, Szabo, CI, Blanco, I, Greene, MH, Karlan, BY, Garber, J, Phelan, CM, Weitzel, JN, Montagna, M, Olah, E, Andrulis, IL, Godwin, AK, Yannoukakos, D, Goldgar, DE, Caldes, T, Nevanlinna, H, Osorio, A, Terry, MB, Daly, MB, van Rensburg, EJ, Hamann, U, Ramus, SJ, Toland, AE, Caligo, MA, Olopade, OI, Tung, N, Claes, K, Beattie, MS, Southey, MC, Imyanitov, EN, Tischkowitz, M, Janavicius, R, John, EM, Kwong, A, Diez, O, Balmana, J, Barkardottir, RB, Arun, BK, Rennert, G, Teo, SH, Ganz, PA, Campbell, I, van der Hout, AH, van Deurzen, Carolien, Seynaeve, Caroline, Garcia, EBG, van Leeuwen, FE, Meijers-Heijboer, HEJ, Gille, JJP, Ausems, MGEM, Blok, MJ, Ligtenberg, MJL, Rookus, MA, Devilee, P, Verhoef, S, van Os, TAM, Wijnen, JT, Frost, D, Ellis, S, Fineberg, E, Platte, R, Evans, DG, Izatt, L, Eeles, RA, Adlard, J, Eccles, DM, Cook, J, Brewer, C, Douglas, F, Hodgson, S, Morrison, PJ, Side, LE, Donaldson, A, Houghton, C, Rogers, MT, Dorkins, H, Eason, J, Gregory, H, McCann, E, Murray, A, Calender, A, Hardouin, A, Berthet, P, Delnatte, C, Nogues, C, Lasset, C, Houdayer, C, Leroux, D, Rouleau, E, Prieur, F, Damiola, F, Sobol, H, Coupier, I, Venat-Bouvet, L, Castera, L, Gauthier-Villars, M, Leone, M, Pujol, P, Mazoyer, S, Bignon, YJ, Zlowocka-Perlowska, E, Gronwald, J, Lubinski, J, Durda, K, Jaworska, K, Huzarski, T, Spurdle, AB, Viel, A, Peissel, B, Bonanni, B, Melloni, G, Ottini, L, Papi, L, Varesco, L, Tibiletti, MG, Peterlongo, P, Volorio, S, Manoukian, S, Pensotti, V, Arnold, N, Engel, C, Deissler, H, Gadzicki, D, Gehrig, A, Kast, K, Rhiem, K, Meindl, A, Niederacher, D, Ditsch, N, Plendl, H, Preisler-Adams, S, Engert, S, Sutter, C, Varon-Mateeva, R, Wappenschmidt, B, Weber, BHF, Arver, B, Stenmark-Askmalm, M, Loman, N, Rosenquist, R, Einbeigi, Z, Nathanson, KL, Rebbeck, TR, Blank, SV, Cohn, DE, Rodriguez, GC, Small, L, Friedlander, M, Bae-Jump, VL, Fink-Retter, A, Rappaport, C, Gschwantler-Kaulich, D, Pfeiler, G, Tea, MK, Lindor, NM, Kaufman, B, Paluch, SS, Laitman, Y, Skytte, AB, Gerdes, AM, Pedersen, IS, Moeller, ST, Kruse, TA, Jensen, UB, Vijai, J, Sarrel, K, Robson, M, Kauff, N, Mulligan, AM, Glendon, G, Ozcelik, H, Ejlertsen, B, Nielsen, FC, Jonson, L, Andersen, MK, Ding, YC, Steele, L, Foretova, L, Teule, A, Lazaro, C (Conxi), Brunet, J, Pujana, MA, Mai, PL, Loud, JT, Walsh, C, Lester, J, Orsulic, S, Narod, SA, Herzog, J, Sand, SR, Tognazzo, S, Agata, S, Vaszko, T, Weaver, J, Stavropoulou, AV, Buys, SS, Romero, A, de la Hoya, M, Aittomaki, K, Muranen, TA, Duran, M (Mercedes), Chung, WK, Lasa, A, Dorfling, CM, Miron, A, Benitez, J, Senter, L, Huo, DZ, Chan, SB, Sokolenko, AP, Chiquette, J, Tihomirova, L, Friebel, TM, Agnarsson, BA, Lu, KH, Lejbkowicz, F, James, PA, Hall, P, Dunning, AM, Tessier, D, Cunningham, J, Slager, SL, Wang, C, Hart, S, Stevens, K, Simard, J, Pastinen, T, Pankratz, VS, Offit, K, Easton, DF, Chenevix-Trench, G, Antoniou, AC, Couch, FJ, Wang, XS, Olswold, C, Kuchenbaecker, KB, Soucy, P, Fredericksen, Z, Barrowdale, D, Dennis, J, Gaudet, MM, Dicks, E, Kosel, M, Healey, S, Sinilnikova, OM, van der Lee, A, Bacot, F, Vincent, D, Hogervorst, FBL, Peock, S, Stoppa-Lyonnet, D, Jakubowska, A, Radice, P, Schmutzler, RK, Domchek, SM, Piedmonte, M, Singer, CF, Friedman, E, Thomassen, Marga, Hansen, TVO, Neuhausen, SL, Szabo, CI, Blanco, I, Greene, MH, Karlan, BY, Garber, J, Phelan, CM, Weitzel, JN, Montagna, M, Olah, E, Andrulis, IL, Godwin, AK, Yannoukakos, D, Goldgar, DE, Caldes, T, Nevanlinna, H, Osorio, A, Terry, MB, Daly, MB, van Rensburg, EJ, Hamann, U, Ramus, SJ, Toland, AE, Caligo, MA, Olopade, OI, Tung, N, Claes, K, Beattie, MS, Southey, MC, Imyanitov, EN, Tischkowitz, M, Janavicius, R, John, EM, Kwong, A, Diez, O, Balmana, J, Barkardottir, RB, Arun, BK, Rennert, G, Teo, SH, Ganz, PA, Campbell, I, van der Hout, AH, van Deurzen, Carolien, Seynaeve, Caroline, Garcia, EBG, van Leeuwen, FE, Meijers-Heijboer, HEJ, Gille, JJP, Ausems, MGEM, Blok, MJ, Ligtenberg, MJL, Rookus, MA, Devilee, P, Verhoef, S, van Os, TAM, Wijnen, JT, Frost, D, Ellis, S, Fineberg, E, Platte, R, Evans, DG, Izatt, L, Eeles, RA, Adlard, J, Eccles, DM, Cook, J, Brewer, C, Douglas, F, Hodgson, S, Morrison, PJ, Side, LE, Donaldson, A, Houghton, C, Rogers, MT, Dorkins, H, Eason, J, Gregory, H, McCann, E, Murray, A, Calender, A, Hardouin, A, Berthet, P, Delnatte, C, Nogues, C, Lasset, C, Houdayer, C, Leroux, D, Rouleau, E, Prieur, F, Damiola, F, Sobol, H, Coupier, I, Venat-Bouvet, L, Castera, L, Gauthier-Villars, M, Leone, M, Pujol, P, Mazoyer, S, Bignon, YJ, Zlowocka-Perlowska, E, Gronwald, J, Lubinski, J, Durda, K, Jaworska, K, Huzarski, T, Spurdle, AB, Viel, A, Peissel, B, Bonanni, B, Melloni, G, Ottini, L, Papi, L, Varesco, L, Tibiletti, MG, Peterlongo, P, Volorio, S, Manoukian, S, Pensotti, V, Arnold, N, Engel, C, Deissler, H, Gadzicki, D, Gehrig, A, Kast, K, Rhiem, K, Meindl, A, Niederacher, D, Ditsch, N, Plendl, H, Preisler-Adams, S, Engert, S, Sutter, C, Varon-Mateeva, R, Wappenschmidt, B, Weber, BHF, Arver, B, Stenmark-Askmalm, M, Loman, N, Rosenquist, R, Einbeigi, Z, Nathanson, KL, Rebbeck, TR, Blank, SV, Cohn, DE, Rodriguez, GC, Small, L, Friedlander, M, Bae-Jump, VL, Fink-Retter, A, Rappaport, C, Gschwantler-Kaulich, D, Pfeiler, G, Tea, MK, Lindor, NM, Kaufman, B, Paluch, SS, Laitman, Y, Skytte, AB, Gerdes, AM, Pedersen, IS, Moeller, ST, Kruse, TA, Jensen, UB, Vijai, J, Sarrel, K, Robson, M, Kauff, N, Mulligan, AM, Glendon, G, Ozcelik, H, Ejlertsen, B, Nielsen, FC, Jonson, L, Andersen, MK, Ding, YC, Steele, L, Foretova, L, Teule, A, Lazaro, C (Conxi), Brunet, J, Pujana, MA, Mai, PL, Loud, JT, Walsh, C, Lester, J, Orsulic, S, Narod, SA, Herzog, J, Sand, SR, Tognazzo, S, Agata, S, Vaszko, T, Weaver, J, Stavropoulou, AV, Buys, SS, Romero, A, de la Hoya, M, Aittomaki, K, Muranen, TA, Duran, M (Mercedes), Chung, WK, Lasa, A, Dorfling, CM, Miron, A, Benitez, J, Senter, L, Huo, DZ, Chan, SB, Sokolenko, AP, Chiquette, J, Tihomirova, L, Friebel, TM, Agnarsson, BA, Lu, KH, Lejbkowicz, F, James, PA, Hall, P, Dunning, AM, Tessier, D, Cunningham, J, Slager, SL, Wang, C, Hart, S, Stevens, K, Simard, J, Pastinen, T, Pankratz, VS, Offit, K, Easton, DF, Chenevix-Trench, G, and Antoniou, AC
Abstract: BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 x 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 x 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 x 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2 x 10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.
Published: 2013

30. Identification of a BRCA2-Specific Modifier Locus at 6p24 Related to Breast Cancer Risk

Author: Gaudet, MM, Kuchenbaecker, KB, Vijai, J, Klein, RJ, Kirchhoff, T, McGuffog, L, Barrowdale, D, Dunning, AM, van der Lee, A, Dennis, J, Healey, S, Dicks, E, Soucy, P, Sinilnikova, O, Pankratz, VS, Wang, XS, Eldridge, RC, Tessier, DC, Vincent, D, Bacot, F, Hogervorst, FBL, Peock, S, Stoppa-Lyonnet, D, Peterlongo, P, Schmutzler, RK, Nathanson, KL, Piedmonte, M, Singer, CF, Thomassen, Marga, Hansen, TVO, Neuhausen, SL, Blanco, I, Greene, MH, Garber, J, Weitzel, JN, Andrulis, IL, Goldgar, DE, D'Andrea, E, Caldes, T, Nevanlinna, H, Osorio, A, van Rensburg, EJ, Arason, A, Rennert, G, van den Ouweland, Ans, van der Hout, AH, Kets, CM, Aalfs, CM, Wijnen, JT, Ausems, MGEM, Frost, D, Ellis, S, Fineberg, E, Platte, R, Evans, DG, Jacobs, C, Adlard, J, Tischkowitz, M, Porteous, ME, Damiola, F, Golmard, L, Barjhoux, L, Longy, M, Belotti, M, Ferrer, SF, Mazoyer, S, Spurdle, AB, Manoukian, S, Barile, M, Genuardi, M, Arnold, N, Meindl, A, Sutter, C, Wappenschmidt, B, Domchek, SM, Pfeiler, G, Friedman, E, Jensen, UB, Robson, M, Shah, S, Lazaro, C (Conxi), Mai, PL, Benitez, J, Southey, MC, Schmidt, Marjanka K, Fasching, PA, Peto, J, Humphreys, MK, Wang, Q (Qing), Michailidou, K, Sawyer, EJ, Burwinkel, B, Guenel, P, Bojesen, SE, Milne, RL, Brenner, H, Lochmann, M, Aittomaki, K, Dork, T, Margolin, S, Mannermaa, A, Lambrechts, D, Chang-Claude, J, Radice, P, Giles, GG, Haiman, CA, Winqvist, R, Devillee, P, Garcia-Closas, M, Schoof, N, Hooning, Maartje, Cox, A, Pharoah, PDP, Jakubowska, A, Orr, N, Gonzalez-Neira, A, Pita, G, Alonso, MR, Hall, P, Couch, FJ, Simard, J, Altshuler, D, Easton, DF, Chenevix-Trench, G, Antoniou, AC, Offit, K, Gaudet, MM, Kuchenbaecker, KB, Vijai, J, Klein, RJ, Kirchhoff, T, McGuffog, L, Barrowdale, D, Dunning, AM, van der Lee, A, Dennis, J, Healey, S, Dicks, E, Soucy, P, Sinilnikova, O, Pankratz, VS, Wang, XS, Eldridge, RC, Tessier, DC, Vincent, D, Bacot, F, Hogervorst, FBL, Peock, S, Stoppa-Lyonnet, D, Peterlongo, P, Schmutzler, RK, Nathanson, KL, Piedmonte, M, Singer, CF, Thomassen, Marga, Hansen, TVO, Neuhausen, SL, Blanco, I, Greene, MH, Garber, J, Weitzel, JN, Andrulis, IL, Goldgar, DE, D'Andrea, E, Caldes, T, Nevanlinna, H, Osorio, A, van Rensburg, EJ, Arason, A, Rennert, G, van den Ouweland, Ans, van der Hout, AH, Kets, CM, Aalfs, CM, Wijnen, JT, Ausems, MGEM, Frost, D, Ellis, S, Fineberg, E, Platte, R, Evans, DG, Jacobs, C, Adlard, J, Tischkowitz, M, Porteous, ME, Damiola, F, Golmard, L, Barjhoux, L, Longy, M, Belotti, M, Ferrer, SF, Mazoyer, S, Spurdle, AB, Manoukian, S, Barile, M, Genuardi, M, Arnold, N, Meindl, A, Sutter, C, Wappenschmidt, B, Domchek, SM, Pfeiler, G, Friedman, E, Jensen, UB, Robson, M, Shah, S, Lazaro, C (Conxi), Mai, PL, Benitez, J, Southey, MC, Schmidt, Marjanka K, Fasching, PA, Peto, J, Humphreys, MK, Wang, Q (Qing), Michailidou, K, Sawyer, EJ, Burwinkel, B, Guenel, P, Bojesen, SE, Milne, RL, Brenner, H, Lochmann, M, Aittomaki, K, Dork, T, Margolin, S, Mannermaa, A, Lambrechts, D, Chang-Claude, J, Radice, P, Giles, GG, Haiman, CA, Winqvist, R, Devillee, P, Garcia-Closas, M, Schoof, N, Hooning, Maartje, Cox, A, Pharoah, PDP, Jakubowska, A, Orr, N, Gonzalez-Neira, A, Pita, G, Alonso, MR, Hall, P, Couch, FJ, Simard, J, Altshuler, D, Easton, DF, Chenevix-Trench, G, Antoniou, AC, and Offit, K
Published: 2013

31. A Nonsynonymous Polymorphism in IRS1 Modifies Risk of Developing Breast and Ovarian Cancers in BRCA1 and Ovarian Cancer in BRCA2 Mutation Carriers

Author: Ding, YC, McGuffog, L, Healey, S, Friedman, E, Laitman, Y, Shani-Paluch-Shimon, Kaufman, B, Liljegren, A, Lindblom, A, Olsson, H, Kristoffersson, U, Stenmark-Askmalm, M, Melin, B, Domchek, SM, Nathanson, KL, Rebbeck, TR, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Gronwald, J, Huzarski, T, Cybulski, C, Byrski, T, Osorio, A, Ramony Cajal, T, Stavropoulou, AV, Benitez, J, Hamann, U, Rookus, M, Aalfs, CM, de Lange, JL, Meijers-Heijboer, HEJ, Oosterwijk, JC, van Asperen, CJ, Garcia, EBG, Hoogerbrugge, N, Jager, A, van der Luijt, RB, Easton, DF, Peock, S, Frost, D, Ellis, SD, Platte, R, Fineberg, E, Evans, DG, Lalloo, F, Izatt, L, Eeles, R, Adlard, J, Davidson, R, Eccles, D, Cole, T, Cook, J, Brewer, C, Tischkowitz, M, Godwin, AK, Pathak, H, Stoppa-Lyonnet, D, Sinilnikova, OM, Mazoyer, S, Barjhoux, L, Leone, M, Gauthier-Villars, M, Caux-Moncoutier, V, de Pauw, A, Hardouin, A, Berthet, P, Dreyfus, H, Ferrer, SF, Collonge-Rame, M-A, Sokolowska, J, Buys, S, Daly, M, Miron, A, Terry, MB, Chung, W, John, EM, Southey, M, Goldgar, D, Singer, CF, Tea, M-KM, Gschwantler-Kaulich, D, Fink-Retter, A, Hansen, TVO, Ejlertsen, B, Johannsson, OT, Offit, K, Sarrel, K, Gaudet, MM, Vijai, J, Robson, M, Piedmonte, MR, Andrews, L, Cohn, D, DeMars, LR, DiSilvestro, P, Rodriguez, G, Toland, AE, Montagna, M, Agata, S, Imyanitov, E, Isaacs, C, Janavicius, R, Lazaro, C, Blanco, I, Ramus, SJ, Sucheston, L, Karlan, BY, Gross, J, Ganz, PA, Beattie, MS, Schmutzler, RK, Wappenschmidt, B, Meindl, A, Arnold, N, Niederacher, D, Preisler-Adams, S, Gadzicki, D, Varon-Mateeva, R, Deissler, H, Gehrig, A, Sutter, C, Kast, K, Nevanlinna, H, Aittomaki, K, Simard, J, Spurdle, AB, Beesley, J, Chen, X, Tomlinson, GE, Weitzel, J, Garber, JE, Olopade, OI, Rubinstein, WS, Tung, N, Blum, JL, Narod, SA, Brummel, S, Gillen, DL, Lindor, N, Fredericksen, Z, Pankratz, VS, Couch, FJ, Radice, P, Peterlongo, P, Greene, MH, Loud, JT, Mai, PL, Andrulis, IL, Glendon, G, Ozcelik, H, Gerdes, A-M, Thomassen, M, Jensen, UB, Skytte, A-B, Caligo, MA, Lee, A, Chenevix-Trench, G, Antoniou, AC, Neuhausen, SL, Ding, YC, McGuffog, L, Healey, S, Friedman, E, Laitman, Y, Shani-Paluch-Shimon, Kaufman, B, Liljegren, A, Lindblom, A, Olsson, H, Kristoffersson, U, Stenmark-Askmalm, M, Melin, B, Domchek, SM, Nathanson, KL, Rebbeck, TR, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Gronwald, J, Huzarski, T, Cybulski, C, Byrski, T, Osorio, A, Ramony Cajal, T, Stavropoulou, AV, Benitez, J, Hamann, U, Rookus, M, Aalfs, CM, de Lange, JL, Meijers-Heijboer, HEJ, Oosterwijk, JC, van Asperen, CJ, Garcia, EBG, Hoogerbrugge, N, Jager, A, van der Luijt, RB, Easton, DF, Peock, S, Frost, D, Ellis, SD, Platte, R, Fineberg, E, Evans, DG, Lalloo, F, Izatt, L, Eeles, R, Adlard, J, Davidson, R, Eccles, D, Cole, T, Cook, J, Brewer, C, Tischkowitz, M, Godwin, AK, Pathak, H, Stoppa-Lyonnet, D, Sinilnikova, OM, Mazoyer, S, Barjhoux, L, Leone, M, Gauthier-Villars, M, Caux-Moncoutier, V, de Pauw, A, Hardouin, A, Berthet, P, Dreyfus, H, Ferrer, SF, Collonge-Rame, M-A, Sokolowska, J, Buys, S, Daly, M, Miron, A, Terry, MB, Chung, W, John, EM, Southey, M, Goldgar, D, Singer, CF, Tea, M-KM, Gschwantler-Kaulich, D, Fink-Retter, A, Hansen, TVO, Ejlertsen, B, Johannsson, OT, Offit, K, Sarrel, K, Gaudet, MM, Vijai, J, Robson, M, Piedmonte, MR, Andrews, L, Cohn, D, DeMars, LR, DiSilvestro, P, Rodriguez, G, Toland, AE, Montagna, M, Agata, S, Imyanitov, E, Isaacs, C, Janavicius, R, Lazaro, C, Blanco, I, Ramus, SJ, Sucheston, L, Karlan, BY, Gross, J, Ganz, PA, Beattie, MS, Schmutzler, RK, Wappenschmidt, B, Meindl, A, Arnold, N, Niederacher, D, Preisler-Adams, S, Gadzicki, D, Varon-Mateeva, R, Deissler, H, Gehrig, A, Sutter, C, Kast, K, Nevanlinna, H, Aittomaki, K, Simard, J, Spurdle, AB, Beesley, J, Chen, X, Tomlinson, GE, Weitzel, J, Garber, JE, Olopade, OI, Rubinstein, WS, Tung, N, Blum, JL, Narod, SA, Brummel, S, Gillen, DL, Lindor, N, Fredericksen, Z, Pankratz, VS, Couch, FJ, Radice, P, Peterlongo, P, Greene, MH, Loud, JT, Mai, PL, Andrulis, IL, Glendon, G, Ozcelik, H, Gerdes, A-M, Thomassen, M, Jensen, UB, Skytte, A-B, Caligo, MA, Lee, A, Chenevix-Trench, G, Antoniou, AC, and Neuhausen, SL
Abstract: BACKGROUND: We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers. METHODS: IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers. RESULTS: Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 (HR, 1.43; 95% confidence interval (CI), 1.06-1.92; P = 0.019) and BRCA2 mutation carriers (HR, 2.21; 95% CI, 1.39-3.52, P = 0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class II mutations than class I mutations (class II HR, 1.86; 95% CI, 1.28-2.70; class I HR, 0.86; 95%CI, 0.69-1.09; P(difference), 0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class II mutation carriers (HR, 2.42; P = 0.03). CONCLUSION: The IRS1 Gly972Arg single-nucleotide polymorphism, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class II mutation carriers. IMPACT: These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers.
Published: 2012

32. Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2

Author: Mulligan, AM, Couch, FJ, Barrowdale, D, Domchek, SM, Eccles, D, Nevanlinna, H, Ramus, SJ, Robson, M, Sherman, M, Spurdle, AB, Wappenschmidt, B, Lee, A, McGuffog, L, Healey, S, Sinilnikova, OM, Janavicius, R, Hansen, TVO, Nielsen, FC, Ejlertsen, B, Osorio, A, Munoz-Repeto, I, Duran, M, Godino, J, Pertesi, M, Benitez, J, Peterlongo, P, Manoukian, S, Peissel, B, Zaffaroni, D, Cattaneo, E, Bonanni, B, Viel, A, Pasini, B, Papi, L, Ottini, L, Savarese, A, Bernard, L, Radice, P, Hamann, U, Verheus, M, Meijers-Heijboer, HEJ, Wijnen, J, Garcia, EBG, Nelen, MR, Kets, CM, Seynaeve, C, Tilanus-Linthorst, MMA, van der Luijt, RB, van Os, T, Rookus, M, Frost, D, Jones, JL, Evans, DG, Lalloo, F, Eeles, R, Izatt, L, Adlard, J, Davidson, R, Cook, J, Donaldson, A, Dorkins, H, Gregory, H, Eason, J, Houghton, C, Barwell, J, Side, LE, McCann, E, Murray, A, Peock, S, Godwin, AK, Schmutzler, RK, Rhiem, K, Engel, C, Meindl, A, Ruehl, I, Arnold, N, Niederacher, D, Sutter, C, Deissler, H, Gadzicki, D, Kast, K, Preisler-Adams, S, Varon-Mateeva, R, Schoenbuchner, I, Fiebig, B, Heinritz, W, Schaefer, D, Gevensleben, H, Caux-Moncoutier, V, Fassy-Colcombet, M, Cornelis, F, Mazoyer, S, Leone, M, Boutry-Kryza, N, Hardouin, A, Berthet, P, Muller, D, Fricker, J-P, Mortemousque, I, Pujol, P, Coupier, I, Lebrun, M, Kientz, C, Longy, M, Sevenet, N, Stoppa-Lyonnet, D, Isaacs, C, Caldes, T, de la Hoya, M, Heikkinen, T, Aittomaki, K, Blanco, I, Lazaro, C, Barkardottir, RB, Soucy, P, Dumont, M, Simard, J, Montagna, M, Tognazzo, S, D'Andrea, E, Fox, S, Yan, M, Rebbeck, T, Olopade, OI, Weitzel, JN, Lynch, HT, Ganz, PA, Tomlinson, GE, Wang, X, Fredericksen, Z, Pankratz, VS, Lindor, NM, Szabo, C, Offit, K, Sakr, R, Gaudet, M, Bhatia, J, Kauff, N, Singer, CF, Tea, M-K, Gschwantler-Kaulich, D, Fink-Retter, A, Mai, PL, Greene, MH, Imyanitov, E, O'Malley, FP, Ozcelik, H, Glendon, G, Toland, AE, Gerdes, A-M, Thomassen, M, Kruse, TA, Jensen, UB, Skytte, A-B, Caligo, MA, Soller, M, Henriksson, K, Wachenfeldt, VA, Arver, B, Stenmark-Askmalm, M, Karlsson, P, Ding, YC, Neuhausen, SL, Beattie, M, Pharoah, PDP, Moysich, KB, Nathanson, KL, Karlan, BY, Gross, J, John, EM, Daly, MB, Buys, SM, Southey, MC, Hopper, JL, Terry, MB, Chung, W, Miron, AF, Goldgar, D, Chenevix-Trench, G, Easton, DF, Andrulis, IL, Antoniou, AC, Mulligan, AM, Couch, FJ, Barrowdale, D, Domchek, SM, Eccles, D, Nevanlinna, H, Ramus, SJ, Robson, M, Sherman, M, Spurdle, AB, Wappenschmidt, B, Lee, A, McGuffog, L, Healey, S, Sinilnikova, OM, Janavicius, R, Hansen, TVO, Nielsen, FC, Ejlertsen, B, Osorio, A, Munoz-Repeto, I, Duran, M, Godino, J, Pertesi, M, Benitez, J, Peterlongo, P, Manoukian, S, Peissel, B, Zaffaroni, D, Cattaneo, E, Bonanni, B, Viel, A, Pasini, B, Papi, L, Ottini, L, Savarese, A, Bernard, L, Radice, P, Hamann, U, Verheus, M, Meijers-Heijboer, HEJ, Wijnen, J, Garcia, EBG, Nelen, MR, Kets, CM, Seynaeve, C, Tilanus-Linthorst, MMA, van der Luijt, RB, van Os, T, Rookus, M, Frost, D, Jones, JL, Evans, DG, Lalloo, F, Eeles, R, Izatt, L, Adlard, J, Davidson, R, Cook, J, Donaldson, A, Dorkins, H, Gregory, H, Eason, J, Houghton, C, Barwell, J, Side, LE, McCann, E, Murray, A, Peock, S, Godwin, AK, Schmutzler, RK, Rhiem, K, Engel, C, Meindl, A, Ruehl, I, Arnold, N, Niederacher, D, Sutter, C, Deissler, H, Gadzicki, D, Kast, K, Preisler-Adams, S, Varon-Mateeva, R, Schoenbuchner, I, Fiebig, B, Heinritz, W, Schaefer, D, Gevensleben, H, Caux-Moncoutier, V, Fassy-Colcombet, M, Cornelis, F, Mazoyer, S, Leone, M, Boutry-Kryza, N, Hardouin, A, Berthet, P, Muller, D, Fricker, J-P, Mortemousque, I, Pujol, P, Coupier, I, Lebrun, M, Kientz, C, Longy, M, Sevenet, N, Stoppa-Lyonnet, D, Isaacs, C, Caldes, T, de la Hoya, M, Heikkinen, T, Aittomaki, K, Blanco, I, Lazaro, C, Barkardottir, RB, Soucy, P, Dumont, M, Simard, J, Montagna, M, Tognazzo, S, D'Andrea, E, Fox, S, Yan, M, Rebbeck, T, Olopade, OI, Weitzel, JN, Lynch, HT, Ganz, PA, Tomlinson, GE, Wang, X, Fredericksen, Z, Pankratz, VS, Lindor, NM, Szabo, C, Offit, K, Sakr, R, Gaudet, M, Bhatia, J, Kauff, N, Singer, CF, Tea, M-K, Gschwantler-Kaulich, D, Fink-Retter, A, Mai, PL, Greene, MH, Imyanitov, E, O'Malley, FP, Ozcelik, H, Glendon, G, Toland, AE, Gerdes, A-M, Thomassen, M, Kruse, TA, Jensen, UB, Skytte, A-B, Caligo, MA, Soller, M, Henriksson, K, Wachenfeldt, VA, Arver, B, Stenmark-Askmalm, M, Karlsson, P, Ding, YC, Neuhausen, SL, Beattie, M, Pharoah, PDP, Moysich, KB, Nathanson, KL, Karlan, BY, Gross, J, John, EM, Daly, MB, Buys, SM, Southey, MC, Hopper, JL, Terry, MB, Chung, W, Miron, AF, Goldgar, D, Chenevix-Trench, G, Easton, DF, Andrulis, IL, and Antoniou, AC
Abstract: INTRODUCTION: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour. METHODS: We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach. RESULTS: The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 × 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status. CONCLUSIONS: The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk mode
Published: 2011

33. Genetic variation at 9p22.2 and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers

Author: Ramus, S, Kartsonaki, C, Gayther, S, Pharoah, P, Sinilnikova, O, Beesley, J, Chen, X, Mcguffog, L, Healey, S, Couch, F, Wang, X, Fredericksen, Z, Peterlongo, P, Manoukian, S, Peissel, B, Zaffaroni, D, Roversi, G, Barile, M, Viel, A, Allavena, A, Ottini, L, Papi, L, Gismondi, V, Capra, F, Radice, P, Greene, M, Mai, P, Andrulis, I, Glendon, G, Ozcelik, H, Thomassen, M, Gerdes, A, Kruse, T, Cruger, D, Jensen, U, Caligo, M, Olsson, H, Kristoffersson, U, Lindblom, A, Arver, B, Karlsson, P, Stenmark Askmalm, M, Borg, A, Neuhausen, S, Ding, Y, Nathanson, K, Domchek, S, Jakubowska, A, Lubiński, J, Huzarski, T, Byrski, T, Gronwald, J, Górski, B, Cybulski, C, Dębniak, T, Osorio, A, Durán, M, Tejada, M, Benítez, J, Hamann, U, Rookus, M, Verhoef, S, Tilanus Linthorst, M, Vreeswijk, M, Bodmer, D, Ausems, M, van Os, T, Asperen, C, Blok, M, Meijers Heijboer, H, Peock, S, Cook, M, Oliver, C, Frost, D, Dunning, A, Evans, D, Eeles, R, Pichert, G, Cole, T, Hodgson, S, Brewer, C, Morrison, P, Porteous, M, Kennedy, M, Rogers, M, Side, L, Donaldson, A, Gregory, H, Godwin, A, Stoppa Lyonnet, D, Moncoutier, V, Castera, L, Mazoyer, S, Barjhoux, L, Bonadona, V, Leroux, D, Faivre, L, Lidereau, R, Nogues, C, Bignon, Y, Prieur, F, Collonge Rame, M, Venat Bouvet, L, Fert Ferrer, S, Miron, A, Buys, S, Hopper, J, Daly, M, John, E, Terry, M, Goldgar, D, Hansen, T, Jønson, L, Ejlertsen, B, Agnarsson, B, Offit, K, Kirchhoff, T, Vijai, J, Dutra Clarke, A, Przybylo, J, Montagna, M, Casella, C, Imyanitov, E, Janavicius, R, Blanco, I, Lázaro, C, Moysich, K, Karlan, B, Gross, J, Beattie, M, Schmutzler, R, Wappenschmidt, B, Meindl, A, Ruehl, I, Fiebig, B, Sutter, C, Arnold, N, Deissler, H, Varon Mateeva, R, Kast, K, Niederacher, D, Gadzicki, D, Caldes, T, de la Hoya, M, Nevanlinna, H, Aittomäki, K, Simard, J, Soucy, P, Spurdle, A, Holland, H, Chenevix Trench, G, Easton, D, Antoniou, A, Ramus, SJ, Gayther, SA, Pharoah, PDP, Sinilnikova, OM, McGuffog, L, Couch, FJ, Greene, MH, Mai, PL, Andrulis, IL, Kruse, TA, Jensen, UB, Caligo, MA, Neuhausen, SL, Ding, YC, Nathanson, KL, Domchek, SM, Rookus, MA, Tilanus Linthorst, MA, Vreeswijk, MP, Ausems, MGEM, van Os, TA, Asperen, CJ, Blok, MJ, Meijers Heijboer, HEJ, Dunning, AM, Evans, DG, Morrison, PJ, Kennedy, MJ, Rogers, MT, Side, LE, Buys, SS, Hopper, JL, Daly, MB, John, EM, Terry, MB, Hansen, TvO, Agnarsson, BA, Dutra Clarke, AVC, Przybylo, JA, Imyanitov, EN, Moysich, KB, Karlan, BY, Beattie, MS, Spurdle, AB, Easton, DF, Antoniou, AC, ROVERSI, GAIA, Ramus, S, Kartsonaki, C, Gayther, S, Pharoah, P, Sinilnikova, O, Beesley, J, Chen, X, Mcguffog, L, Healey, S, Couch, F, Wang, X, Fredericksen, Z, Peterlongo, P, Manoukian, S, Peissel, B, Zaffaroni, D, Roversi, G, Barile, M, Viel, A, Allavena, A, Ottini, L, Papi, L, Gismondi, V, Capra, F, Radice, P, Greene, M, Mai, P, Andrulis, I, Glendon, G, Ozcelik, H, Thomassen, M, Gerdes, A, Kruse, T, Cruger, D, Jensen, U, Caligo, M, Olsson, H, Kristoffersson, U, Lindblom, A, Arver, B, Karlsson, P, Stenmark Askmalm, M, Borg, A, Neuhausen, S, Ding, Y, Nathanson, K, Domchek, S, Jakubowska, A, Lubiński, J, Huzarski, T, Byrski, T, Gronwald, J, Górski, B, Cybulski, C, Dębniak, T, Osorio, A, Durán, M, Tejada, M, Benítez, J, Hamann, U, Rookus, M, Verhoef, S, Tilanus Linthorst, M, Vreeswijk, M, Bodmer, D, Ausems, M, van Os, T, Asperen, C, Blok, M, Meijers Heijboer, H, Peock, S, Cook, M, Oliver, C, Frost, D, Dunning, A, Evans, D, Eeles, R, Pichert, G, Cole, T, Hodgson, S, Brewer, C, Morrison, P, Porteous, M, Kennedy, M, Rogers, M, Side, L, Donaldson, A, Gregory, H, Godwin, A, Stoppa Lyonnet, D, Moncoutier, V, Castera, L, Mazoyer, S, Barjhoux, L, Bonadona, V, Leroux, D, Faivre, L, Lidereau, R, Nogues, C, Bignon, Y, Prieur, F, Collonge Rame, M, Venat Bouvet, L, Fert Ferrer, S, Miron, A, Buys, S, Hopper, J, Daly, M, John, E, Terry, M, Goldgar, D, Hansen, T, Jønson, L, Ejlertsen, B, Agnarsson, B, Offit, K, Kirchhoff, T, Vijai, J, Dutra Clarke, A, Przybylo, J, Montagna, M, Casella, C, Imyanitov, E, Janavicius, R, Blanco, I, Lázaro, C, Moysich, K, Karlan, B, Gross, J, Beattie, M, Schmutzler, R, Wappenschmidt, B, Meindl, A, Ruehl, I, Fiebig, B, Sutter, C, Arnold, N, Deissler, H, Varon Mateeva, R, Kast, K, Niederacher, D, Gadzicki, D, Caldes, T, de la Hoya, M, Nevanlinna, H, Aittomäki, K, Simard, J, Soucy, P, Spurdle, A, Holland, H, Chenevix Trench, G, Easton, D, Antoniou, A, Ramus, SJ, Gayther, SA, Pharoah, PDP, Sinilnikova, OM, McGuffog, L, Couch, FJ, Greene, MH, Mai, PL, Andrulis, IL, Kruse, TA, Jensen, UB, Caligo, MA, Neuhausen, SL, Ding, YC, Nathanson, KL, Domchek, SM, Rookus, MA, Tilanus Linthorst, MA, Vreeswijk, MP, Ausems, MGEM, van Os, TA, Asperen, CJ, Blok, MJ, Meijers Heijboer, HEJ, Dunning, AM, Evans, DG, Morrison, PJ, Kennedy, MJ, Rogers, MT, Side, LE, Buys, SS, Hopper, JL, Daly, MB, John, EM, Terry, MB, Hansen, TvO, Agnarsson, BA, Dutra Clarke, AVC, Przybylo, JA, Imyanitov, EN, Moysich, KB, Karlan, BY, Beattie, MS, Spurdle, AB, Easton, DF, Antoniou, AC, and ROVERSI, GAIA
Abstract: Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers. Although several common variants have been associated with breast cancer susceptibility in mutation carriers, none have been associated with ovarian cancer susceptibility. A genome-wide association study recently identified an association between the rare allele of the single-nucleotide polymorphism (SNP) rs3814113 (ie, the C allele) at 9p22.2 and decreased risk of ovarian cancer for women in the general population. We evaluated the association of this SNP with ovarian cancer risk among BRCA1 or BRCA2 mutation carriers by use of data from the Consortium of Investigators of Modifiers of BRCA1/2.
Published: 2011

34. Protein expression studies of desmoplakin mutations in cardiomyopathy patients reveal different molecular disease mechanisms

Author: Rasmussen, TB, primary, Hansen, J, additional, Nissen, PH, additional, Palmfeldt, J, additional, Dalager, S, additional, Jensen, UB, additional, Kim, WY, additional, Heickendorff, L, additional, Mølgaard, H, additional, Jensen, HK, additional, Sørensen, KE, additional, Baandrup, UT, additional, Bross, P, additional, and Mogensen, J, additional
Published: 2012
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35. Phylloid Hypermelanosis in a Child with Psychomotor Delay, Cicatricial Alopecia, Hearing Loss and Polythelia

Author: Bygum, A, primary, Petkov, Y, additional, Graakjaer, J, additional, Jensen, UB, additional, and Fagerberg, C, additional
Published: 2012
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36. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer

Author: Phelan, CM, Kuchenbaecker, KB, Tyrer, JP, Kar, SP, Lawrenson, K, Winham, SJ, Dennis, J, Pirie, A, Riggan, MJ, Chornokur, G, Earp, MA, Lyra, PC, Lee, JM, Coetzee, S, Beesley, J, McGuffog, L, Soucy, P, Dicks, E, Lee, A, Barrowdale, D, Lecarpentier, J, Leslie, G, Aalfs, CM, Aben, KKH, Adams, M, Adlard, J, Andrulis, IL, Anton-Culver, H, Antonenkova, N, AOCS Study Group, Aravantinos, G, Arnold, N, Arun, BK, Arver, B, Azzollini, J, Balmaña, J, Banerjee, SN, Barjhoux, L, Barkardottir, RB, Bean, Y, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bermisheva, M, Bernardini, MQ, Birrer, MJ, Bjorge, L, Black, A, Blankstein, K, Blok, MJ, Bodelon, C, Bogdanova, N, Bojesen, A, Bonanni, B, Borg, Å, Bradbury, AR, Brenton, JD, Brewer, C, Brinton, L, Broberg, P, Brooks-Wilson, A, Bruinsma, F, Brunet, J, Buecher, B, Butzow, R, Buys, SS, Caldes, T, Caligo, MA, Campbell, I, Cannioto, R, Carney, ME, Cescon, T, Chan, SB, Chang-Claude, J, Chanock, S, Chen, XQ, Chiew, Y-E, Chiquette, J, Chung, WK, Claes, KBM, Conner, T, Cook, LS, Cook, J, Cramer, DW, Cunningham, JM, D'Aloisio, AA, Daly, MB, Damiola, F, Damirovna, SD, Dansonka-Mieszkowska, A, Dao, F, Davidson, R, DeFazio, A, Delnatte, C, Doheny, KF, Diez, O, Ding, YC, Doherty, JA, Domchek, SM, Dorfling, CM, Dörk, T, Dossus, L, Duran, M, Dürst, M, Dworniczak, B, Eccles, D, Edwards, T, Eeles, R, Eilber, U, Ejlertsen, B, Ekici, AB, Ellis, S, Elvira, M, EMBRACE Study, Eng, KH, Engel, C, Evans, DG, Fasching, PA, Ferguson, S, Ferrer, SF, Flanagan, JM, Fogarty, ZC, Fortner, RT, Fostira, F, Foulkes, WD, Fountzilas, G, Fridley, BL, Friebel, TM, Friedman, E, Frost, D, Ganz, PA, Garber, J, García, MJ, Garcia-Barberan, V, Gehrig, A, GEMO Study Collaborators, Gentry-Maharaj, A, Gerdes, A-M, Giles, GG, Glasspool, R, Glendon, G, Godwin, AK, Goldgar, DE, Goranova, T, Gore, M, Greene, MH, Gronwald, J, Gruber, S, Hahnen, E, Haiman, CA, Håkansson, N, Hamann, U, Hansen, TVO, Harrington, PA, Harris, HR, Hauke, J, HEBON Study, Hein, A, Henderson, A, Hildebrandt, MAT, Hillemanns, P, Hodgson, S, Høgdall, CK, Høgdall, E, Hogervorst, FBL, Holland, H, Hooning, MJ, Hosking, K, Huang, R-Y, Hulick, PJ, Hung, J, Hunter, DJ, Huntsman, DG, Huzarski, T, Imyanitov, EN, Isaacs, C, Iversen, ES, Izatt, L, Izquierdo, A, Jakubowska, A, James, P, Janavicius, R, Jernetz, M, Jensen, A, Jensen, UB, John, EM, Johnatty, S, Jones, ME, Kannisto, P, Karlan, BY, Karnezis, A, Kast, K, KConFab Investigators, Kennedy, CJ, Khusnutdinova, E, Kiemeney, LA, Kiiski, JI, Kim, S-W, Kjaer, SK, Köbel, M, Kopperud, RK, Kruse, TA, Kupryjanczyk, J, Kwong, A, Laitman, Y, Lambrechts, D, Larrañaga, N, Larson, MC, Lazaro, C, Le, ND, Le Marchand, L, Lee, JW, Lele, SB, Leminen, A, Leroux, D, Lester, J, Lesueur, F, Levine, DA, Liang, D, Liebrich, C, Lilyquist, J, Lipworth, L, Lissowska, J, Lu, KH, Lubinński, J, Luccarini, C, Lundvall, L, Mai, PL, Mendoza-Fandiño, G, Manoukian, S, Massuger, LFAG, May, T, Mazoyer, S, McAlpine, JN, McGuire, V, McLaughlin, McNeish, I, Meijers-Heijboer, H, Meindl, A, Menon, U, Mensenkamp, AR, Merritt, MA, Milne, RL, Mitchell, G, Modugno, F, Moes-Sosnowska, J, Moffitt, M, Montagna, M, Moysich, KB, Mulligan, AM, Musinsky, J, Nathanson, KL, Nedergaard, L, Ness, RB, Neuhausen, SL, Nevanlinna, H, Niederacher, D, Nussbaum, RL, Odunsi, K, Olah, E, Olopade, OI, Olsson, H, Olswold, C, O'Malley, DM, Ong, K-R, Onland-Moret, NC, OPAL Study Group, Orr, N, Orsulic, S, Osorio, A, Palli, D, Papi, L, Park-Simon, T-W, Paul, J, Pearce, CL, Pedersen, IS, Peeters, PHM, Peissel, B, Peixoto, A, Pejovic, T, Pelttari, LM, Permuth, JB, Peterlongo, P, Pezzani, L, Pfeiler, G, Phillips, K-A, Piedmonte, M, Pike, MC, Piskorz, AM, Poblete, Pocza, T, Poole, EM, Poppe, B, Porteous, ME, Prieur, F, Prokofyeva, D, Pugh, E, Pujana, MA, Pujol, P, Radice, P, Rantala, J, Rappaport-Fuerhauser, C, Rennert, G, Rhiem, K, Rice, P, Richardson, A, Robson, M, Rodriguez, GC, Rodríguez-Antona, C, Romm, J, Rookus, MA, Rossing, MA, Rothstein, JH, Rudolph, A, Runnebaum, IB, Salvesen, HB, Sandler, DP, Schoemaker, MJ, Senter, L, Setiawan, VW, Severi, G, Sharma, P, Shelford, T, Siddiqui, N, Side, LE, Sieh, W, Singer, CF, Sobol, H, Song, H, Southey, MC, Spurdle, AB, Stadler, Z, Steinemann, D, Stoppa-Lyonnet, D, Sucheston-Campbell, LE, Sukiennicki, G, Sutphen, R, Sutter, C, Swerdlow, AJ, Szabo, CI, Szafron, L, Tan, YY, Taylor, JA, Tea, M-K, Teixeira, MR, Teo, S-H, Terry, KL, Thompson, PJ, Thomsen, LCV, Thull, DL, Tihomirova, L, Tinker, AV, Tischkowitz, M, Tognazzo, S, Toland, AE, Tone, A, Trabert, B, Travis, RC, Trichopoulou, A, Tung, N, Tworoger, SS, Van Altena, AM, Van Den Berg, D, Van Der Hout, AH, Van Der Luijt, RB, Van Heetvelde, M, Van Nieuwenhuysen, E, Van Rensburg, EJ, Vanderstichele, A, Varon-Mateeva, R, Vega, A, Edwards, DV, Vergote, I, Vierkant, RA, Vijai, J, Vratimos, A, Walker, L, Walsh, C, Wand, D, Wang-Gohrke, S, Wappenschmidt, B, Webb, PM, Weinberg, CR, Weitzel, JN, Wentzensen, N, Whittemore, AS, Wijnen, JT, Wilkens, LR, Wolk, A, Woo, M, Wu, X, Wu, AH, Yang, H, Yannoukakos, D, Ziogas, A, Zorn, KK, Narod, SA, Easton, DF, Amos, CI, Schildkraut, JM, Ramus, SJ, Ottini, L, Goodman, MT, Park, SK, Kelemen, LE, Risch, HA, Thomassen, M, Offit, K, Simard, J, Schmutzler, RK, Hazelett, D, Monteiro, AN, Couch, FJ, Berchuck, A, Chenevix-Trench, G, Goode, EL, Sellers, TA, Gayther, SA, Antoniou, AC, and Pharoah, PDP
Subjects: ovarian cancer, endocrine system diseases, genome-wide association studies, epidemiology, female genital diseases and pregnancy complications, 3. Good health
Abstract: To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 $\textit{BRCA1}$ and $\textit{BRCA2}$ mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.

37. Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer

Author: Couch, FJ, Kuchenbaecker, KB, Michailidou, K, Mendoza-Fandino, GA, Nord, S, Lilyquist, J, Olswold, C, Hallberg, E, Agata, S, Ahsan, H, Aittomäki, K, Ambrosone, C, Andrulis, IL, Anton-Culver, H, Arndt, V, Arun, BK, Arver, B, Barile, M, Barkardottir, RB, Barrowdale, D, Beckmann, L, Beckmann, MW, Benitez, J, Blank, SV, Blomqvist, C, Bogdanova, NV, Bojesen, SE, Bolla, MK, Bonanni, B, Brauch, H, Brenner, H, Burwinkel, B, Buys, SS, Caldes, T, Caligo, MA, Canzian, F, Carpenter, J, Chang-Claude, J, Chanock, SJ, Chung, WK, Claes, KBM, Cox, A, Cross, SS, Cunningham, JM, Czene, K, Daly, MB, Damiola, F, Darabi, H, De La Hoya, M, Devilee, P, Diez, O, Ding, YC, Dolcetti, R, Domchek, SM, Dorfling, CM, Dos-Santos-Silva, I, Dumont, M, Dunning, AM, Eccles, DM, Ehrencrona, H, Ekici, AB, Eliassen, H, Ellis, S, Fasching, PA, Figueroa, J, Flesch-Janys, D, Försti, A, Fostira, F, Foulkes, WD, Friebel, T, Friedman, E, Frost, D, Gabrielson, M, Gammon, MD, Ganz, PA, Gapstur, SM, Garber, J, Gaudet, MM, Gayther, SA, Gerdes, A-M, Ghoussaini, M, Giles, GG, Glendon, G, Godwin, AK, Goldberg, MS, Goldgar, DE, González-Neira, A, Greene, MH, Gronwald, J, Guénel, P, Gunter, M, Haeberle, L, Haiman, CA, Hamann, U, Hansen, TVO, Hart, S, Healey, S, Heikkinen, T, Henderson, BE, Herzog, J, Hogervorst, FBL, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Humphreys, K, Hunter, DJ, Huzarski, T, Imyanitov, EN, Isaacs, C, Jakubowska, A, James, P, Janavicius, R, Jensen, UB, John, EM, Jones, M, Kabisch, M, Kar, S, Karlan, BY, Khan, S, Khaw, K-T, Kibriya, MG, Knight, JA, Ko, Y-D, Konstantopoulou, I, Kosma, V-M, Kristensen, V, Kwong, A, Laitman, Y, Lambrechts, D, Lazaro, C, Lee, E, Le Marchand, L, Lester, J, Lindblom, A, Lindor, N, Lindstrom, S, Liu, J, Long, J, Lubinski, J, Mai, PL, Makalic, E, Malone, KE, Mannermaa, A, Manoukian, S, Margolin, S, Marme, F, Martens, JWM, McGuffog, L, Meindl, A, Miller, A, Milne, RL, Miron, P, Montagna, M, Mazoyer, S, Mulligan, AM, Muranen, TA, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nordestgaard, BG, Nussbaum, RL, Offit, K, Olah, E, Olopade, OI, Olson, JE, Osorio, A, Park, SK, Peeters, PH, Peissel, B, Peterlongo, P, Peto, J, Phelan, CM, Pilarski, R, Poppe, B, Pylkäs, K, Radice, P, Rahman, N, Rantala, J, Rappaport, C, Rennert, G, Richardson, A, Robson, M, Romieu, I, Rudolph, A, Rutgers, EJ, Sanchez, M-J, Santella, RM, Sawyer, EJ, Schmidt, DF, Schmidt, MK, Schmutzler, RK, Schumacher, F, Scott, R, Senter, L, Sharma, P, Simard, J, Singer, CF, Sinilnikova, OM, Soucy, P, Southey, M, Steinemann, D, Stenmark-Askmalm, M, Stoppa-Lyonnet, D, Swerdlow, A, Szabo, CI, Tamimi, R, Tapper, W, Teixeira, MR, Teo, S-H, Terry, MB, Thomassen, M, Thompson, D, Tihomirova, L, Toland, AE, Tollenaar, RAEM, Tomlinson, I, Truong, T, Tsimiklis, H, Teulé, A, Tumino, R, Tung, N, Turnbull, C, Ursin, G, Van Deurzen, CHM, Van Rensburg, EJ, Varon-Mateeva, R, Wang, Z, Wang-Gohrke, S, Weiderpass, E, Weitzel, JN, Whittemore, A, Wildiers, H, Winqvist, R, Yang, XR, Yannoukakos, D, Yao, S, Zamora, MP, Zheng, W, Hall, P, Kraft, P, Vachon, C, Slager, S, Chenevix-Trench, G, Pharoah, PDP, Monteiro, AAN, García-Closas, M, Easton, DF, and Antoniou, AC
Subjects: Heterozygote, tRNA Methyltransferases, Genotype, BRCA1 Protein, Breast Neoplasms, Polymorphism, Single Nucleotide, 3. Good health, Cyclophilins, Receptors, Estrogen, Risk Factors, Chromosomes, Human, Pair 2, Mutation, Humans, Female, Genetic Predisposition to Disease, Genome-Wide Association Study
Abstract: This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms11375, Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P

38. Hypohidrotic ectodermal dysplasia caused by an intragenic duplication in EDAR.

Author: Graversen L, Sommerlund M, Kruse C, Gjørup H, Gregersen PA, Jensen UB, and Blechingberg J
Abstract: Hypohidrotic Ectodermal Dysplasia is a syndrome with hypotrichosis, hypohidrosis, and hypodontia as the main symptoms. The prevalence is estimated to one in 5000-10,000 persons. In 10-15% the disease is caused by pathogenic variants in EDAR, and most of the known causal variants to date are missense or nonsense variants. We present a patient with classic Hypohidrotic Ectodermal Dysplasia and mammary gland aplasia with a duplication within EDAR as the likely cause. The duplication is de novo in the patient, and genome sequencing of DNA extracted from blood has revealed that the duplication is in tandem conformation, most likely entailing an altered EDAR protein with a dominant negative effect. This is to our knowledge the first report of an intragenic duplication in EDAR as causal for Hypohidrotic Ectodermal Dysplasia., Competing Interests: Declaration of Competing interest The authors have no conflict of interests., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Published: 2024
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39. Compound heterozygosity for two variants in BMP5 in human skeletal dysostosis with atrioventricular septal defect.

Author: Gregersen PA, Hammarsjö A, Graversen L, Brix N, Lindelöf H, Jensen UB, Farholt S, Rubak S, Bjerre J, Piticchio SG, Terkelsen T, Nishimura G, Hellfritzsch MB, and Grigelioniene G
Abstract: The growth and development of the skeleton is regulated by bone morphogenetic proteins of which several are linked to genetic skeletal disorders. So far, no human skeletal malformations have been associated with variants in BMP5. Here, we report a patient with biallelic loss of function variants in BMP5 and a syndromic phenotype including skeletal dysostosis, dysmorphic features, hypermobility, laryngo-tracheo-bronchomalacia and atrioventricular septal defect. We discuss the phenotype in relation to the known tissue-specific expression of Bmp5 and similar morphological abnormalities previously reported in experimental animal models. Our findings suggest a new association between BMP5 variants and a range of developmental anomalies, involving ears, heart and skeleton, thereby increasing understanding of BMP5's role in human development., (© 2024 The Author(s). Clinical Genetics published by John Wiley & Sons Ltd.)
Published: 2024
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40. CRISPR activation to characterize splice-altering variants in easily accessible cells.

Author: Terkelsen T, Mikkelsen NS, Bak EN, Vad-Nielsen J, Blechingberg J, Weiss S, Drue SO, Andersen H, Andresen BS, Bak RO, and Jensen UB
Subjects: Humans, RNA, Messenger, Central Nervous System, Spastin, Clustered Regularly Interspaced Short Palindromic Repeats, RNA Splicing genetics
Abstract: Genetic variants that affect mRNA splicing are a major cause of hereditary disorders, but the spliceogenicity of variants is challenging to predict. RNA diagnostics of clinically accessible tissues enable rapid functional characterization of splice-altering variants within their natural genetic context. However, this analysis cannot be offered to all individuals as one in five human disease genes are not expressed in easily accessible cell types. To overcome this problem, we have used CRISPR activation (CRISPRa) based on a dCas9-VPR mRNA-based delivery platform to induce expression of the gene of interest in skin fibroblasts from individuals with suspected monogenic disorders. Using this ex vivo splicing assay, we characterized the splicing patterns associated with germline variants in the myelin protein zero gene (MPZ), which is exclusively expressed in Schwann cells of the peripheral nerves, and the spastin gene (SPAST), which is predominantly expressed in the central nervous system. After overnight incubation, CRISPRa strongly upregulated MPZ and SPAST transcription in skin fibroblasts, which enabled splice variant profiling using reverse transcription polymerase chain reaction, next-generation sequencing, and long-read sequencing. Our investigations show proof of principle of a promising genetic diagnostic tool that involves CRISPRa to activate gene expression in easily accessible cells to study the functional impact of genetic variants. The procedure is easy to perform in a diagnostic laboratory with equipment and reagents all readily available., Competing Interests: Declaration of interests R.O.B. holds equity in Graphite Bio and UNIKUM Tx and is a paid consultant of UNIKUM Therapeutics., (Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
Published: 2024
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41. Male with an apparently normal phenotype carrying a BRCA1 exon 20 duplication in trans to a BRCA1 frameshift variant.

Author: Block I, Mateu-Regué À, Do TTN, Miceikaite I, Sdogati D, Larsen MJ, Hao Q, Nielsen HR, Boonen SE, Skytte AB, Jensen UB, Høffding LK, De Nicolo A, Viel A, Tudini E, Parsons MT, Hansen TVO, Rossing M, Kruse TA, Spurdle AB, and Thomassen M
Subjects: Humans, Male, BRCA1 Protein genetics, Exons genetics, Mitomycin, Phenotype, Breast Neoplasms, Fanconi Anemia genetics
Abstract: Background: Reports of dual carriers of pathogenic BRCA1 variants in trans are extremely rare, and so far, most individuals have been associated with a Fanconi Anemia-like phenotype., Methods: We identified two families with a BRCA1 in-frame exon 20 duplication (Ex20dup). In one male individual, the variant was in trans with the BRCA1 frameshift variant c.2475delC p.(Asp825Glufs*21). We performed splicing analysis and used a transcription activation domain (TAD) assay to assess the functional impact of Ex20dup. We collected pedigrees and mapped the breakpoints of the duplication by long- and short-read genome sequencing. In addition, we performed a mitomycin C (MMC) assay from the dual carrier using cultured lymphoblastoid cells., Results: Genome sequencing and RNA analysis revealed the BRCA1 exon 20 duplication to be in tandem. The duplication was expressed without skipping any one of the two exon 20 copies, resulting in a lack of wild-type transcripts from this allele. TAD assay indicated that the Ex20dup variant has a functional level similar to the well-known moderate penetrant pathogenic BRCA1 variant c.5096G > A p.(Arg1699Gln). MMC assay of the dual carrier indicated a slightly impaired chromosomal repair ability., Conclusions: This is the first reported case where two BRCA1 variants with demonstrated functional impact are identified in trans in a male patient with an apparently normal clinical phenotype and no BRCA1-associated cancer. The results pinpoint a minimum necessary BRCA1 protein activity to avoid a Fanconi Anemia-like phenotype in compound heterozygous status and yet still predispose carriers to hormone-related cancers. These findings urge caution when counseling families regarding potential Fanconi Anemia risk. Furthermore, prudence should be taken when classifying individual variants as benign based on co-occurrence in trans with well-established pathogenic variants., (© 2024. The Author(s).)
Published: 2024
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42. Enhanced production of mesencephalic dopaminergic neurons from lineage-restricted human undifferentiated stem cells.

Author: Maimaitili M, Chen M, Febbraro F, Ucuncu E, Kelly R, Niclis JC, Christiansen JR, Mermet-Joret N, Niculescu D, Lauritsen J, Iannielli A, Klæstrup IH, Jensen UB, Qvist P, Nabavi S, Broccoli V, Nykjær A, Romero-Ramos M, and Denham M
Subjects: Humans, Rats, Animals, Transcription Factors metabolism, Cell Differentiation physiology, Mesencephalon, Dopaminergic Neurons metabolism, Pluripotent Stem Cells metabolism
Abstract: Current differentiation protocols for generating mesencephalic dopaminergic (mesDA) neurons from human pluripotent stem cells result in grafts containing only a small proportion of mesDA neurons when transplanted in vivo. In this study, we develop lineage-restricted undifferentiated stem cells (LR-USCs) from pluripotent stem cells, which enhances their potential for differentiating into caudal midbrain floor plate progenitors and mesDA neurons. Using a ventral midbrain protocol, 69% of LR-USCs become bona fide caudal midbrain floor plate progenitors, compared to only 25% of human embryonic stem cells (hESCs). Importantly, LR-USCs generate significantly more mesDA neurons under midbrain and hindbrain conditions in vitro and in vivo. We demonstrate that midbrain-patterned LR-USC progenitors transplanted into 6-hydroxydopamine-lesioned rats restore function in a clinically relevant non-pharmacological behavioral test, whereas midbrain-patterned hESC-derived progenitors do not. This strategy demonstrates how lineage restriction can prevent the development of undesirable lineages and enhance the conditions necessary for mesDA neuron generation., (© 2023. The Author(s).)
Published: 2023
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43. Author Correction: Validation of the BOADICEA model for predicting the likelihood of carrying pathogenic variants in eight breast and ovarian cancer susceptibility genes.

Author: Møller NB, Boonen DS, Feldner ES, Hao Q, Larsen M, Lænkholm AV, Borg Å, Kvist A, Törngren T, Jensen UB, Boonen SE, Thomassen M, and Terkelsen T
Published: 2023
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44. Lack of guidelines and translational knowledge is hindering the implementation of psychiatric genetic counseling and testing within Europe - A multi-professional survey study.

Author: Koido K, Malmgren CI, Pojskic L, Almos PZ, Bergen SE, Borg I, Božina N, Coviello DA, Degenhardt F, Ganoci L, Jensen UB, Durand-Lennad L, Laurent-Levinson C, McQuillin A, Navickas A, Pace NP, Paneque M, Rietschel M, Grigoroiu-Serbanescu M, Soller MJ, Suvisaari J, Utkus A, Van Assche E, Vissouze L, Zuckerman S, Chaumette B, and Tammimies K
Subjects: Humans, Surveys and Questionnaires, Europe, European Union, Genetic Counseling methods, Genetic Testing methods
Abstract: Genetic research has identified a large number of genetic variants, both rare and common, underlying neurodevelopmental disorders (NDD) and major psychiatric disorders. Currently, these findings are being translated into clinical practice. However, there is a lack of knowledge and guidelines for psychiatric genetic testing (PsychGT) and genetic counseling (PsychGC). The European Union-funded COST action EnGagE (CA17130) network was started to investigate the current implementation status of PsychGT and PsychGC across 35 participating European countries. Here, we present the results of a pan-European online survey in which we gathered the opinions, knowledge, and practices of a self-selected sample of professionals involved/interested in the field. We received answers from 181 respondents. The three main occupational categories were genetic counselor (21.0%), clinical geneticist (24.9%), and researcher (25.4%). Of all 181 respondents, 106 provide GC for any psychiatric disorder or NDD, corresponding to 58.6% of the whole group ranging from 43.2% in Central Eastern Europe to 66.1% in Western Europe. Overall, 65.2% of the respondents reported that genetic testing is offered to individuals with NDD, and 26.5% indicated the same for individuals with major psychiatric disorders. Only 22.1% of the respondents indicated that they have guidelines for PsychGT. Pharmacogenetic testing actionable for psychiatric disorders was offered by 15%. Interestingly, when genetic tests are fully covered by national health insurance, more genetic testing is provided for individuals with NDD but not those with major psychiatric disorders. Our qualitative analyses of responses highlight the lack of guidelines and knowledge on utilizing and using genetic tests and education and training as the major obstacles to implementation. Indeed, the existence of psychiatric genetic training courses was confirmed by only 11.6% of respondents. The question on the relevance of up-to-date education and training in psychiatric genetics on everyday related practice was highly relevant. We provide evidence that PsychGC and PsychGT are already in use across European countries, but there is a lack of guidelines and education. Harmonization of practice and development of guidelines for genetic counseling, testing, and training professionals would improve equality and access to quality care for individuals with psychiatric disorders within Europe., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Published: 2023
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45. Validation of the BOADICEA model for predicting the likelihood of carrying pathogenic variants in eight breast and ovarian cancer susceptibility genes.

Author: Møller NB, Boonen DS, Feldner ES, Hao Q, Larsen M, Lænkholm AV, Borg Å, Kvist A, Törngren T, Jensen UB, Boonen SE, Thomassen M, and Terkelsen T
Subjects: Humans, Female, Retrospective Studies, Genetic Testing, Genes, BRCA2, Genetic Predisposition to Disease, Breast Neoplasms diagnosis, Ovarian Neoplasms genetics, Ovarian Neoplasms epidemiology
Abstract: BOADICEA is a comprehensive risk prediction model for breast and/or ovarian cancer (BC/OC) and for carrying pathogenic variants (PVs) in cancer susceptibility genes. In addition to BRCA1 and BRCA2, BOADICEA version 6 includes PALB2, CHEK2, ATM, BARD1, RAD51C and RAD51D. To validate its predictions for these genes, we conducted a retrospective study including 2033 individuals counselled at clinical genetics departments in Denmark. All counselees underwent comprehensive genetic testing by next generation sequencing on suspicion of hereditary susceptibility to BC/OC. Likelihoods of PVs were predicted from information about diagnosis, family history and tumour pathology. Calibration was examined using the observed-to-expected ratio (O/E) and discrimination using the area under the receiver operating characteristics curve (AUC). The O/E was 1.11 (95% CI 0.97-1.26) for all genes combined. At sub-categories of predicted likelihood, the model performed well with limited misestimation at the extremes of predicted likelihood. Discrimination was acceptable with an AUC of 0.70 (95% CI 0.66-0.74), although discrimination was better for BRCA1 and BRCA2 than for the other genes in the model. This suggests that BOADICEA remains a valid decision-making aid for determining which individuals to offer comprehensive genetic testing for hereditary susceptibility to BC/OC despite suboptimal calibration for individual genes in this population., (© 2023. The Author(s).)
Published: 2023
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46. Clinical, splicing, and functional analysis to classify BRCA2 exon 3 variants: Application of a points-based ACMG/AMP approach.

Author: Thomassen M, Mesman RLS, Hansen TVO, Menendez M, Rossing M, Esteban-Sánchez A, Tudini E, Törngren T, Parsons MT, Pedersen IS, Teo SH, Kruse TA, Møller P, Borg Å, Jensen UB, Christensen LL, Singer CF, Muhr D, Santamarina M, Brandao R, Andresen BS, Feng BJ, Canson D, Richardson ME, Karam R, Pesaran T, LaDuca H, Conner BR, Abualkheir N, Hoang L, Calléja FMGR, Andrews L, James PA, Bunyan D, Hamblett A, Radice P, Goldgar DE, Walker LC, Engel C, Claes KBM, Macháčková E, Baralle D, Viel A, Wappenschmidt B, Lazaro C, Vega A, Vreeswijk MPG, de la Hoya M, and Spurdle AB
Subjects: Animals, Humans, Mice, Alternative Splicing, BRCA2 Protein genetics, BRCA2 Protein metabolism, RNA Splicing, RNA, Messenger genetics, RNA, Messenger metabolism, Genes, BRCA2, RNA Splice Sites
Abstract: Skipping of BRCA2 exon 3 (∆E3) is a naturally occurring splicing event, complicating clinical classification of variants that may alter ∆E3 expression. This study used multiple evidence types to assess pathogenicity of 85 variants in/near BRCA2 exon 3. Bioinformatically predicted spliceogenic variants underwent mRNA splicing analysis using minigenes and/or patient samples. ∆E3 was measured using quantitative analysis. A mouse embryonic stem cell (mESC) based assay was used to determine the impact of 18 variants on mRNA splicing and protein function. For each variant, population frequency, bioinformatic predictions, clinical data, and existing mRNA splicing and functional results were collated. Variant class was assigned using a gene-specific adaptation of ACMG/AMP guidelines, following a recently proposed points-based system. mRNA and mESC analysis combined identified six variants with transcript and/or functional profiles interpreted as loss of function. Cryptic splice site use for acceptor site variants generated a transcript encoding a shorter protein that retains activity. Overall, 69/85 (81%) variants were classified using the points-based approach. Our analysis shows the value of applying gene-specific ACMG/AMP guidelines using a points-based approach and highlights the consideration of cryptic splice site usage to appropriately assign PVS1 code strength., (© 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.)
Published: 2022
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47. Clinical implications of genetic testing in familial intermediate and late-onset colorectal cancer.

Author: Djursby M, Hansen TVO, Wadt KAW, Madsen MB, Berchtold LA, Lautrup CK, Markholt S, Jensen UB, Krogh LN, Lundsgaard M, Gerdes AM, Nilbert M, and Therkildsen C
Subjects: Humans, Middle Aged, DNA Mismatch Repair genetics, Genetic Testing, Genetic Predisposition to Disease, DNA-Binding Proteins genetics, Germ-Line Mutation, Microsatellite Instability, Colorectal Neoplasms, Hereditary Nonpolyposis diagnosis, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, Colorectal Neoplasms, Hereditary Nonpolyposis pathology, Colorectal Neoplasms diagnosis, Colorectal Neoplasms genetics
Abstract: The genetic background of familial, late-onset colorectal cancer (CRC) (i.e., onset > age 50 years) has not been studied as thoroughly as other subgroups of familial CRC, and the proportion of families with a germline genetic predisposition to CRC remains to be defined. To define the contribution of known or suggested CRC predisposition genes to familial late-onset CRC, we analyzed 32 well-established or candidate CRC predisposition genes in 75 families with late-onset CRC. We identified pathogenic or likely pathogenic variants in five patients in MSH6 (n = 1), MUTYH (monoallelic; n = 2) and NTHL1 (monoallelic; n = 2). In addition, we identified a number of variants of unknown significance in particular in the lower penetrant Lynch syndrome-associated mismatch repair (MMR) gene MSH6 (n = 6). In conclusion, screening using a comprehensive cancer gene panel in families with accumulation of late-onset CRC appears not to have a significant clinical value due to the low level of high-risk pathogenic variants detected. Our data suggest that only patients with abnormal MMR immunohistochemistry (IHC) or microsatellite instability (MSI) analyses, suggestive of Lynch syndrome, or a family history indicating another cancer predisposition syndrome should be prioritized for such genetic evaluations. Variants in MSH6 and MUTYH have previously been proposed to be involved in digenic or oligogenic hereditary predisposition to CRC. Accumulation of variants in MSH6 and monoallelic, pathogenic variants in MUTYH in our study indicates that digenic or oligogenic inheritance might be involved in late-onset CRC and warrants further studies of complex types of inheritance., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Published: 2022
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48. Novel homozygous CD46 variant with C-isoform expression affects C3b inactivation in atypical hemolytic uremic syndrome.

Author: Schack VR, Herlin MK, Pedersen H, Jensen JMB, Faerch M, Bundgaard B, Jensen RK, Jensen UB, Christensen R, Andersen GR, Thiel S, and Höllsberg P
Subjects: Child, Complement C3b, Complement System Proteins, Humans, Membrane Cofactor Protein genetics, Mutation, Protein Isoforms genetics, Atypical Hemolytic Uremic Syndrome genetics
Abstract: Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy that may lead to organ failure. Dysregulation of the complement system can cause aHUS, and various disease-related variants in the complement regulatory protein CD46 are described. We here report a pediatric patient with aHUS carrying a hitherto unreported homozygous variant in CD46 (NM_172359.3:c.602C>T p.(Ser201Leu)). In our functional analyses, this variant caused complement dysregulation through three separate mechanisms. First, CD46 surface expression on the patient's blood cells was significantly reduced. Second, stably expressing CD46(Ser201Leu) cells bound markedly less to patterns of C3b than CD46 WT cells. Third, the patient predominantly expressed the rare isoforms of CD46 (C dominated) instead of the more common isoforms (BC dominated). Using BC1 and C1 expressing cell lines, we found that the C1 isoform bound markedly less C3b than the BC1 isoform. These results highlight the coexistence of multiple mechanisms that may act synergistically to disrupt CD46 function during aHUS development., (© 2022 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)
Published: 2022
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49. Mono-allelic loss of YTHDF3 and neurodevelopmental disorder: clinical features of four individuals with 8q12.3 deletions.

Author: Terkelsen T, Brasch-Andersen C, Illum N, Busa T, Missirian C, Chandler K, Holden ST, Jensen UB, and Fagerberg CR
Subjects: Adolescent, Child, Female, Genetic Association Studies, Humans, Loss of Heterozygosity, Male, Phenotype, Young Adult, Alleles, Chromosome Deletion, Chromosomes, Human, Pair 8, Genetic Predisposition to Disease, Neurodevelopmental Disorders diagnosis, Neurodevelopmental Disorders genetics, RNA-Binding Proteins genetics
Abstract: The YTH domain family member 3 gene (YTHDF3) encodes a reader of the abundant N6-methyladenosine (m 6 A) modification of eukaryotic mRNA, which plays an essential role in regulating mRNA stability and is necessary to achieve normal development of the central nervous system in animal models. YTHDF3 has not previously been implicated in Mendelian disease despite a high probability of loss of function intolerance and statistical evidence of enrichment for gene-disruptive de novo variants in large-scale studies of individuals with intellectual disability and/or developmental delay. We report four individuals with deletion of 8q12.3, deletion size 1.38-2.60 Mb, encompassing YTHDF3, three of them were de novo, and in one case, the inheritance was unknown. Common features of the individuals (age range, 4-22 years) were developmental delay and/or intellectual disability. Two individuals underwent squint surgery. We suggest that haploinsufficiency of YTHDF3 causes a neurodevelopmental disorder with developmental delay and intellectual disability of variable degree., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
Published: 2022
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50. Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores.

Author: Barnes DR, Silvestri V, Leslie G, McGuffog L, Dennis J, Yang X, Adlard J, Agnarsson BA, Ahmed M, Aittomäki K, Andrulis IL, Arason A, Arnold N, Auber B, Azzollini J, Balmaña J, Barkardottir RB, Barrowdale D, Barwell J, Belotti M, Benitez J, Berthet P, Boonen SE, Borg Å, Bozsik A, Brady AF, Brennan P, Brewer C, Brunet J, Bucalo A, Buys SS, Caldés T, Caligo MA, Campbell I, Cassingham H, Christensen LL, Cini G, Claes KBM, Cook J, Coppa A, Cortesi L, Damante G, Darder E, Davidson R, de la Hoya M, De Leeneer K, de Putter R, Del Valle J, Diez O, Ding YC, Domchek SM, Donaldson A, Eason J, Eeles R, Engel C, Evans DG, Feliubadaló L, Fostira F, Frone M, Frost D, Gallagher D, Gehrig A, Giraud S, Glendon G, Godwin AK, Goldgar DE, Greene MH, Gregory H, Gross E, Hahnen E, Hamann U, Hansen TVO, Hanson H, Hentschel J, Horvath J, Izatt L, Izquierdo A, James PA, Janavicius R, Jensen UB, Johannsson OT, John EM, Kramer G, Kroeldrup L, Kruse TA, Lautrup C, Lazaro C, Lesueur F, Lopez-Fernández A, Mai PL, Manoukian S, Matrai Z, Matricardi L, Maxwell KN, Mebirouk N, Meindl A, Montagna M, Monteiro AN, Morrison PJ, Muranen TA, Murray A, Nathanson KL, Neuhausen SL, Nevanlinna H, Nguyen-Dumont T, Niederacher D, Olah E, Olopade OI, Palli D, Parsons MT, Pedersen IS, Peissel B, Perez-Segura P, Peterlongo P, Petersen AH, Pinto P, Porteous ME, Pottinger C, Pujana MA, Radice P, Ramser J, Rantala J, Robson M, Rogers MT, Rønlund K, Rump A, Sánchez de Abajo AM, Shah PD, Sharif S, Side LE, Singer CF, Stadler Z, Steele L, Stoppa-Lyonnet D, Sutter C, Tan YY, Teixeira MR, Teulé A, Thull DL, Tischkowitz M, Toland AE, Tommasi S, Toss A, Trainer AH, Tripathi V, Valentini V, van Asperen CJ, Venturelli M, Viel A, Vijai J, Walker L, Wang-Gohrke S, Wappenschmidt B, Whaite A, Zanna I, Offit K, Thomassen M, Couch FJ, Schmutzler RK, Simard J, Easton DF, Chenevix-Trench G, Antoniou AC, and Ottini L
Subjects: Aged, 80 and over, BRCA1 Protein genetics, BRCA2 Protein genetics, Genetic Predisposition to Disease, Heterozygote, Humans, Male, Mutation, Polymorphism, Single Nucleotide, Risk Assessment, Risk Factors, Breast Neoplasms epidemiology, Breast Neoplasms genetics, Prostatic Neoplasms epidemiology, Prostatic Neoplasms genetics
Abstract: Background: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers., Methods: 483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)-negative (PRSER-), or ER-positive (PRSER+) breast cancer risk., Results: PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions., Conclusions: Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management., (© The Author(s) 2021. Published by Oxford University Press.)
Published: 2022
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