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1. Risk-reducing mastectomy and breast cancer mortality in women with a BRCA1 or BRCA2 pathogenic variant: an international analysis

Author: Metcalfe, K, Huzarski, T, Gronwald, J, Kotsopoulos, J, Kim, R, Moller, P, Pal, T, Aeilts, A, Eisen, A, Karlan, B, Bordeleau, L, Tung, N, Olopade, O, Zakalik, D, Singer, C, Foulkes, W, Couch, F, Neuhausen, S, Eng, C, Sun, P, Lubinski, J, Narod, S, Velsher, L, Poll, A, Warner, E, Mccuaig, J, Armel, S, Saal, H, Steele, L, Lemire, E, Serfas, K, Senter, L, Sweet, K, Panchal, S, Cullinane, C, Blum, J, Rayson, D, Ramon y Cajal, T, Dungan, J, Fruscio, R, Zovato, S, Cohen, S, Metcalfe K., Huzarski T., Gronwald J., Kotsopoulos J., Kim R., Moller P., Pal T., Aeilts A., Eisen A., Karlan B., Bordeleau L., Tung N., Olopade O., Zakalik D., Singer C. F., Foulkes W., Couch F., Neuhausen S. L., Eng C., Sun P., Lubinski J., Narod S. A., Velsher L., Poll A., Warner E., McCuaig J., Armel S., Saal H., Steele L., Lemire E., Serfas K., Senter L., Sweet K., Panchal S., Cullinane C. A., Blum J. L., Rayson D., Ramon y Cajal T., Dungan J., Fruscio R., Zovato S., Cohen S., Metcalfe, K, Huzarski, T, Gronwald, J, Kotsopoulos, J, Kim, R, Moller, P, Pal, T, Aeilts, A, Eisen, A, Karlan, B, Bordeleau, L, Tung, N, Olopade, O, Zakalik, D, Singer, C, Foulkes, W, Couch, F, Neuhausen, S, Eng, C, Sun, P, Lubinski, J, Narod, S, Velsher, L, Poll, A, Warner, E, Mccuaig, J, Armel, S, Saal, H, Steele, L, Lemire, E, Serfas, K, Senter, L, Sweet, K, Panchal, S, Cullinane, C, Blum, J, Rayson, D, Ramon y Cajal, T, Dungan, J, Fruscio, R, Zovato, S, Cohen, S, Metcalfe K., Huzarski T., Gronwald J., Kotsopoulos J., Kim R., Moller P., Pal T., Aeilts A., Eisen A., Karlan B., Bordeleau L., Tung N., Olopade O., Zakalik D., Singer C. F., Foulkes W., Couch F., Neuhausen S. L., Eng C., Sun P., Lubinski J., Narod S. A., Velsher L., Poll A., Warner E., McCuaig J., Armel S., Saal H., Steele L., Lemire E., Serfas K., Senter L., Sweet K., Panchal S., Cullinane C. A., Blum J. L., Rayson D., Ramon y Cajal T., Dungan J., Fruscio R., Zovato S., and Cohen S.
Abstract: Background: Risk-reducing mastectomy (RRM) is offered to women with a BRCA1 or BRCA2 pathogenic variant, however, there are limited data on the impact on breast cancer mortality. Methods: Participants were identified from a registry of women with BRCA1/2 pathogenic variants. We used a pseudo-randomised trial design and matched one woman with a RRM to one woman without a RRM on year of birth, gene, and country. We estimated the hazard ratio (HR) and 95% confidence intervals (CI) for dying of breast cancer in the follow-up period. Results: There were 1654 women included; 827 assigned to the RRM arm and 827 assigned to the control arm. After a mean follow-up of 6.3 years, there were 20 incident breast cancers (including 15 occult cancers) and two breast cancer deaths in the RRM arm, and 100 incident breast cancers and 7 breast cancer deaths in the control arm (HR = 0.26; 95% CI 0.05–1.35; p = 0.11). The probability of dying of breast cancer within 15 years after RRM was 0.95%. Conclusions: In women with a BRCA1 or BRCA2 pathogenic variant, RRM reduces the risk of breast cancer, and the probability of dying of breast cancer is low.
Published: 2024

2. Bilateral Oophorectomy and All-Cause Mortality in Women With BRCA1 and BRCA2 Sequence Variations

Author: Kotsopoulos, J, Gronwald, J, Huzarski, T, Møller, P, Pal, T, Mccuaig, J, Singer, C, Karlan, B, Aeilts, A, Eng, C, Eisen, A, Bordeleau, L, Foulkes, W, Tung, N, Couch, F, Fruscio, R, Neuhausen, S, Zakalik, D, Cybulski, C, Metcalfe, K, Olopade, O, Sun, P, Lubinski, J, Narod, S, Kotsopoulos, Joanne, Gronwald, Jacek, Huzarski, Tomasz, Møller, Pål, Pal, Tuya, McCuaig, Jeanna M, Singer, Christian F, Karlan, Beth Y, Aeilts, Amber, Eng, Charis, Eisen, Andrea, Bordeleau, Louise, Foulkes, William D, Tung, Nadine, Couch, Fergus J, Fruscio, Robert, Neuhausen, Susan L, Zakalik, Dana, Cybulski, Cezary, Metcalfe, Kelly, Olopade, Olufunmilayo I, Sun, Ping, Lubinski, Jan, Narod, Steven A, Kotsopoulos, J, Gronwald, J, Huzarski, T, Møller, P, Pal, T, Mccuaig, J, Singer, C, Karlan, B, Aeilts, A, Eng, C, Eisen, A, Bordeleau, L, Foulkes, W, Tung, N, Couch, F, Fruscio, R, Neuhausen, S, Zakalik, D, Cybulski, C, Metcalfe, K, Olopade, O, Sun, P, Lubinski, J, Narod, S, Kotsopoulos, Joanne, Gronwald, Jacek, Huzarski, Tomasz, Møller, Pål, Pal, Tuya, McCuaig, Jeanna M, Singer, Christian F, Karlan, Beth Y, Aeilts, Amber, Eng, Charis, Eisen, Andrea, Bordeleau, Louise, Foulkes, William D, Tung, Nadine, Couch, Fergus J, Fruscio, Robert, Neuhausen, Susan L, Zakalik, Dana, Cybulski, Cezary, Metcalfe, Kelly, Olopade, Olufunmilayo I, Sun, Ping, Lubinski, Jan, and Narod, Steven A
Abstract: IMPORTANCE Preventive bilateral salpingo-oophorectomy is offered to women at high risk of ovarian cancer who carry a pathogenic variant in BRCA1 or BRCA2; however, the association of oophorectomy with all-cause mortality has not been clearly defined. OBJECTIVE To evaluate the association between bilateral oophorectomy and all-cause mortality among women with a BRCA1 or BRCA2 sequence variation. DESIGN, SETTING, AND PARTICIPANTS In this international, longitudinal cohort study ofwomen with BRCA sequence variations, information on bilateral oophorectomy was obtained via biennial questionnaire. Participants were women with a BRCA1 or BRCA2 sequence variation, no prior history of cancer, and at least 1 follow-up questionnaire completed. Women were followed up from age 35 to 75 years for incident cancers and deaths. Cox proportional hazards regression was used to estimate the hazard ratios (HRs) and 95% CIs for all-cause mortality associated with a bilateral oophorectomy (time dependent). Data analysis was performed from January 1 to June 1, 2023. EXPOSURES Self-reported bilateral oophorectomy (with or without salpingectomy). MAIN OUTCOMES AND MEASURES All-cause mortality, breast cancer-specific mortality, and ovarian cancer-specific mortality. RESULTS There were 4332 women (mean age, 42.6 years) enrolled in the cohort, of whom 2932 (67.8%) chose to undergo a preventive oophorectomy at a mean (range) age of 45.4 (23.0-77.0) years. After a mean follow-up of 9.0 years, 851 women had developed cancer and 228 had died; 57 died of ovarian or fallopian tube cancer, 58 died of breast cancer, 16 died of peritoneal cancer, and 97 died of other causes. The age-adjusted HR for all-cause mortality associated with oophorectomy was 0.32 (95% CI, 0.24-0.42; P < .001). The age-adjusted HR was 0.28 (95% CI, 0.20-0.38; P < .001) and 0.43 (95% CI, 0.22-0.90; P = .03) for women with BRCA1 and BRCA2 sequence variations, respectively. For women with BRCA1 sequence variations, the estima
Published: 2024

3. MRI Surveillance and Breast Cancer Mortality in Women With BRCA1 and BRCA2 Sequence Variations

Author: Lubinski, J, Kotsopoulos, J, Moller, P, Pal, T, Eisen, A, Peck, L, Karlan, B, Aeilts, A, Eng, C, Bordeleau, L, Foulkes, W, Tung, N, Couch, F, Fruscio, R, Ramon Y Cajal, T, Singer, C, Neuhausen, S, Zakalik, D, Cybulski, C, Gronwald, J, Huzarski, T, Stempa, K, Dungan, J, Cullinane, C, Olopade, O, Metcalfe, K, Sun, P, Narod, S, Lubinski, Jan, Kotsopoulos, Joanne, Moller, Pal, Pal, Tuya, Eisen, Andrea, Peck, Larissa, Karlan, Beth Y, Aeilts, Amber, Eng, Charis, Bordeleau, Louise, Foulkes, William D, Tung, Nadine, Couch, Fergus J, Fruscio, Robert, Ramon Y Cajal, Teresa, Singer, Christian F, Neuhausen, Susan L, Zakalik, Dana, Cybulski, Cezary, Gronwald, Jacek, Huzarski, Tomasz, Stempa, Klaudia, Dungan, Jeffrey, Cullinane, Carey, Olopade, Olufunmilayo I, Metcalfe, Kelly, Sun, Ping, Narod, Steven A, Lubinski, J, Kotsopoulos, J, Moller, P, Pal, T, Eisen, A, Peck, L, Karlan, B, Aeilts, A, Eng, C, Bordeleau, L, Foulkes, W, Tung, N, Couch, F, Fruscio, R, Ramon Y Cajal, T, Singer, C, Neuhausen, S, Zakalik, D, Cybulski, C, Gronwald, J, Huzarski, T, Stempa, K, Dungan, J, Cullinane, C, Olopade, O, Metcalfe, K, Sun, P, Narod, S, Lubinski, Jan, Kotsopoulos, Joanne, Moller, Pal, Pal, Tuya, Eisen, Andrea, Peck, Larissa, Karlan, Beth Y, Aeilts, Amber, Eng, Charis, Bordeleau, Louise, Foulkes, William D, Tung, Nadine, Couch, Fergus J, Fruscio, Robert, Ramon Y Cajal, Teresa, Singer, Christian F, Neuhausen, Susan L, Zakalik, Dana, Cybulski, Cezary, Gronwald, Jacek, Huzarski, Tomasz, Stempa, Klaudia, Dungan, Jeffrey, Cullinane, Carey, Olopade, Olufunmilayo I, Metcalfe, Kelly, Sun, Ping, and Narod, Steven A
Abstract: IMPORTANCE Magnetic resonance imaging (MRI) surveillance is offered to women with a pathogenic variant in the BRCA1 or BRCA2 gene who face a high lifetime risk of breast cancer. Surveillance with MRI is effective in downstaging breast cancers, but the association of MRI surveillance with mortality risk has not been well defined. OBJECTIVE To compare breast cancer mortality rates in women with a BRCA1 or BRCA2 sequence variation who entered an MRI surveillance program with those who did not. DESIGN, SETTING, AND PARTICIPANTS Women with a BRCA1 or BRCA2 sequence variation were identified from 59 participating centers in 11 countries. Participants completed a baseline questionnaire between 1995 and 2015 and a follow-up questionnaire every 2 years to document screening histories, incident cancers, and vital status. Women who had breast cancer, a screening MRI examination, or bilateral mastectomy prior to enrollment were excluded. Participants were followed up from age 30 years (or the date of the baseline questionnaire, whichever was later) until age 75 years, the last follow-up, or death from breast cancer. Data were analyzed from January 1 to July 31, 2023. EXPOSURES Entrance into an MRI surveillance program. MAIN OUTCOMES AND MEASURES Cox proportional hazards modelingwas used to estimate the hazard ratios (HRs) and 95% CIs for breast cancer mortality associated with MRI surveillance compared with no MRI surveillance using a time-dependent analysis. RESULTS A total of 2488 women (mean [range] age at study entry 41.2 [30-69] years), with a sequence variation in the BRCA1 (n = 2004) or BRCA2 (n = 484) genes were included in the analysis. Of these participants, 1756 (70.6%) had at least 1 screening MRI examination and 732 women (29.4%) did not. After a mean follow-up of 9.2 years, 344 women (13.8%) developed breast cancer and 35 women (1.4%) died of breast cancer. The age-adjusted HRs for breast cancer mortality associated with entering an MRI surveillance program were 0
Published: 2024

4. Prognostic gene expression signature for high-grade serous ovarian cancer

Author: Bowtell, D., Chenevix-Trench, G., Green, A., Webb, P., DeFazio, A., Gertig, D., Traficante, N., Fereday, S., Moore, S., Hung, J., Harrap, K., Sadkowsky, T., Pandeya, N., Malt, M., Mellon, A., Robertson, R., Vanden Bergh, T., Jones, M., Mackenzie, P., Maidens, J., Nattress, K., Chiew, Y.E., Stenlake, A., Sullivan, H., Alexander, B., Ashover, P., Brown, S., Corrish, T., Green, L., Jackman, L., Ferguson, K., Martin, K., Martyn, A., Ranieri, B., White, J., Jayde, V., Mamers, P., Bowes, L., Galletta, L., Giles, D., Hendley, J., Alsop, K., Schmidt, T., Shirley, H., Ball, C., Young, C., Viduka, S., Tran, Hoa, Bilic, Sanela, Glavinas, Lydia, Brooks, Julia, Stuart-Harris, R., Kirsten, F., Rutovitz, J., Clingan, P., Glasgow, A., Proietto, A., Braye, S., Otton, G., Shannon, J., Bonaventura, T., Stewart, J., Begbie, S., Friedlander, M., Bell, D., Baron-Hay, S., Ferrier,a, A., Gard, G., Nevell, D., Pavlakis, N., Valmadre, S., Young, B., Camaris, C., Crouch, R., Edwards, L., Hacker, N., Marsden, D., Robertson, G., Beale, P., Beith, J., Carter, J., Dalrymple, C., Houghton, R., Russell, P., Links, M., Grygiel, J., Hill, J., Brand, A., Byth, K., Jaworski, R., Harnett, P., Sharma, R., Wain, G., Ward, B., Papadimos, D., Crandon, A., Cummings, M., Horwood, K., Obermair, A., Perrin, L., Wyld, D., Nicklin, J., Davy, M., Oehler, M.K., Hall, C., Dodd, T., Healy, T., Pittman, K., Henderson, D., Miller, J., Pierdes, J., Blomfield, P., Challis, D., McIntosh, R., Parker, A., Brown, B., Rome, R., Allen, D., Grant, P., Hyde, S., Laurie, R., Robbie, M., Healy, D., Jobling, T., Manolitsas, T., McNealage, J., Rogers, P., Susil, B., Sumithran, E., Simpson, I., Phillips, K., Rischin, D., Fox, S., Johnson, D., Lade, S., Loughrey, M., O’Callaghan, N., Murray, W., Waring, P., Billson, V., Pyman, J., Neesham, D., Quinn, M., Underhill, C., Bell, R., Ng, L.F., Blum, R., Ganju, V., Hammond, I., Leung, Y., McCartney, A., Buck, M., Haviv, I., Purdie, D., Whiteman, D., Zeps, N., Millstein, J., Budden, T., Goode, E.L., Anglesio, M.S., Talhouk, A., Intermaggio, M.P., Leong, H.S., Chen, S., Elatre, W., Gilks, B., Nazeran, T., Volchek, M., Bentley, R.C., Wang, C., Chiu, D.S., Kommoss, S., Leung, S.C.Y., Senz, J., Lum, A., Chow, V., Sudderuddin, H., Mackenzie, R., George, J., Steed, H., Koziak, J.M., Köbel, M., McNeish, I.A., Goranova, T., Ennis, D., Macintyre, G., Silva De Silva, D., Ramón y Cajal, T., García-Donas, J., Hernando Polo, S., Rodriguez, G.C., Cushing-Haugen, K.L., Harris, H.R., Greene, C.S., Zelaya, R.A., Behrens, S., Fortner, R.T., Sinn, P., Herpel, E., Lester, J., Lubiński, J., Oszurek, O., Tołoczko, A., Cybulski, C., Menkiszak, J., Pearce, C.L., Pike, M.C., Tseng, C., Alsop, J., Rhenius, V., Song, H., Jimenez-Linan, M., Piskorz, A.M., Gentry-Maharaj, A., Karpinskyj, C., Widschwendter, M., Singh, N., Kennedy, C.J., Harnett, P.R., Gao, B., Johnatty, S.E., Sayer, R., Boros, J., Winham, S.J., Keeney, G.L., Kaufmann, S.H., Larson, M.C., Luk, H., Hernandez, B.Y., Thompson, P.J., Wilkens, L.R., Carney, M.E., Trabert, B., Lissowska, J., Brinton, L., Sherman, M.E., Bodelon, C., Hinsley, S., Lewsley, L.A., Glasspool, R., Banerjee, S.N., Stronach, E.A., Haluska, P., Ray-Coquard, I., Mahner, S., Winterhoff, B., Slamon, D., Levine, D.A., Kelemen, L.E., Benitez, J., Chang-Claude, J., Gronwald, J., Wu, A.H., Menon, U., Goodman, M.T., Schildkraut, J.M., Wentzensen, N., Brown, R., Berchuck, A., deFazio, A., Gayther, S.A., García, M.J., Henderson, M.J., Rossing, M.A., Beeghly-Fadiel, A., Fasching, P.A., Orsulic, S., Karlan, B.Y., Konecny, G.E., Huntsman, D.G., Bowtell, D.D., Brenton, J.D., Doherty, J.A., Pharoah, P.D.P., and Ramus, S.J.
Published: 2020
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5. Genetic variation in the immunosuppression pathway genes and breast cancer susceptibility: a pooled analysis of 42,510 cases and 40,577 controls from the Breast Cancer Association Consortium

Author: Lei, J, Rudolph, A, Moysich, KB, Behrens, S, Goode, EL, Bolla, MK, Dennis, J, Dunning, AM, Easton, DF, Wang, Q, Benitez, J, Hopper, JL, Southey, MC, Schmidt, MK, Broeks, A, Fasching, PA, Haeberle, L, Peto, J, dos-Santos-Silva, I, Sawyer, EJ, Tomlinson, I, Burwinkel, B, Marmé, F, Guénel, P, Truong, T, Bojesen, SE, Flyger, H, Nielsen, SF, Nordestgaard, BG, González-Neira, A, Menéndez, P, Anton-Culver, H, Neuhausen, SL, Brenner, H, Arndt, V, Meindl, A, Schmutzler, RK, Brauch, H, Hamann, U, Nevanlinna, H, Fagerholm, R, Dörk, T, Bogdanova, NV, Mannermaa, A, Hartikainen, JM, Australian Ovarian Study Group, kConFab Investigators, Van Dijck, L, Smeets, A, Flesch-Janys, D, Eilber, U, Radice, P, Peterlongo, P, Couch, FJ, Hallberg, E, Giles, GG, Milne, RL, Haiman, CA, Schumacher, F, Simard, J, Goldberg, MS, Kristensen, V, Borresen-Dale, AL, Zheng, W, Beeghly-Fadiel, A, Winqvist, R, Grip, M, Andrulis, IL, Glendon, G, García-Closas, M, Figueroa, J, Czene, K, Brand, JS, Darabi, H, Eriksson, M, Hall, P, Li, J, Cox, A, Cross, SS, Pharoah, PDP, Shah, M, Kabisch, M, Torres, D, Jakubowska, A, Lubinski, J, Ademuyiwa, F, Ambrosone, CB, Swerdlow, A, Jones, M, and Chang-Claude, J
Subjects: Genetics, Complementary and Alternative Medicine, Paediatrics and Reproductive Medicine, Genetics & Heredity
Abstract: Immunosuppression plays a pivotal role in assisting tumors to evade immune destruction and promoting tumor development. We hypothesized that genetic variation in the immunosuppression pathway genes may be implicated in breast cancer tumorigenesis. We included 42,510 female breast cancer cases and 40,577 controls of European ancestry from 37 studies in the Breast Cancer Association Consortium (2015) with available genotype data for 3595 single nucleotide polymorphisms (SNPs) in 133 candidate genes. Associations between genotyped SNPs and overall breast cancer risk, and secondarily according to estrogen receptor (ER) status, were assessed using multiple logistic regression models. Gene-level associations were assessed based on principal component analysis. Gene expression analyses were conducted using RNA sequencing level 3 data from The Cancer Genome Atlas for 989 breast tumor samples and 113 matched normal tissue samples. SNP rs1905339 (A>G) in the STAT3 region was associated with an increased breast cancer risk (per allele odds ratio 1.05, 95 % confidence interval 1.03–1.08; p value = 1.4 × 10−6). The association did not differ significantly by ER status. On the gene level, in addition to TGFBR2 and CCND1, IL5 and GM-CSF showed the strongest associations with overall breast cancer risk (p value = 1.0 × 10−3 and 7.0 × 10−3, respectively). Furthermore, STAT3 and IL5 but not GM-CSF were differentially expressed between breast tumor tissue and normal tissue (p value = 2.5 × 10−3, 4.5 × 10−4 and 0.63, respectively). Our data provide evidence that the immunosuppression pathway genes STAT3,IL5, and GM-CSF may be novel susceptibility loci for breast cancer in women of European ancestry.
Published: 2016

6. Epithelial-Mesenchymal Transition (EMT) Gene Variants and Epithelial Ovarian Cancer (EOC) Risk

Author: Amankwah, EK, Lin, HY, Tyrer, JP, Lawrenson, K, Dennis, J, Chornokur, G, Aben, KKH, Anton-Culver, H, Antonenkova, N, Bruinsma, F, Bandera, EV, Bean, YT, Beckmann, MW, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bunker, CH, Butzow, R, Campbell, IG, Carty, K, Chen, Z, Chen, YA, Chang-Claude, J, Cook, LS, Cramer, DW, Cunningham, JM, Cybulski, C, Dansonka-Mieszkowska, A, du Bois, A, Despierre, E, Dicks, E, Doherty, JA, Dörk, T, Dürst, M, Easton, DF, Eccles, DM, Edwards, RP, Ekici, AB, Fasching, PA, Fridley, BL, Gao, YT, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Goodman, MT, Gronwald, J, Harrington, P, Harter, P, Hasmad, HN, Hein, A, Heitz, F, Hildebrandt, MAT, Hillemanns, P, Hogdall, CK, Hogdall, E, Hosono, S, Iversen, ES, Jakubowska, A, Jensen, A, Ji, BT, Karlan, BY, Jim, H, Kellar, M, Kiemeney, LA, Krakstad, C, Kjaer, SK, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Le, ND, Lee, AW, Lele, S, Leminen, A, Lester, J, Levine, DA, Liang, D, Lim, BK, Lissowska, J, Lu, K, Lubinski, J, Lundvall, L, Massuger, LFAG, Matsuo, K, Mcguire, V, Mclaughlin, JR, Mcneish, I, Menon, U, Milne, RL, Modugno, F, Moysich, KB, Ness, RB, Nevanlinna, H, Eilber, U, Odunsi, K, Olson, SH, Orlow, I, Orsulic, S, and Weber, RP
Subjects: Epidemiology, Public Health and Health Services, Genetics
Abstract: Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to epithelial ovarian carcinoma (EOC) risk have been based on small sample sizes and none have sought replication in an independent population. We screened 15,816 single-nucleotide polymorphisms (SNPs) in 296 genes in a discovery phase using data from a genome-wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT-related genes that were nominally (P < 0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive-cancer patients and 23,447 controls. A P-value
Published: 2015

7. Erratum: Correction to: Survival from breast cancer in women with a BRCA2 mutation by treatment (British journal of cancer (2021) 124 9 (1524-1532))

Author: Evans D. G., Evans, D, Phillips, K, Milne, R, Fruscio, R, Cybulski, C, Gronwald, J, Lubinski, J, Huzarski, T, Hyder, Z, Forde, C, Metcalfe, K, Senter, L, Weitzel, J, Tung, N, Zakalik, D, Ekholm, M, Sun, P, Narod, S, Evans D. G., Phillips K. -A., Milne R. L., Fruscio R., Cybulski C., Gronwald J., Lubinski J., Huzarski T., Hyder Z., Forde C., Metcalfe K., Senter L., Weitzel J., Tung N., Zakalik D., Ekholm M., Sun P., Narod S. A., Evans D. G., Evans, D, Phillips, K, Milne, R, Fruscio, R, Cybulski, C, Gronwald, J, Lubinski, J, Huzarski, T, Hyder, Z, Forde, C, Metcalfe, K, Senter, L, Weitzel, J, Tung, N, Zakalik, D, Ekholm, M, Sun, P, Narod, S, Evans D. G., Phillips K. -A., Milne R. L., Fruscio R., Cybulski C., Gronwald J., Lubinski J., Huzarski T., Hyder Z., Forde C., Metcalfe K., Senter L., Weitzel J., Tung N., Zakalik D., Ekholm M., Sun P., and Narod S. A.
Published: 2023

8. 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, Zlowowcka-Perlowska, E, Osorio, A, Duran, M, Andres, R, Benitez, J, Hamann, U, Hogervorst, FB, van Os, TA, Verhoef, S, Meijers-Heijboer, HEJ, Wijnen, J, Garcia, EBG, Ligtenberg, MJ, Kriege, M, Collee, M, Ausems, MGEM, 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, Leone, M, Bressac-de Paillerets, B, Caron, O, Sobol, H, Frenay, M, Prieur, F, Ferrer, SF, Mortemousque, I, Buys, S, Daly, M, Miron, A, Terry, MB, Hopper, JL, John, EM, Southey, M, Goldgar, D, Singer, CF, Fink-Retter, A, Tea, M-K, Kaulich, DG, Hansen, TVO, Nielsen, FC, Barkardottir, RB, Gaudet, M, Kirchhoff, T, Joseph, V, Dutra-Clarke, A, Offit, K, and Piedmonte, M
Published: 2012

9. The BOADICEA model of genetic susceptibility to breast and ovarian cancers: updates and extensions

Author: Antoniou, AC, Cunningham, AP, Peto, J, Evans, DG, Lalloo, F, Narod, SA, Risch, HA, Eyfjord, JE, Hopper, JL, Southey, MC, Olsson, H, Johannsson, O, Borg, A, Passini, B, Radice, P, Manoukian, S, Eccles, DM, Tang, N, Olah, E, Anton-Culver, H, Warner, E, Lubinski, J, Gronwald, J, Gorski, B, Tryggvadottir, L, Syrjakoski, K, Kallioniemi, O-P, Eerola, H, Nevanlinna, H, Pharoah, PDP, and Easton, DF
Subjects: Breast Cancer, Ovarian Cancer, Cancer, Genetics, Genetic Testing, Rare Diseases, Prevention, Aetiology, 2.1 Biological and endogenous factors, 2.2 Factors relating to the physical environment, 2.6 Resources and infrastructure (aetiology), Adult, Age Factors, Aged, Breast Neoplasms, Female, Genes, BRCA1, Genes, BRCA2, Genetic Carrier Screening, Genetic Predisposition to Disease, Humans, Middle Aged, Models, Genetic, Mutation, Neoplasms, Second Primary, Ovarian Neoplasms, BRCA1, BRCA2, cancer risk model, genetic testing, Oncology and Carcinogenesis, Public Health and Health Services, Oncology & Carcinogenesis
Abstract: Multiple genetic loci confer susceptibility to breast and ovarian cancers. We have previously developed a model (BOADICEA) under which susceptibility to breast cancer is explained by mutations in BRCA1 and BRCA2, as well as by the joint multiplicative effects of many genes (polygenic component). We have now updated BOADICEA using additional family data from two UK population-based studies of breast cancer and family data from BRCA1 and BRCA2 carriers identified by 22 population-based studies of breast or ovarian cancer. The combined data set includes 2785 families (301 BRCA1 positive and 236 BRCA2 positive). Incidences were smoothed using locally weighted regression techniques to avoid large variations between adjacent intervals. A birth cohort effect on the cancer risks was implemented, whereby each individual was assumed to develop cancer according to calendar period-specific incidences. The fitted model predicts that the average breast cancer risks in carriers increase in more recent birth cohorts. For example, the average cumulative breast cancer risk to age 70 years among BRCA1 carriers is 50% for women born in 1920-1929 and 58% among women born after 1950. The model was further extended to take into account the risks of male breast, prostate and pancreatic cancer, and to allow for the risk of multiple cancers. BOADICEA can be used to predict carrier probabilities and cancer risks to individuals with any family history, and has been implemented in a user-friendly Web-based program (http://www.srl.cam.ac.uk/genepi/boadicea/boadicea_home.html).
Published: 2008

10. Breast and ovarian cancer risks to carriers of the BRCA1 5382insC and 185delAG and BRCA2 6174delT mutations: a combined analysis of 22 population based studies

Author: Antoniou, AC, Pharoah, PDP, Narod, S, Risch, HA, Eyfjord, JE, Hopper, JL, Olsson, H, Johannsson, O, Borg, A, Pasini, B, Radice, P, Manoukian, S, Eccles, DM, Tang, N, Olah, E, Anton-Culver, H, Warner, E, Lubinski, J, Gronwald, J, Gorski, B, Tulinius, H, Thorlacius, S, Eerola, H, Nevanlinna, H, Syrjäkoski, K, Kallioniemi, O-P, Thompson, D, Evans, C, Peto, J, Lalloo, F, Evans, DG, and Easton, DF
Subjects: Breast Cancer, Ovarian Cancer, Rare Diseases, Cancer, Aetiology, 2.1 Biological and endogenous factors, Adult, Aged, Breast Neoplasms, Female, Founder Effect, Genes, BRCA1, Genes, BRCA2, Heterozygote, Humans, Incidence, Jews, Meta-Analysis as Topic, Middle Aged, Mutation, Ovarian Neoplasms, Penetrance, Prevalence, Risk Assessment, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract: A recent report estimated the breast cancer risks in carriers of the three Ashkenazi founder mutations to be higher than previously published estimates derived from population based studies. In an attempt to confirm this, the breast and ovarian cancer risks associated with the three Ashkenazi founder mutations were estimated using families included in a previous meta-analysis of populatrion based studies. The estimated breast cancer risks for each of the founder BRCA1 and BRCA2 mutations were similar to the corresponding estimates based on all BRCA1 or BRCA2 mutations in the meta-analysis. These estimates appear to be consistent with the observed prevalence of the mutations in the Ashkenazi Jewish population.
Published: 2005

11. The risks of cancer in older women with BRCA pathogenic variants: How far have we come?

Author: Metcalfe, K, Gronwald, J, Tung, N, Mccuaig, J, Eisen, A, Elser, C, Foulkes, W, Neuhausen, S, Senter, L, Moller, P, Bordeleau, L, Fruscio, R, Velsher, L, Zakalik, D, Olopade, O, Eng, C, Pal, T, Cullinane, C, Couch, F, Kotsopoulos, J, Sun, P, Lubinski, J, Narod, S, Metcalfe K. A., Gronwald J., Tung N. M., McCuaig J. M., Eisen A., Elser C., Foulkes W. D., Neuhausen S. L., Senter L., Moller P., Bordeleau L., Fruscio R., Velsher L., Zakalik D., Olopade O. I., Eng C., Pal T., Cullinane C. A., Couch F. J., Kotsopoulos J., Sun P., Lubinski J., Narod S. A., Metcalfe, K, Gronwald, J, Tung, N, Mccuaig, J, Eisen, A, Elser, C, Foulkes, W, Neuhausen, S, Senter, L, Moller, P, Bordeleau, L, Fruscio, R, Velsher, L, Zakalik, D, Olopade, O, Eng, C, Pal, T, Cullinane, C, Couch, F, Kotsopoulos, J, Sun, P, Lubinski, J, Narod, S, Metcalfe K. A., Gronwald J., Tung N. M., McCuaig J. M., Eisen A., Elser C., Foulkes W. D., Neuhausen S. L., Senter L., Moller P., Bordeleau L., Fruscio R., Velsher L., Zakalik D., Olopade O. I., Eng C., Pal T., Cullinane C. A., Couch F. J., Kotsopoulos J., Sun P., Lubinski J., and Narod S. A.
Abstract: Background: The purpose of this study was to estimate the cumulative risks of all cancers in women from 50 to 75 years of age with a BRCA1 or BRCA2 pathogenic variant. Methods: Participants were women with BRCA1 or BRCA2 pathogenic variants from 85 centers in 16 countries. Women were eligible if they had no cancer before the age of 50 years. Participants completed a baseline questionnaire and follow-up questionnaires every 2 years. Women were followed from age 50 until a diagnosis of cancer, death, age 75, or last follow-up. The risk of all cancers combined from age 50 to 75 was estimated using the Kaplan-Meier method. Results: There were 2211 women included (1470 BRCA1 and 742 BRCA2). There were 379 cancers diagnosed in the cohort between 50 and 75 years. The actuarial risk of any cancer from age 50 to 75 was 49% for BRCA1 and 43% for BRCA2. Breast (n = 186) and ovarian (n = 45) were the most frequent cancers observed. For women who had both risk-reducing mastectomy and bilateral salpingo-oophorectomy before age 50, the risk of developing any cancer between age 50 and 75 was 9%. Conclusion: Women with a BRCA1 or BRCA2 pathogenic variant have a high risk of cancer between the ages of 50 and 75 years and should be counselled appropriately.
Published: 2022

12. Contraceptive use and the risk of ovarian cancer among women with a BRCA1 or BRCA2 mutation

Author: Xia, Y, Gronwald, J, Karlan, B, Lubinski, J, Mccuaig, J, Brooks, J, Moller, P, Eisen, A, Sun, S, Senter, L, Bordeleau, L, Neuhausen, S, Singer, C, Tung, N, Foulkes, W, Sun, P, Narod, S, Kotsopoulos, J, Yerushalmi, R, Fruscio, R, Rastelli, A, Zovato, S, Hyder, Z, Huzarski, T, Cybulski, C, Sweet, K, Wood, M, Mckinnon, W, Elser, C, Pal, T, Wiesner, G, Friedman, E, Meschino, W, Snyder, C, Metcalfe, K, Poll, A, Gojska, N, Warner, E, Kim, R, Rosen, B, Demsky, R, Ainsworth, P, Panabaker, K, Steele, L, Saal, H, Serfas, K, Panchal, S, Cullinane, A, Reilly, R, Blum, J, Kwong, A, Rayson, D, Isaacs, C, Ramón y Cajal, T, Dungan, J, Cohen, S, Xia Y. Y., Gronwald J., Karlan B., Lubinski J., McCuaig J. M., Brooks J., Moller P., Eisen A., Sun S., Senter L., Bordeleau L., Neuhausen S. L., Singer C. F., Tung N., Foulkes W. D., Sun P., Narod S. A., Kotsopoulos J., Yerushalmi R., Fruscio R., Rastelli A., Zovato S, Hyder Z., Huzarski T., Cybulski C, Sweet K., Wood M., McKinnon W., Elser C., Pal T., Wiesner G., Friedman E., Meschino W., Snyder C., Metcalfe K., Poll A., Gojska N., Warner E., Kim R. H., Rosen B., Demsky R., Ainsworth P., Panabaker K., Steele L., Saal H., Serfas K., Panchal S., Cullinane A., Reilly R. E., Blum J. L., Kwong A., Cybulski C., Rayson D., Isaacs C., Ramón y Cajal T., Dungan J., Cohen S., Xia, Y, Gronwald, J, Karlan, B, Lubinski, J, Mccuaig, J, Brooks, J, Moller, P, Eisen, A, Sun, S, Senter, L, Bordeleau, L, Neuhausen, S, Singer, C, Tung, N, Foulkes, W, Sun, P, Narod, S, Kotsopoulos, J, Yerushalmi, R, Fruscio, R, Rastelli, A, Zovato, S, Hyder, Z, Huzarski, T, Cybulski, C, Sweet, K, Wood, M, Mckinnon, W, Elser, C, Pal, T, Wiesner, G, Friedman, E, Meschino, W, Snyder, C, Metcalfe, K, Poll, A, Gojska, N, Warner, E, Kim, R, Rosen, B, Demsky, R, Ainsworth, P, Panabaker, K, Steele, L, Saal, H, Serfas, K, Panchal, S, Cullinane, A, Reilly, R, Blum, J, Kwong, A, Rayson, D, Isaacs, C, Ramón y Cajal, T, Dungan, J, Cohen, S, Xia Y. Y., Gronwald J., Karlan B., Lubinski J., McCuaig J. M., Brooks J., Moller P., Eisen A., Sun S., Senter L., Bordeleau L., Neuhausen S. L., Singer C. F., Tung N., Foulkes W. D., Sun P., Narod S. A., Kotsopoulos J., Yerushalmi R., Fruscio R., Rastelli A., Zovato S, Hyder Z., Huzarski T., Cybulski C, Sweet K., Wood M., McKinnon W., Elser C., Pal T., Wiesner G., Friedman E., Meschino W., Snyder C., Metcalfe K., Poll A., Gojska N., Warner E., Kim R. H., Rosen B., Demsky R., Ainsworth P., Panabaker K., Steele L., Saal H., Serfas K., Panchal S., Cullinane A., Reilly R. E., Blum J. L., Kwong A., Cybulski C., Rayson D., Isaacs C., Ramón y Cajal T., Dungan J., and Cohen S.
Abstract: Background BRCA1 and BRCA2 (BRCA) mutation carriers face a high lifetime risk of developing ovarian cancer. Oral contraceptives are protective in this population; however, the impact of other types of contraception (e.g. intrauterine devices, implants, injections) is unknown. We undertook a matched case-control study to evaluate the relationship between type of contraception and risk of ovarian cancer among women with BRCA mutations. Methods A total of 1733 matched pairs were included in this analysis. Women were matched according to year of birth, date of study entry, country of residence, BRCA mutation type and history of breast cancer. Detailed information on hormonal, reproductive and lifestyle exposures were collected from a routinely administered questionnaire. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) associated with each contraceptive exposure. Results Ever use of any contraceptive was significantly associated with reduced risk of ovarian cancer (OR = 0.62; 95% CI 0.52–0.75; P < 0.0001), which was driven by significant inverse associations with oral contraceptives (OR = 0.66; 95% CI 0.54–0.79; P < 0.0001) and contraceptive implants (OR = 0.30; 95% CI 0.12–0.73; P = 0.008). We observed a similar effect with use of injections (OR = 0.37; 95% CI 0.10–1.38; P = 0.14), but this did not achieve significance. No significant associations were observed between patterns of intrauterine device use and risk of ovarian cancer. Conclusions These findings support a protective effect of oral contraceptives and implants on risk of ovarian cancer among women with BRCA mutations. The possible protective effect of injections requires further evaluation.
Published: 2022

13. CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study

Author: Kang, E-Y, Weir, A, Meagher, NS, Farrington, K, Nelson, GS, Ghatage, P, Lee, C-H, Riggan, MJ, Bolithon, A, Popovic, G, Leung, B, Tang, K, Lambie, N, Millstein, J, Alsop, J, Anglesio, MS, Ataseven, B, Barlow, E, Beckmann, MW, Berger, J, Bisinotto, C, Boesmueller, H, Boros, J, Brand, AH, Brooks-Wilson, A, Brucker, SY, Carney, ME, Casablanca, Y, Cazorla-Jimenez, A, Cohen, PA, Conrads, TP, Cook, LS, Coulson, P, Courtney-Brooks, M, Cramer, DW, Crowe, P, Cunningham, JM, Cybulski, C, Darcy, KM, El-Bahrawy, MA, Elishaev, E, Erber, R, Farrell, R, Fereday, S, Fischer, A, Garcia, MJ, Gayther, SA, Gentry-Maharaj, A, Gilks, CB, Grube, M, Harnett, PR, Harrington, SP, Harter, P, Hartmann, A, Hecht, JL, Heikaus, S, Hein, A, Heitz, F, Hendley, J, Hernandez, BY, Hernando Polo, S, Heublein, S, Hirasawa, A, Hogdall, E, Hogdall, CK, Horlings, HM, Huntsman, DG, Huzarski, T, Jewell, A, Jimenez-Linan, M, Jones, ME, Kaufmann, SH, Kennedy, CJ, Khabele, D, Kommoss, FKF, Kruitwagen, RFPM, Lambrechts, D, Le, ND, Lener, M, Lester, J, Leung, Y, Linder, A, Loverix, L, Lubinski, J, Madan, R, Maxwell, GL, Modugno, F, Neuhausen, SL, Olawaiye, A, Olbrecht, S, Orsulic, S, Palacios, J, Pearce, CL, Pike, MC, Quinn, CM, Mohan, GR, Rodriguez-Antona, C, Ruebner, M, Ryan, A, Salfinger, SG, Sasamoto, N, Schildkraut, JM, Schoemaker, MJ, Shah, M, Sharma, R, Shvetsov, YB, Singh, N, Sonke, GS, Steele, L, Stewart, CJR, Sundfeldt, K, Swerdlow, AJ, Talhouk, A, Tan, A, Taylor, SE, Terry, KL, Toloczko, A, Traficante, N, Van de Vijver, KK, van der Aa, MA, Van Gorp, T, Van Nieuwenhuysen, E, Van-Wagensveld, L, Vergote, I, Vierkant, RA, Wang, C, Wilkens, LR, Winham, SJ, Wu, AH, Benitez, J, Berchuck, A, Candido Dos Reis, FJ, DeFazio, A, Fasching, PA, Goode, EL, Goodman, MT, Gronwald, J, Karlan, BY, Kommoss, S, Menon, U, Sinn, H-P, Staebler, A, Brenton, JD, Bowtell, DD, Pharoah, PDP, Ramus, SJ, Kobel, M, Kang, E-Y, Weir, A, Meagher, NS, Farrington, K, Nelson, GS, Ghatage, P, Lee, C-H, Riggan, MJ, Bolithon, A, Popovic, G, Leung, B, Tang, K, Lambie, N, Millstein, J, Alsop, J, Anglesio, MS, Ataseven, B, Barlow, E, Beckmann, MW, Berger, J, Bisinotto, C, Boesmueller, H, Boros, J, Brand, AH, Brooks-Wilson, A, Brucker, SY, Carney, ME, Casablanca, Y, Cazorla-Jimenez, A, Cohen, PA, Conrads, TP, Cook, LS, Coulson, P, Courtney-Brooks, M, Cramer, DW, Crowe, P, Cunningham, JM, Cybulski, C, Darcy, KM, El-Bahrawy, MA, Elishaev, E, Erber, R, Farrell, R, Fereday, S, Fischer, A, Garcia, MJ, Gayther, SA, Gentry-Maharaj, A, Gilks, CB, Grube, M, Harnett, PR, Harrington, SP, Harter, P, Hartmann, A, Hecht, JL, Heikaus, S, Hein, A, Heitz, F, Hendley, J, Hernandez, BY, Hernando Polo, S, Heublein, S, Hirasawa, A, Hogdall, E, Hogdall, CK, Horlings, HM, Huntsman, DG, Huzarski, T, Jewell, A, Jimenez-Linan, M, Jones, ME, Kaufmann, SH, Kennedy, CJ, Khabele, D, Kommoss, FKF, Kruitwagen, RFPM, Lambrechts, D, Le, ND, Lener, M, Lester, J, Leung, Y, Linder, A, Loverix, L, Lubinski, J, Madan, R, Maxwell, GL, Modugno, F, Neuhausen, SL, Olawaiye, A, Olbrecht, S, Orsulic, S, Palacios, J, Pearce, CL, Pike, MC, Quinn, CM, Mohan, GR, Rodriguez-Antona, C, Ruebner, M, Ryan, A, Salfinger, SG, Sasamoto, N, Schildkraut, JM, Schoemaker, MJ, Shah, M, Sharma, R, Shvetsov, YB, Singh, N, Sonke, GS, Steele, L, Stewart, CJR, Sundfeldt, K, Swerdlow, AJ, Talhouk, A, Tan, A, Taylor, SE, Terry, KL, Toloczko, A, Traficante, N, Van de Vijver, KK, van der Aa, MA, Van Gorp, T, Van Nieuwenhuysen, E, Van-Wagensveld, L, Vergote, I, Vierkant, RA, Wang, C, Wilkens, LR, Winham, SJ, Wu, AH, Benitez, J, Berchuck, A, Candido Dos Reis, FJ, DeFazio, A, Fasching, PA, Goode, EL, Goodman, MT, Gronwald, J, Karlan, BY, Kommoss, S, Menon, U, Sinn, H-P, Staebler, A, Brenton, JD, Bowtell, DD, Pharoah, PDP, Ramus, SJ, and Kobel, M
Abstract: BACKGROUND: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. METHODS: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. RESULTS: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. CONCLUSION: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.
Published: 2023

14. FANCM missense variants and breast cancer risk: a case-control association study of 75,156 European women

Author: Figlioli, G, Billaud, A, Ahearn, TU, Antonenkova, NN, Becher, H, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Blok, MJ, Bogdanova, N, Bonanni, B, Burwinkel, B, Camp, NJ, Campbell, A, Castelao, JE, Cessna, MH, Chanock, SJ, Czene, K, Devilee, P, Doerk, T, Engel, C, Eriksson, M, Fasching, PA, Figueroa, JD, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Gonzalez-Neira, A, Grassmann, F, Guenel, P, Gundert, M, Hadjisavvas, A, Hahnen, E, Hall, P, Hamann, U, Harrington, PA, He, W, Hillemanns, P, Hollestelle, A, Hooning, MJ, Hoppe, R, Howell, A, Humphreys, K, Jager, A, Jakubowska, A, Khusnutdinova, EK, Ko, Y-D, Kristensen, VN, Lindblom, A, Lissowska, J, Lubinski, J, Mannermaa, A, Manoukian, S, Margolin, S, Mavroudis, D, Newman, WG, Obi, N, Panayiotidis, M, Rashid, MU, Rhenius, V, Rookus, MA, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Shah, M, Sironen, R, Southey, MC, Suvanto, M, Tollenaar, RAEM, Tomlinson, I, Truong, T, van der Kolk, LE, van Veen, EM, Wappenschmidt, B, Yang, XR, Bolla, MK, Dennis, J, Dunning, AM, Easton, DF, Lush, M, Michailidou, K, Pharoah, PDP, Wang, Q, Adank, MA, Schmidt, MK, Andrulis, IL, Chang-Claude, J, Nevanlinna, H, Chenevix-Trench, G, Evans, DG, Milne, RL, Radice, P, Peterlongo, P, Figlioli, G, Billaud, A, Ahearn, TU, Antonenkova, NN, Becher, H, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Blok, MJ, Bogdanova, N, Bonanni, B, Burwinkel, B, Camp, NJ, Campbell, A, Castelao, JE, Cessna, MH, Chanock, SJ, Czene, K, Devilee, P, Doerk, T, Engel, C, Eriksson, M, Fasching, PA, Figueroa, JD, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Gonzalez-Neira, A, Grassmann, F, Guenel, P, Gundert, M, Hadjisavvas, A, Hahnen, E, Hall, P, Hamann, U, Harrington, PA, He, W, Hillemanns, P, Hollestelle, A, Hooning, MJ, Hoppe, R, Howell, A, Humphreys, K, Jager, A, Jakubowska, A, Khusnutdinova, EK, Ko, Y-D, Kristensen, VN, Lindblom, A, Lissowska, J, Lubinski, J, Mannermaa, A, Manoukian, S, Margolin, S, Mavroudis, D, Newman, WG, Obi, N, Panayiotidis, M, Rashid, MU, Rhenius, V, Rookus, MA, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Shah, M, Sironen, R, Southey, MC, Suvanto, M, Tollenaar, RAEM, Tomlinson, I, Truong, T, van der Kolk, LE, van Veen, EM, Wappenschmidt, B, Yang, XR, Bolla, MK, Dennis, J, Dunning, AM, Easton, DF, Lush, M, Michailidou, K, Pharoah, PDP, Wang, Q, Adank, MA, Schmidt, MK, Andrulis, IL, Chang-Claude, J, Nevanlinna, H, Chenevix-Trench, G, Evans, DG, Milne, RL, Radice, P, and Peterlongo, P
Abstract: Evidence from literature, including the BRIDGES study, indicates that germline protein truncating variants (PTVs) in FANCM confer moderately increased risk of ER-negative and triple-negative breast cancer (TNBC), especially for women with a family history of the disease. Association between FANCM missense variants (MVs) and breast cancer risk has been postulated. In this study, we further used the BRIDGES study to test 689 FANCM MVs for association with breast cancer risk, overall and in ER-negative and TNBC subtypes, in 39,885 cases (7566 selected for family history) and 35,271 controls of European ancestry. Sixteen common MVs were tested individually; the remaining rare 673 MVs were tested by burden analyses considering their position and pathogenicity score. We also conducted a meta-analysis of our results and those from published studies. We did not find evidence for association for any of the 16 variants individually tested. The rare MVs were significantly associated with increased risk of ER-negative breast cancer by burden analysis comparing familial cases to controls (OR = 1.48; 95% CI 1.07-2.04; P = 0.017). Higher ORs were found for the subgroup of MVs located in functional domains or predicted to be pathogenic. The meta-analysis indicated that FANCM MVs overall are associated with breast cancer risk (OR = 1.22; 95% CI 1.08-1.38; P = 0.002). Our results support the definition from previous analyses of FANCM as a moderate-risk breast cancer gene and provide evidence that FANCM MVs could be low/moderate risk factors for ER-negative and TNBC subtypes. Further genetic and functional analyses are necessary to clarify better the increased risks due to FANCM MVs.
Published: 2023

15. Increased FOXJ1 protein expression is associated with improved overall survival in high-grade serous ovarian carcinoma: an Ovarian Tumor Tissue Analysis Consortium Study

Author: Weir, A, Kang, E-Y, Meagher, NS, Nelson, GS, Ghatage, P, Lee, C-H, Riggan, MJ, Gentry-Maharaj, A, Ryan, A, Singh, N, Widschwendter, M, Alsop, J, Anglesio, MS, Beckmann, MW, Berger, J, Bisinotto, C, Boros, J, Brand, AH, Brenton, JD, Brooks-Wilson, A, Carney, ME, Cunningham, JM, Cushing-Haugen, KL, Cybulski, C, Elishaev, E, Erber, R, Fereday, S, Fischer, A, Paz-Ares, L, Gayarre, J, Gilks, BC, Grube, M, Harnett, PR, Harris, HR, Hartmann, A, Hein, A, Hendley, J, Hernandez, BY, Heublein, S, Huang, Y, Huzarski, T, Jakubowska, A, Jimenez-Linan, M, Kennedy, CJ, Kommoss, FKF, Koziak, JM, Kraemer, B, Le, ND, Lesnock, J, Lester, J, Lubinski, J, Menkiszak, J, Ney, B, Olawaiye, A, Orsulic, S, Osorio, A, Robles-Diaz, L, Ruebner, M, Shah, M, Sharma, R, Shvetsov, YB, Steed, H, Talhouk, A, Taylor, SE, Traficante, N, Vierkant, RA, Wang, C, Wilkens, LR, Winham, SJ, Benitez, J, Berchuck, A, Bowtell, DD, Candido dos Reis, FJ, Cook, LS, DeFazio, A, Doherty, JA, Fasching, PA, Garcia, MJ, Goode, EL, Goodman, MT, Gronwald, J, Huntsman, DG, Karlan, BY, Kommoss, S, Modugno, F, Schildkraut, JM, Sinn, H-P, Staebler, A, Kelemen, LE, Ford, CE, Menon, U, Pharoah, PDP, Koebel, M, Ramus, SJ, Bowtell, D, Brand, A, Harnett, P, Weir, A, Kang, E-Y, Meagher, NS, Nelson, GS, Ghatage, P, Lee, C-H, Riggan, MJ, Gentry-Maharaj, A, Ryan, A, Singh, N, Widschwendter, M, Alsop, J, Anglesio, MS, Beckmann, MW, Berger, J, Bisinotto, C, Boros, J, Brand, AH, Brenton, JD, Brooks-Wilson, A, Carney, ME, Cunningham, JM, Cushing-Haugen, KL, Cybulski, C, Elishaev, E, Erber, R, Fereday, S, Fischer, A, Paz-Ares, L, Gayarre, J, Gilks, BC, Grube, M, Harnett, PR, Harris, HR, Hartmann, A, Hein, A, Hendley, J, Hernandez, BY, Heublein, S, Huang, Y, Huzarski, T, Jakubowska, A, Jimenez-Linan, M, Kennedy, CJ, Kommoss, FKF, Koziak, JM, Kraemer, B, Le, ND, Lesnock, J, Lester, J, Lubinski, J, Menkiszak, J, Ney, B, Olawaiye, A, Orsulic, S, Osorio, A, Robles-Diaz, L, Ruebner, M, Shah, M, Sharma, R, Shvetsov, YB, Steed, H, Talhouk, A, Taylor, SE, Traficante, N, Vierkant, RA, Wang, C, Wilkens, LR, Winham, SJ, Benitez, J, Berchuck, A, Bowtell, DD, Candido dos Reis, FJ, Cook, LS, DeFazio, A, Doherty, JA, Fasching, PA, Garcia, MJ, Goode, EL, Goodman, MT, Gronwald, J, Huntsman, DG, Karlan, BY, Kommoss, S, Modugno, F, Schildkraut, JM, Sinn, H-P, Staebler, A, Kelemen, LE, Ford, CE, Menon, U, Pharoah, PDP, Koebel, M, Ramus, SJ, Bowtell, D, Brand, A, and Harnett, P
Abstract: BACKGROUND: Recently, we showed a >60% difference in 5-year survival for patients with tubo-ovarian high-grade serous carcinoma (HGSC) when stratified by a 101-gene mRNA expression prognostic signature. Given the varied patient outcomes, this study aimed to translate prognostic mRNA markers into protein expression assays by immunohistochemistry and validate their survival association in HGSC. METHODS: Two prognostic genes, FOXJ1 and GMNN, were selected based on high-quality antibodies, correlation with protein expression and variation in immunohistochemical scores in a preliminary cohort (n = 134 and n = 80, respectively). Six thousand four hundred and thirty-four (FOXJ1) and 5470 (GMNN) formalin-fixed, paraffin-embedded ovarian neoplasms (4634 and 4185 HGSC, respectively) represented on tissue microarrays from the Ovarian Tumor Tissue Analysis consortium underwent immunohistochemical staining and scoring, then univariate and multivariate survival analysis. RESULTS: Consistent with mRNA, FOXJ1 protein expression exhibited a linear, increasing association with improved overall survival in HGSC patients. Women with >50% expression had the most favourable outcomes (HR = 0.78, 95% CI 0.67-0.91, p < 0.0001). GMNN protein expression was not significantly associated with overall HSGC patient survival. However, HGSCs with >35% GMNN expression showed a trend for better outcomes, though this was not significant. CONCLUSION: We provide foundational evidence for the prognostic value of FOXJ1 in HGSC, validating the prior mRNA-based prognostic association by immunohistochemistry.
Published: 2023

16. p53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study

Author: Kobel, M, Kang, E-Y, Weir, A, Rambau, PF, Lee, C-H, Nelson, GS, Ghatage, P, Meagher, NS, Riggan, MJ, Alsop, J, Anglesio, MS, Beckmann, MW, Bisinotto, C, Boisen, M, Boros, J, Brand, AH, Brooks-Wilson, A, Carney, ME, Coulson, P, Courtney-Brooks, M, Cushing-Haugen, KL, Cybulski, C, Deen, S, El-Bahrawy, MA, Elishaev, E, Erber, R, Fereday, S, Fischer, A, Gayther, SA, Barquin-Garcia, A, Gentry-Maharaj, A, Gilks, CB, Gronwald, H, Grube, M, Harnett, PR, Harris, HR, Hartkopf, AD, Hartmann, A, Hein, A, Hendley, J, Hernandez, BY, Huang, Y, Jakubowska, A, Jimenez-Linan, M, Jones, ME, Kennedy, CJ, Kluz, T, Koziak, JM, Lesnock, J, Lester, J, Lubinski, J, Longacre, TA, Lycke, M, Mateoiu, C, McCauley, BM, McGuire, V, Ney, B, Olawaiye, A, Orsulic, S, Osorio, A, Paz-Ares, L, Ramon Y Cajal, T, Rothstein, JH, Ruebner, M, Schoemaker, MJ, Shah, M, Sharma, R, Sherman, ME, Shvetsov, YB, Singh, N, Steed, H, Storr, SJ, Talhouk, A, Traficante, N, Wang, C, Whittemore, AS, Widschwendter, M, Wilkens, LR, Winham, SJ, Benitez, J, Berchuck, A, Bowtell, DD, Candido dos Reis, FJ, Campbell, I, Cook, LS, DeFazio, A, Doherty, JA, Fasching, PA, Fortner, RT, Garcia, MJ, Goodman, MT, Goode, EL, Gronwald, J, Huntsman, DG, Karlan, BY, Kelemen, LE, Kommoss, S, Le, ND, Martin, SG, Menon, U, Modugno, F, Pharoah, PDP, Schildkraut, JM, Sieh, W, Staebler, A, Sundfeldt, K, Swerdlow, AJ, Ramus, SJ, Brenton, JD, Kobel, M, Kang, E-Y, Weir, A, Rambau, PF, Lee, C-H, Nelson, GS, Ghatage, P, Meagher, NS, Riggan, MJ, Alsop, J, Anglesio, MS, Beckmann, MW, Bisinotto, C, Boisen, M, Boros, J, Brand, AH, Brooks-Wilson, A, Carney, ME, Coulson, P, Courtney-Brooks, M, Cushing-Haugen, KL, Cybulski, C, Deen, S, El-Bahrawy, MA, Elishaev, E, Erber, R, Fereday, S, Fischer, A, Gayther, SA, Barquin-Garcia, A, Gentry-Maharaj, A, Gilks, CB, Gronwald, H, Grube, M, Harnett, PR, Harris, HR, Hartkopf, AD, Hartmann, A, Hein, A, Hendley, J, Hernandez, BY, Huang, Y, Jakubowska, A, Jimenez-Linan, M, Jones, ME, Kennedy, CJ, Kluz, T, Koziak, JM, Lesnock, J, Lester, J, Lubinski, J, Longacre, TA, Lycke, M, Mateoiu, C, McCauley, BM, McGuire, V, Ney, B, Olawaiye, A, Orsulic, S, Osorio, A, Paz-Ares, L, Ramon Y Cajal, T, Rothstein, JH, Ruebner, M, Schoemaker, MJ, Shah, M, Sharma, R, Sherman, ME, Shvetsov, YB, Singh, N, Steed, H, Storr, SJ, Talhouk, A, Traficante, N, Wang, C, Whittemore, AS, Widschwendter, M, Wilkens, LR, Winham, SJ, Benitez, J, Berchuck, A, Bowtell, DD, Candido dos Reis, FJ, Campbell, I, Cook, LS, DeFazio, A, Doherty, JA, Fasching, PA, Fortner, RT, Garcia, MJ, Goodman, MT, Goode, EL, Gronwald, J, Huntsman, DG, Karlan, BY, Kelemen, LE, Kommoss, S, Le, ND, Martin, SG, Menon, U, Modugno, F, Pharoah, PDP, Schildkraut, JM, Sieh, W, Staebler, A, Sundfeldt, K, Swerdlow, AJ, Ramus, SJ, and Brenton, JD
Abstract: Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36-3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11-2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.
Published: 2023

17. Tamoxifen and the risk of breast cancer in women with a BRCA1 or BRCA2 mutation

Author: Kotsopoulos, J, Gronwald, J, Huzarski, T, Aeilts, A, Randall Armel, S, Karlan, B, Singer, C, Eisen, A, Tung, N, Olopade, O, Bordeleau, L, Eng, C, Foulkes, W, Neuhausen, S, Cullinane, C, Pal, T, Fruscio, R, Lubinski, J, Metcalfe, K, Sun, P, Narod, S, Kotsopoulos, Joanne, Gronwald, Jacek, Huzarski, Tomasz, Aeilts, Amber, Randall Armel, Susan, Karlan, Beth, Singer, Christian F, Eisen, Andrea, Tung, Nadine, Olopade, Olufunmilayo, Bordeleau, Louise, Eng, Charis, Foulkes, William D, Neuhausen, Susan L, Cullinane, Carey A, Pal, Tuya, Fruscio, Robert, Lubinski, Jan, Metcalfe, Kelly, Sun, Ping, Narod, Steven A, Kotsopoulos, J, Gronwald, J, Huzarski, T, Aeilts, A, Randall Armel, S, Karlan, B, Singer, C, Eisen, A, Tung, N, Olopade, O, Bordeleau, L, Eng, C, Foulkes, W, Neuhausen, S, Cullinane, C, Pal, T, Fruscio, R, Lubinski, J, Metcalfe, K, Sun, P, Narod, S, Kotsopoulos, Joanne, Gronwald, Jacek, Huzarski, Tomasz, Aeilts, Amber, Randall Armel, Susan, Karlan, Beth, Singer, Christian F, Eisen, Andrea, Tung, Nadine, Olopade, Olufunmilayo, Bordeleau, Louise, Eng, Charis, Foulkes, William D, Neuhausen, Susan L, Cullinane, Carey A, Pal, Tuya, Fruscio, Robert, Lubinski, Jan, Metcalfe, Kelly, Sun, Ping, and Narod, Steven A
Abstract: Purpose: Chemoprevention with a selective estrogen receptor modulator (tamoxifen or raloxifene) is a non-surgical option offered to high-risk women to reduce the risk of breast cancer. The evidence for tamoxifen benefit is based on trials conducted among predominantly postmenopausal women from the general population and on studies of contralateral breast cancer in women with a pathogenic variant (mutation hereafter) in BRCA1 or BRCA2. Tamoxifen has not been assessed as a primary prevention agent in women with an inherited BRCA mutation. Methods: We conducted a prospective analysis of tamoxifen chemoprevention and the risk of breast cancer in women with a BRCA1 or BRCA2 mutation. Data on tamoxifen (and raloxifene) use was collected by questionnaire and updated biennially. Information on incident cancers was collected by self-report and was confirmed by medical record review. In a matched analysis, we estimated the hazard ratio (HR) and 95% confidence intervals (CI) for developing a first primary breast cancer associated with tamoxifen or raloxifene use, using Cox proportional hazards analysis. Results: There were 4578 unaffected women in the cohort, of whom 137 reported tamoxifen use (3%), 83 reported raloxifene use (2%) and 12 used both drugs (0.3%). Women who used tamoxifen or raloxifene were matched 1:3 with women who used neither drug on year of birth, country of residence, year of study entry and gene (BRCA1 or BRCA2). We generated 202 matched pairs. After a mean follow-up of 6.8 years, there were 22 incident breast cancers diagnosed among tamoxifen/raloxifene users (10.9% of users) and 71 cases diagnosed among non-users (14.3% of non-users; HR = 0.64; 95% CI 0.40–1.03; P = 0.07). Conclusion: Chemoprevention may be an effective risk-reduction option for BRCA mutation carriers, but further studies with longer follow-up are necessary.
Published: 2023

18. Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants.

Author: Wang, A, Shen, J, Rodriguez, AA, Saunders, EJ, Chen, F, Janivara, R, Darst, BF, Sheng, X, Xu, Y, Chou, AJ, Benlloch, S, Dadaev, T, Brook, MN, Plym, A, Sahimi, A, Hoffman, TJ, Takahashi, A, Matsuda, K, Momozawa, Y, Fujita, M, Laisk, T, Figuerêdo, J, Muir, K, Ito, S, Liu, X, Biobank Japan Project, Uchio, Y, Kubo, M, Kamatani, Y, Lophatananon, A, Wan, P, Andrews, C, Lori, A, Choudhury, PP, Schleutker, J, Tammela, TLJ, Sipeky, C, Auvinen, A, Giles, GG, Southey, MC, MacInnis, RJ, Cybulski, C, Wokolorczyk, D, Lubinski, J, Rentsch, CT, Cho, K, Mcmahon, BH, Neal, DE, Donovan, JL, Hamdy, FC, Martin, RM, Nordestgaard, BG, Nielsen, SF, Weischer, M, Bojesen, SE, Røder, A, Stroomberg, HV, Batra, J, Chambers, S, Horvath, L, Clements, JA, Tilly, W, Risbridger, GP, Gronberg, H, Aly, M, Szulkin, R, Eklund, M, Nordstrom, T, Pashayan, N, Dunning, AM, Ghoussaini, M, Travis, RC, Key, TJ, Riboli, E, Park, JY, Sellers, TA, Lin, H-Y, Albanes, D, Weinstein, S, Cook, MB, Mucci, LA, Giovannucci, E, Lindstrom, S, Kraft, P, Hunter, DJ, Penney, KL, Turman, C, Tangen, CM, Goodman, PJ, Thompson, IM, Hamilton, RJ, Fleshner, NE, Finelli, A, Parent, M-É, Stanford, JL, Ostrander, EA, Koutros, S, Beane Freeman, LE, Stampfer, M, Wolk, A, Håkansson, N, Andriole, GL, Hoover, RN, Machiela, MJ, Sørensen, KD, Borre, M, Blot, WJ, Zheng, W, Yeboah, ED, Mensah, JE, Lu, Y-J, Zhang, H-W, Feng, N, Mao, X, Wu, Y, Zhao, S-C, Sun, Z, Thibodeau, SN, McDonnell, SK, Schaid, DJ, West, CML, Barnett, G, Maier, C, Schnoeller, T, Luedeke, M, Kibel, AS, Drake, BF, Cussenot, O, Cancel-Tassin, G, Menegaux, F, Truong, T, Koudou, YA, John, EM, Grindedal, EM, Maehle, L, Khaw, K-T, Ingles, SA, Stern, MC, Vega, A, Gómez-Caamaño, A, Fachal, L, Rosenstein, BS, Kerns, SL, Ostrer, H, Teixeira, MR, Paulo, P, Brandão, A, Watya, S, Lubwama, A, Bensen, JT, Butler, EN, Mohler, JL, Taylor, JA, Kogevinas, M, Dierssen-Sotos, T, Castaño-Vinyals, G, Cannon-Albright, L, Teerlink, CC, Huff, CD, Pilie, P, Yu, Y, Bohlender, RJ, Gu, J, Strom, SS, Multigner, L, Blanchet, P, Brureau, L, Kaneva, R, Slavov, C, Mitev, V, Leach, RJ, Brenner, H, Chen, X, Holleczek, B, Schöttker, B, Klein, EA, Hsing, AW, Kittles, RA, Murphy, AB, Logothetis, CJ, Kim, J, Neuhausen, SL, Steele, L, Ding, YC, Isaacs, WB, Nemesure, B, Hennis, AJM, Carpten, J, Pandha, H, Michael, A, De Ruyck, K, De Meerleer, G, Ost, P, Xu, J, Razack, A, Lim, J, Teo, S-H, Newcomb, LF, Lin, DW, Fowke, JH, Neslund-Dudas, CM, Rybicki, BA, Gamulin, M, Lessel, D, Kulis, T, Usmani, N, Abraham, A, Singhal, S, Parliament, M, Claessens, F, Joniau, S, Van den Broeck, T, Gago-Dominguez, M, Castelao, JE, Martinez, ME, Larkin, S, Townsend, PA, Aukim-Hastie, C, Bush, WS, Aldrich, MC, Crawford, DC, Srivastava, S, Cullen, J, Petrovics, G, Casey, G, Wang, Y, Tettey, Y, Lachance, J, Tang, W, Biritwum, RB, Adjei, AA, Tay, E, Truelove, A, Niwa, S, Yamoah, K, Govindasami, K, Chokkalingam, AP, Keaton, JM, Hellwege, JN, Clark, PE, Jalloh, M, Gueye, SM, Niang, L, Ogunbiyi, O, Shittu, O, Amodu, O, Adebiyi, AO, Aisuodionoe-Shadrach, OI, Ajibola, HO, Jamda, MA, Oluwole, OP, Nwegbu, M, Adusei, B, Mante, S, Darkwa-Abrahams, A, Diop, H, Gundell, SM, Roobol, MJ, Jenster, G, van Schaik, RHN, Hu, JJ, Sanderson, M, Kachuri, L, Varma, R, McKean-Cowdin, R, Torres, M, Preuss, MH, Loos, RJF, Zawistowski, M, Zöllner, S, Lu, Z, Van Den Eeden, SK, Easton, DF, Ambs, S, Edwards, TL, Mägi, R, Rebbeck, TR, Fritsche, L, Chanock, SJ, Berndt, SI, Wiklund, F, Nakagawa, H, Witte, JS, Gaziano, JM, Justice, AC, Mancuso, N, Terao, C, Eeles, RA, Kote-Jarai, Z, Madduri, RK, Conti, DV, Haiman, CA, Wang, A, Shen, J, Rodriguez, AA, Saunders, EJ, Chen, F, Janivara, R, Darst, BF, Sheng, X, Xu, Y, Chou, AJ, Benlloch, S, Dadaev, T, Brook, MN, Plym, A, Sahimi, A, Hoffman, TJ, Takahashi, A, Matsuda, K, Momozawa, Y, Fujita, M, Laisk, T, Figuerêdo, J, Muir, K, Ito, S, Liu, X, Biobank Japan Project, Uchio, Y, Kubo, M, Kamatani, Y, Lophatananon, A, Wan, P, Andrews, C, Lori, A, Choudhury, PP, Schleutker, J, Tammela, TLJ, Sipeky, C, Auvinen, A, Giles, GG, Southey, MC, MacInnis, RJ, Cybulski, C, Wokolorczyk, D, Lubinski, J, Rentsch, CT, Cho, K, Mcmahon, BH, Neal, DE, Donovan, JL, Hamdy, FC, Martin, RM, Nordestgaard, BG, Nielsen, SF, Weischer, M, Bojesen, SE, Røder, A, Stroomberg, HV, Batra, J, Chambers, S, Horvath, L, Clements, JA, Tilly, W, Risbridger, GP, Gronberg, H, Aly, M, Szulkin, R, Eklund, M, Nordstrom, T, Pashayan, N, Dunning, AM, Ghoussaini, M, Travis, RC, Key, TJ, Riboli, E, Park, JY, Sellers, TA, Lin, H-Y, Albanes, D, Weinstein, S, Cook, MB, Mucci, LA, Giovannucci, E, Lindstrom, S, Kraft, P, Hunter, DJ, Penney, KL, Turman, C, Tangen, CM, Goodman, PJ, Thompson, IM, Hamilton, RJ, Fleshner, NE, Finelli, A, Parent, M-É, Stanford, JL, Ostrander, EA, Koutros, S, Beane Freeman, LE, Stampfer, M, Wolk, A, Håkansson, N, Andriole, GL, Hoover, RN, Machiela, MJ, Sørensen, KD, Borre, M, Blot, WJ, Zheng, W, Yeboah, ED, Mensah, JE, Lu, Y-J, Zhang, H-W, Feng, N, Mao, X, Wu, Y, Zhao, S-C, Sun, Z, Thibodeau, SN, McDonnell, SK, Schaid, DJ, West, CML, Barnett, G, Maier, C, Schnoeller, T, Luedeke, M, Kibel, AS, Drake, BF, Cussenot, O, Cancel-Tassin, G, Menegaux, F, Truong, T, Koudou, YA, John, EM, Grindedal, EM, Maehle, L, Khaw, K-T, Ingles, SA, Stern, MC, Vega, A, Gómez-Caamaño, A, Fachal, L, Rosenstein, BS, Kerns, SL, Ostrer, H, Teixeira, MR, Paulo, P, Brandão, A, Watya, S, Lubwama, A, Bensen, JT, Butler, EN, Mohler, JL, Taylor, JA, Kogevinas, M, Dierssen-Sotos, T, Castaño-Vinyals, G, Cannon-Albright, L, Teerlink, CC, Huff, CD, Pilie, P, Yu, Y, Bohlender, RJ, Gu, J, Strom, SS, Multigner, L, Blanchet, P, Brureau, L, Kaneva, R, Slavov, C, Mitev, V, Leach, RJ, Brenner, H, Chen, X, Holleczek, B, Schöttker, B, Klein, EA, Hsing, AW, Kittles, RA, Murphy, AB, Logothetis, CJ, Kim, J, Neuhausen, SL, Steele, L, Ding, YC, Isaacs, WB, Nemesure, B, Hennis, AJM, Carpten, J, Pandha, H, Michael, A, De Ruyck, K, De Meerleer, G, Ost, P, Xu, J, Razack, A, Lim, J, Teo, S-H, Newcomb, LF, Lin, DW, Fowke, JH, Neslund-Dudas, CM, Rybicki, BA, Gamulin, M, Lessel, D, Kulis, T, Usmani, N, Abraham, A, Singhal, S, Parliament, M, Claessens, F, Joniau, S, Van den Broeck, T, Gago-Dominguez, M, Castelao, JE, Martinez, ME, Larkin, S, Townsend, PA, Aukim-Hastie, C, Bush, WS, Aldrich, MC, Crawford, DC, Srivastava, S, Cullen, J, Petrovics, G, Casey, G, Wang, Y, Tettey, Y, Lachance, J, Tang, W, Biritwum, RB, Adjei, AA, Tay, E, Truelove, A, Niwa, S, Yamoah, K, Govindasami, K, Chokkalingam, AP, Keaton, JM, Hellwege, JN, Clark, PE, Jalloh, M, Gueye, SM, Niang, L, Ogunbiyi, O, Shittu, O, Amodu, O, Adebiyi, AO, Aisuodionoe-Shadrach, OI, Ajibola, HO, Jamda, MA, Oluwole, OP, Nwegbu, M, Adusei, B, Mante, S, Darkwa-Abrahams, A, Diop, H, Gundell, SM, Roobol, MJ, Jenster, G, van Schaik, RHN, Hu, JJ, Sanderson, M, Kachuri, L, Varma, R, McKean-Cowdin, R, Torres, M, Preuss, MH, Loos, RJF, Zawistowski, M, Zöllner, S, Lu, Z, Van Den Eeden, SK, Easton, DF, Ambs, S, Edwards, TL, Mägi, R, Rebbeck, TR, Fritsche, L, Chanock, SJ, Berndt, SI, Wiklund, F, Nakagawa, H, Witte, JS, Gaziano, JM, Justice, AC, Mancuso, N, Terao, C, Eeles, RA, Kote-Jarai, Z, Madduri, RK, Conti, DV, and Haiman, CA
Abstract: The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.
Published: 2023

19. Dissecting the genetic heterogeneity of gastric cancer

Author: Hess, T., Maj, C., Gehlen, J., Borisov, O., Haas, S. L., Gockel, I., Vieth, M., Piessen, G., Alakus, H., Vashist, Y., Pereira, C., Knapp, M., Schuller, V., Quaas, A., Grabsch, H. I., Trautmann, J., Malecka-Wojciesko, E., Mokrowiecka, A., Speller, J., Mayr, A., Schroder, J., Hillmer, A. M., Heider, D., Lordick, F., Perez-Aisa, A., Campo, R., Espinel, J., Geijo, F., Thomson, C., Bujanda, L., Sopena, F., Lanas, A., Pellise, M., Pauligk, C., Goetze, T. O., Zelck, C., Reingruber, J., Hassanin, E., Elbe, P., Alsabeah, S., Lindblad, M., Nilsson, M., Kreuser, N., Thieme, R., Tavano, F., Pastorino, Roberta, Arzani, D., Persiani, Roberto, Jung, J. -O., Nienhuser, H., Ott, K., Schumann, R. R., Kumpf, O., Burock, S., Arndt, V., Jakubowska, A., Lawniczak, M., Moreno, V., Martin, V., Kogevinas, M., Pollan, M., Dabrowska, J., Salas, A., Cussenot, O., Boland-Auge, A., Daian, D., Deleuze, J. -F., Salvi, E., Teder-Laving, M., Tomasello, G., Ratti, M., Senti, C., De Re, V., Steffan, A., Holscher, A. H., Messerle, K., Bruns, C. J., Sivins, A., Bogdanova, I., Skieceviciene, J., Arstikyte, J., Moehler, M., Lang, H., Grimminger, P. P., Kruschewski, M., Vassos, N., Schildberg, C., Lingohr, P., Ridwelski, K., Lippert, H., Fricker, N., Krawitz, P., Hoffmann, Christian Pieter, Nothen, M. M., Veits, L., Izbicki, J. R., Mostowska, A., Martinon-Torres, F., Cusi, D., Adolfsson, R., Cancel-Tassin, G., Hoblinger, A., Rodermann, E., Ludwig, M., Keller, G., Metspalu, A., Brenner, H., Heller, J., Neef, M., Schepke, M., Dumoulin, F. L., Hamann, L., Cannizzaro, Rino, Ghidini, Maria Candida, Plassmann, D., Geppert, M., Malfertheiner, P., Gehlen, O., Skoczylas, T., Majewski, M., Lubinski, J., Palmieri, O., Boccia, Stefania, Latiano, A., Aragones, N., Schmidt, T., Dinis-Ribeiro, M., Medeiros, R., Al-Batran, S. -E., Leja, M., Kupcinskas, J., Garcia-Gonzalez, M. A., Venerito, M., Schumacher, J., Pastorino R. (ORCID:0000-0001-5013-0733), Persiani R. (ORCID:0000-0002-1537-5097), Hoffmann P., Cannizzaro R., Ghidini M., Boccia S. (ORCID:0000-0002-1864-749X), Hess, T., Maj, C., Gehlen, J., Borisov, O., Haas, S. L., Gockel, I., Vieth, M., Piessen, G., Alakus, H., Vashist, Y., Pereira, C., Knapp, M., Schuller, V., Quaas, A., Grabsch, H. I., Trautmann, J., Malecka-Wojciesko, E., Mokrowiecka, A., Speller, J., Mayr, A., Schroder, J., Hillmer, A. M., Heider, D., Lordick, F., Perez-Aisa, A., Campo, R., Espinel, J., Geijo, F., Thomson, C., Bujanda, L., Sopena, F., Lanas, A., Pellise, M., Pauligk, C., Goetze, T. O., Zelck, C., Reingruber, J., Hassanin, E., Elbe, P., Alsabeah, S., Lindblad, M., Nilsson, M., Kreuser, N., Thieme, R., Tavano, F., Pastorino, Roberta, Arzani, D., Persiani, Roberto, Jung, J. -O., Nienhuser, H., Ott, K., Schumann, R. R., Kumpf, O., Burock, S., Arndt, V., Jakubowska, A., Lawniczak, M., Moreno, V., Martin, V., Kogevinas, M., Pollan, M., Dabrowska, J., Salas, A., Cussenot, O., Boland-Auge, A., Daian, D., Deleuze, J. -F., Salvi, E., Teder-Laving, M., Tomasello, G., Ratti, M., Senti, C., De Re, V., Steffan, A., Holscher, A. H., Messerle, K., Bruns, C. J., Sivins, A., Bogdanova, I., Skieceviciene, J., Arstikyte, J., Moehler, M., Lang, H., Grimminger, P. P., Kruschewski, M., Vassos, N., Schildberg, C., Lingohr, P., Ridwelski, K., Lippert, H., Fricker, N., Krawitz, P., Hoffmann, Christian Pieter, Nothen, M. M., Veits, L., Izbicki, J. R., Mostowska, A., Martinon-Torres, F., Cusi, D., Adolfsson, R., Cancel-Tassin, G., Hoblinger, A., Rodermann, E., Ludwig, M., Keller, G., Metspalu, A., Brenner, H., Heller, J., Neef, M., Schepke, M., Dumoulin, F. L., Hamann, L., Cannizzaro, Rino, Ghidini, Maria Candida, Plassmann, D., Geppert, M., Malfertheiner, P., Gehlen, O., Skoczylas, T., Majewski, M., Lubinski, J., Palmieri, O., Boccia, Stefania, Latiano, A., Aragones, N., Schmidt, T., Dinis-Ribeiro, M., Medeiros, R., Al-Batran, S. -E., Leja, M., Kupcinskas, J., Garcia-Gonzalez, M. A., Venerito, M., Schumacher, J., Pastorino R. (ORCID:0000-0001-5013-0733), Persiani R. (ORCID:0000-0002-1537-5097), Hoffmann P., Cannizzaro R., Ghidini M., and Boccia S. (ORCID:0000-0002-1864-749X)
Abstract: Background: Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture. Methods: We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO. Findings: Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level. Interpretation: Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular me
Published: 2023

20. 41P HLA genotypes modify the age-related penetrance of BRCA1 pathogenic variants in breast cancer patients

Author: Kuligina, E.S., Romanko, A.A., Martianov, A.S., Gorgul, J.A., Kashyap, A., Cybulski, C., Lubinski, J., Trofimov, D.S., Jankevic, T., and Imyanitov, E.
Published: 2023
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21. Serum selenium levels predict survival after breast cancer

Author: Lubinski, J., Marciniak, W., Muszynska, M., Huzarski, T., Gronwald, J., Cybulski, C., Jakubowska, A., Debniak, T., Falco, M., Kladny, J., Kotsopoulos, J., Sun, P., and Narod, S. A.
Published: 2017
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22. PredictCBC-2.0: a contralateral breast cancer risk prediction model developed and validated in similar to 200,000 patients (vol 24, 69, 2022)

Author: Giardiello, D., Hooning, M.J., Hauptmann, M., Keeman, R., Heemskerk-Gerritsen, B.A.M., Becher, H., Blomqvist, C., Bojesen, S.E., Bolla, M.K., Camp, N.J., Czene, K., Devilee, P., Eccles, D.M., Fasching, P.A., Figueroa, J.D., Flyger, H., Garcia-Closas, M., Haiman, C.A., Hamann, U., Hopper, J.L., Jakubowska, A., Leeuwen, F.E., Lindblom, A., Lubinski, J., Margolin, S., Martinez, M.E., Nevanlinna, H., Nevelsteen, I., Pelders, S., Pharoah, P.D.P., Siesling, S., Southey, M.C., Hout, A.H. van der, Hest, L.P. van, Chang-Claude, J., Hall, P., Easton, D.F., Steyerberg, E.W., and Schmidt, M.K.
Published: 2022

23. PredictCBC-2.0: a contralateral breast cancer risk prediction model developed and validated in ~ 200,000 patients

Author: Giardiello, D., Hooning, M.J., Hauptmann, M., Keeman, R., Heemskerk-Gerritsen, B.A.M., Becher, H., Blomqvist, C., Bojesen, S.E., Bolla, M.K., Camp, N.J., Czene, K., Devilee, P., Eccles, D.M., Fasching, P.A., Figueroa, J.D., Flyger, H., Garcia-Closas, M., Haiman, C.A., Hamann, U., Hopper, J.L., Jakubowska, A., Leeuwen, F.E., Lindblom, A., Lubinski, J., Margolin, S., Martinez, M.E., Nevanlinna, H., Nevelsteen, I., Pelders, S., Pharoah, P.D.P., Siesling, S., Southey, M.C., Hout, A.H. van der, Hest, L.P. van, Chang-Claude, J., Hall, P., Easton, D.F., Steyerberg, E.W., Schmidt, M.K., Medical Oncology, Public Health, Human genetics, CCA - Cancer Treatment and quality of life, Apollo - University of Cambridge Repository, Faculteit Medische Wetenschappen/UMCG, Medicum, HUS Comprehensive Cancer Center, Department of Oncology, Clinicum, University of Helsinki, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, and García-Closas, Montserrat [0000-0003-1033-2650]
Subjects: Clinical Decision-making, 3122 Cancers, Oncology and Carcinogenesis, Breast Neoplasms, BRCA1/2 germline mutation, Polygenic risk score, SDG 3 - Good Health and Well-being, Breast Cancer Genetic Predisposition, Risk Factors, Breast Cancer, Genetics, Humans, ddc:610, Oncology & Carcinogenesis, Contralateral Preventive Mastectomy, BCAC, Breast cancer genetic predisposition, Mastectomy, Germ-Line Mutation, Cancer, Polygenic Risk Score, Prevention, Research, Brca1/2 Germline Mutation, Risk prediction, Contralateral preventive mastectomy, Prophylactic Mastectomy, Prediction Performance, Contralateral breast cancer, Breast Cancer Association Consortium, Prediction performance, Contralateral Breast Cancer, Female, Risk Prediction, Bcac, Clinical decision-making
Abstract: Background Prediction of contralateral breast cancer (CBC) risk is challenging due to moderate performances of the known risk factors. We aimed to improve our previous risk prediction model (PredictCBC) by updated follow-up and including additional risk factors. Methods We included data from 207,510 invasive breast cancer patients participating in 23 studies. In total, 8225 CBC events occurred over a median follow-up of 10.2 years. In addition to the previously included risk factors, PredictCBC-2.0 included CHEK2 c.1100delC, a 313 variant polygenic risk score (PRS-313), body mass index (BMI), and parity. Fine and Gray regression was used to fit the model. Calibration and a time-dependent area under the curve (AUC) at 5 and 10 years were assessed to determine the performance of the models. Decision curve analysis was performed to evaluate the net benefit of PredictCBC-2.0 and previous PredictCBC models. Results The discrimination of PredictCBC-2.0 at 10 years was higher than PredictCBC with an AUC of 0.65 (95% prediction intervals (PI) 0.56–0.74) versus 0.63 (95%PI 0.54–0.71). PredictCBC-2.0 was well calibrated with an observed/expected ratio at 10 years of 0.92 (95%PI 0.34–2.54). Decision curve analysis for contralateral preventive mastectomy (CPM) showed the potential clinical utility of PredictCBC-2.0 between thresholds of 4 and 12% 10-year CBC risk for BRCA1/2 mutation carriers and non-carriers. Conclusions Additional genetic information beyond BRCA1/2 germline mutations improved CBC risk prediction and might help tailor clinical decision-making toward CPM or alternative preventive strategies. Identifying patients who benefit from CPM, especially in the general breast cancer population, remains challenging.
Published: 2022
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24. Activity of trabectedin in germline BRCA1/2-mutated metastatic breast cancer: results of an international first-in-class phase II study

Author: Delaloge, S., Wolp-Diniz, R., Byrski, T., Blum, J.L., Gonçalves, A., Campone, M., Lardelli, P., Kahatt, C., Nieto, A., Cullell-Young, M., and Lubinski, J.
Published: 2014
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25. Breast cancer risk after age 60 among BRCA1 and BRCA2 mutation carriers

Author: Stjepanovic, N, Lubinski, J, Moller, P, Randall Armel, S, Foulkes, W, Tung, N, Neuhausen, S, Kotsopoulos, J, Sun, P, Sun, S, Eisen, A, Narod, S, Senter, L, Couch, C, Fruscio, R, Weitzel, J, Olopade, O, Singer, C, Pal, T, Huzarski, T, Cybulski, C, Sweet, K, Zakalik, D, Wood, M, Mckinnon, W, Elser, C, Wiesner, G, Friedman, E, Meschino, W, Snyder, C, Metcalfe, K, Poll, A, Warner, E, Kim, R, Demsky, R, Ainsworth, P, Steele, L, Saal, H, Serfas, K, Panchal, S, Cullinane, C, Reilly, R, Blum, J, Kwong, A, Rayson, D, Cajal, T, Dungan, J, Yerushalmi, R, Ginsburg, O, Schraeder, I, Cohen, S, Lemirelemire, E, Zovato, S, Rastelli, A, Gronwald, J, Mccuaig, J, Karlan, B, Bordeleau, L, Stjepanovic N., Lubinski J., Moller P., Randall Armel S., Foulkes W. D., Tung N., Neuhausen S. L., Kotsopoulos J., Sun P., Sun S., Eisen A., Narod S. A., Senter L., Couch C. E. F., Fruscio R., Weitzel J. N., Olopade O., Singer C. F., Pal T., Huzarski T., Cybulski C., Sweet K., Zakalik D., Wood M., McKinnon W., Elser C., Wiesner G., Friedman E., Meschino W., Snyder C., Metcalfe K., Poll A., Warner E., Kim R., Demsky R., Ainsworth P., Steele L., Saal H., Serfas K., Panchal S., Cullinane C. A., Reilly R. E., Blum J. L., Kwong A., Rayson D., Cajal T. R., Dungan J., Yerushalmi R., Ginsburg O., Schraeder I., Cohen S., LemireLemire E., Zovato S., Rastelli A., Gronwald J., McCuaig J., Karlan B., Bordeleau L., Stjepanovic, N, Lubinski, J, Moller, P, Randall Armel, S, Foulkes, W, Tung, N, Neuhausen, S, Kotsopoulos, J, Sun, P, Sun, S, Eisen, A, Narod, S, Senter, L, Couch, C, Fruscio, R, Weitzel, J, Olopade, O, Singer, C, Pal, T, Huzarski, T, Cybulski, C, Sweet, K, Zakalik, D, Wood, M, Mckinnon, W, Elser, C, Wiesner, G, Friedman, E, Meschino, W, Snyder, C, Metcalfe, K, Poll, A, Warner, E, Kim, R, Demsky, R, Ainsworth, P, Steele, L, Saal, H, Serfas, K, Panchal, S, Cullinane, C, Reilly, R, Blum, J, Kwong, A, Rayson, D, Cajal, T, Dungan, J, Yerushalmi, R, Ginsburg, O, Schraeder, I, Cohen, S, Lemirelemire, E, Zovato, S, Rastelli, A, Gronwald, J, Mccuaig, J, Karlan, B, Bordeleau, L, Stjepanovic N., Lubinski J., Moller P., Randall Armel S., Foulkes W. D., Tung N., Neuhausen S. L., Kotsopoulos J., Sun P., Sun S., Eisen A., Narod S. A., Senter L., Couch C. E. F., Fruscio R., Weitzel J. N., Olopade O., Singer C. F., Pal T., Huzarski T., Cybulski C., Sweet K., Zakalik D., Wood M., McKinnon W., Elser C., Wiesner G., Friedman E., Meschino W., Snyder C., Metcalfe K., Poll A., Warner E., Kim R., Demsky R., Ainsworth P., Steele L., Saal H., Serfas K., Panchal S., Cullinane C. A., Reilly R. E., Blum J. L., Kwong A., Rayson D., Cajal T. R., Dungan J., Yerushalmi R., Ginsburg O., Schraeder I., Cohen S., LemireLemire E., Zovato S., Rastelli A., Gronwald J., McCuaig J., Karlan B., and Bordeleau L.
Abstract: Purpose: It is not known whether the risk of breast cancer among BRCA1 and BRCA2 mutation carriers after age 60 is high enough to justify intensive screening or prophylactic surgery. Thus, we conducted a prospective analysis of breast cancer risk in BRCA1 and BRCA2 mutation carriers from age 60 until age 80. Methods: Subjects had no history of cancer and both breasts intact at age 60 (n = 699). Women were followed until a breast cancer diagnosis, prophylactic bilateral mastectomy or death. We calculated the annual cancer rate and cumulative incidence of breast cancer (invasive and in situ) from age 60 to age 80. We assessed the associations between hormone replacement therapy, family history of breast cancer and bilateral oophorectomy and breast cancer risk. Results: Over a mean follow-up of 7.9 years, 61 invasive and 20 in situ breast cancers were diagnosed in the cohort. The mean annual rate of invasive breast cancer was 1.8% for BRCA1 mutation carriers and 1.7% for BRCA2 mutation carriers. The cumulative risk of invasive breast cancer from age 60 to 80 was 20.1% for women with a BRCA1 mutation and was 17.3% for women with a BRCA2 mutation. Hormone replacement therapy, family history and oophorectomy were not associated with breast cancer risk. Conclusions: Findings from this large prospective study indicate that the risk of developing breast cancer remains high after age 60 in both BRCA1 and BRCA2 mutation carriers. These findings warrant further evaluation of the role of breast cancer screening in older mutation carriers.
Published: 2021

26. Breast cancer risks associated with missense variants in breast cancer susceptibility genes

Author: Dorling, L., Carvalho, S., Allen, J., Parsons, M.T., Fortuno, C., Gonzalez-Neira, A., Heijl, S.M., Adank, M.A., Ahearn, T.U., Andrulis, I.L., Auvinen, P., Becher, H., Beckmann, M.W., Behrens, S., Bermisheva, M., Bogdanova, N.V., Bojesen, S.E., Bolla, M.K., Bremer, M., Briceno, I., Camp, N.J., Campbell, A., Castelao, J.E., Chang-Claude, J., Chanock, S.J., Chenevix-Trench, G., Collee, J.M., Czene, K., Dennis, J., Dork, T., Eriksson, M., Evans, D.G., Fasching, P.A., Figueroa, J., Flyger, H., Gabrielson, M., Gago-Dominguez, M., Garcia-Closas, M., Giles, G.G., Glendon, G., Guenel, P., Gundert, M., Hadjisavvas, A., Hahnen, E., Hall, P., Hamann, U., Harkness, E.F., Hartman, M., Hogervorst, F.B.L., Hollestelle, A., Hoppe, R., Howell, A., Jakubowska, A., Jung, A., Khusnutdinova, E., Kim, S.W., Ko, Y.D., Kristensen, V.N., Lakeman, I.M.M., Li, J.M., Lindblom, A., Loizidou, M.A., Lophatananon, A., Lubinski, J., Luccarini, C., Madsen, M.J., Mannermaa, A., Manoochehri, M., Margolin, S., Mavroudis, D., Milne, R.L., Taib, N.A.M., Muir, K., Nevanlinna, H., Newman, W.G., Oosterwijk, J.C., Park, S.K., Peterlongo, P., Radice, P., Saloustros, E., Sawyer, E.J., Schmutzler, R.K., Shah, M.T., Sim, X., Southey, M.C., Surowy, H., Suvanto, M., Tomlinson, I., Torres, D., Truong, T., Asperen, C.J. van, Waltes, R., Wang, Q., Yang, X.H.R., Pharoah, P.D.P., Schmidt, M.K., Benitez, J., Vroling, B., Dunning, A.M., Teo, S.H., Kvist, A., Hoya, M. de la, Devilee, P., Spurdle, A.B., Vreeswijk, M.P.G., Easton, D.F., NBCS Collaborators, KConFab Investigators, SGBCC Investigators, Clinical Genetics, Medical Oncology, Apollo - University of Cambridge Repository, Dennis, Joe [0000-0003-4591-1214], Pharoah, Paul [0000-0001-8494-732X], Easton, Douglas [0000-0003-2444-3247], Targeted Gynaecologic Oncology (TARGON), Damage and Repair in Cancer Development and Cancer Treatment (DARE), University of Helsinki, Clinicum, Department of Obstetrics and Gynecology, HUS Gynecology and Obstetrics, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Wellcome Trust, WT: 633784, v203477/Z/16/Z, Horizon 2020 Framework Programme, H2020, Cancer Research UK, CRUK: C1287/A16563, The sequencing and analysis for this project was funded by the European Union’s Horizon 2020 Research and Innovation Programme (BRIDGES: grant number 634935) and the Wellcome Trust [grant no: v203477/Z/16/Z]. BCAC co-ordination was additionally funded by the European Union’s Horizon 2020 Research and Innovation Programme (BRIDGES: grant number 634935, BCAST: grant number 633784) and by Cancer Research UK [C1287/A16563]. Study specific funding is given in the Additional Note., and HAL UVSQ, Équipe
Subjects: Mutation, Missense, Breast Neoplasms, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Breast Neoplasms/genetics, Breast Cancer, Genetic Epidemiology, Missense Variants, Risk Prediction, CLASSIFICATION, Breast cancer, Missense variants, SDG 3 - Good Health and Well-being, 3123 Gynaecology and paediatrics, SEQUENCE VARIANTS, Genetics, Humans, Genetic Predisposition to Disease, Genetic epidemiology, ddc:610, skin and connective tissue diseases, Molecular Biology, Genetics (clinical), MUTATIONS, Research, UNKNOWN CLINICAL-SIGNIFICANCE, 1184 Genetics, developmental biology, physiology, FRAMEWORK, BRCA1, Risk prediction, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, SUBSTITUTIONS, Case-Control Studies, Mutation, Molecular Medicine, Female, Missense, PATHOGENICITY
Abstract: Background Protein truncating variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain. Methods We analyzed data on 59,639 breast cancer cases and 53,165 controls from studies participating in the Breast Cancer Association Consortium BRIDGES project. We sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1146 training variants), BRCA1 (644), BRCA2 (1425), CHEK2 (325), and PALB2 (472). We evaluated breast cancer risks according to five in silico prediction-of-deleteriousness algorithms, functional protein domain, and frequency, using logistic regression models and also mixture models in which a subset of variants was assumed to be risk-associated. Results The most predictive in silico algorithms were Helix (BRCA1, BRCA2 and CHEK2) and CADD (ATM). Increased risks appeared restricted to functional protein domains for ATM (FAT and PIK domains) and BRCA1 (RING and BRCT domains). For ATM, BRCA1, and BRCA2, data were compatible with small subsets (approximately 7%, 2%, and 0.6%, respectively) of rare missense variants giving similar risk to those of protein truncating variants in the same gene. For CHEK2, data were more consistent with a large fraction (approximately 60%) of rare missense variants giving a lower risk (OR 1.75, 95% CI (1.47–2.08)) than CHEK2 protein truncating variants. There was little evidence for an association with risk for missense variants in PALB2. The best fitting models were well calibrated in the validation set. Conclusions These results will inform risk prediction models and the selection of candidate variants for functional assays and could contribute to the clinical reporting of gene panel testing for breast cancer susceptibility.
Published: 2022

27. Breast Cancer Risk Genes — Association Analysis in More than 113,000 Women

Author: Dorling, L., Carvalho, S., Allen, J., Gonzalez-Neira, A., Luccarini, C., Wahlstrom, C., Pooley, K.A., Parsons, M.T., Fortuno, C., Wang, Q., Bolla, M.K., Dennis, J., Keeman, R., Alonso, M.R., Alvarez, N., Herraez, B., Fernandez, V., Nunez-Torres, R., Osorio, A., Valcich, J., Li, M., Torngren, T., Harrington, P.A., Baynes, C., Conroy, D.M., Decker, B., Fachal, L., Mavaddat, N., Ahearn, T., Aittomaki, K., Antonenkova, N.N., Arnold, N., Arveux, P., Ausems, M.G.E.M., Auvinen, P., Becher, H., Beckmann, M.W., Behrens, S., Bermisheva, M., Bialkowska, K., Blomqvist, C., Bogdanova, N.V., Bogdanova-Markov, N., Bojesen, S.E., Bonanni, B., Borresen-Dale, A.L., Brauch, H., Bremer, M., Briceno, I., Bruning, T., Burwinkel, B., Cameron, D.A., Camp, N.J., Campbell, A., Carracedo, A., Castelao, J.E., Cessna, M.H., Chanock, S.J., Christiansen, H., Collee, J.M., Cordina-Duverger, E., Cornelissen, S., Czene, K., Dork, T., Ekici, A.B., Engel, C., Eriksson, M., Fasching, P.A., Figueroa, J., Flyger, H., Forsti, A., Gabrielson, M., Gago-Dominguez, M., Georgoulias, V., Gil, F., Giles, G.G., Glendon, G., Garcia, E.B.G., Alnaes, G.I.G., Guenel, P., Hadjisavvas, A., Haeberle, L., Hahnen, E., Hall, P., Hamann, U., Harkness, E.F., Hartikainen, J.M., Hartman, M., He, W., Heemskerk-Gerritsen, B.A.M., Hillemanns, P., Hogervorst, F.B.L., Hollestelle, A., Ho, W.K., Hooning, M.J., Howell, A., Humphreys, K., Idris, F., Jakubowska, A., Jung, A., Kapoor, P.M., Kerin, M.J., Khusnutdinova, E., Kim, S.W., Ko, Y.D., Kosma, V.M., Kristensen, V.N., Kyriacou, K., Lakeman, I.M.M., Lee, J.W., Lee, M.H., Li, J.M., Lindblom, A., W.Y. lo, Loizidou, M.A., Lophatananon, A., Lubinski, J., MacInnis, R.J., Madsen, M.J., Mannermaa, A., Manoochehri, M., Manoukian, S., Margolin, S., Martinez, M.E., Maurer, T., Mavroudis, D., McLean, C., Meindl, A., Mensenkamp, A.R., Michailidou, K., Miller, N., Taib, N.A.M., Muir, K., Mulligan, A.M., Nevanlinna, H., Newman, W.G., Nordestgaard, B.G., Ng, P.S., Oosterwijk, J.C., Park, S.K., Park-Simon, T.W., Perez, J.I.A., Peterlongo, P., Porteous, D.J., Prajzendanc, K., Prokofyeva, D., Radice, P., Rashid, M.U., Rhenius, V., Rookus, M.A., Rudiger, T., Saloustros, E., Sawyer, E.J., Schmutzler, R.K., Schneeweiss, A., Schurmann, P., Shah, M., Sohn, C., Southey, M.C., Surowy, H., Suvanto, M., Thanasitthichai, S., Tomlinson, I., Torres, D., Truong, T., Tzardi, M., Valova, Y., Asperen, C.J. van, Dam, R.M. van, Ouweland, A.M.W. van den, Kolk, L.E. van der, Veen, E.M. van, Wendt, C., Williams, J.A., Yang, X.H.R., Yoon, S.Y., Zamora, M.P., Evans, D.G., Hoya, M. de la, Simard, J., Antoniou, A.C., Borg, A., Andrulis, I.L., Chang-Claude, J., Garcia-Closas, M., Chenevix-Trench, G., Milne, R.L., Pharoah, P.D.P., Schmidt, M.K., Spurdle, A.B., Vreeswijk, M.P.G., Benitez, J., Dunning, A.M., Kvist, A., Teo, S.H., Devilee, P., Easton, D.F., Breast Canc Assoc Consortium, Erasmus MC other, Medical Oncology, Clinical Genetics, Keeman, Renske [0000-0002-5452-9933], Decker, Brennan [0000-0003-4516-7421], Eriksson, Mikael [0000-0001-8135-4270], Martinez, Maria Elena [0000-0002-6728-1834], Surowy, Harald [0000-0002-3595-9188], Pharoah, Paul DP [0000-0001-8494-732X], Apollo - University of Cambridge Repository, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), and Klinische Genetica
Subjects: Adult, Risk, Oncology, medicine.medical_specialty, Adolescent, PALB2, Genetic counseling, Genes, BRCA2, Mutation, Missense, Genes, BRCA1, Estrogen receptor, Breast Neoplasms, 030204 cardiovascular system & hematology, OVARIAN-CANCER, Article, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, Odds Ratio, medicine, Humans, Genetic Predisposition to Disease, 030212 general & internal medicine, skin and connective tissue diseases, CHEK2, Aged, Genetic testing, Genetic association, Aged, 80 and over, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], medicine.diagnostic_test, MUTATIONS, business.industry, Age Factors, Genetic Variation, Sequence Analysis, DNA, General Medicine, Odds ratio, Middle Aged, BRCA1, medicine.disease, 3. Good health, Logistic Models, Female, business
Abstract: BACKGROUNDGenetic testing for breast cancer susceptibility is widely used, but for many genes,evidence of an association with breast cancer is weak, underlying risk estimatesare imprecise, and reliable subtype-specific risk estimates are lacking.METHODSWe used a panel of 34 putative susceptibility genes to perform sequencing onsamples from 60,466 women with breast cancer and 53,461 controls. In separateanalyses for protein-truncating variants and rare missense variants in these genes,we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluatedmissense-variant associations according to domain and classification of pathogenicity.RESULTSProtein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2)were associated with a risk of breast cancer overall with a P value of less than0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D,and TP53) were associated with a risk of breast cancer overall with a P value ofless than 0.05 and a Bayesian false-discovery probability of less than 0.05. Forprotein-truncating variants in 19 of the remaining 25 genes, the upper limit ofthe 95% confidence interval of the odds ratio for breast cancer overall was lessthan 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios werehigher for estrogen receptor (ER)–positive disease than for ER-negative disease;for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, andRAD51D, odds ratios were higher for ER-negative disease than for ER-positivedisease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 wereassociated with a risk of breast cancer overall with a P value of less than 0.001.For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a riskof breast cancer overall, with the risk being similar to that of protein-truncatingvariants.CONCLUSIONSThe results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimatesof the risks associated with protein-truncating variants, to guide genetic counseling. (Funded by European Union Horizon 2020 programs and others.)
Published: 2021

28. Evaluation of Minimal Residual Disease (MRD) in Children with B-Cell Acute Lymphoblastic Leukemia after Completion of Induction Therapy

Author: Peregud-Pogorzelski, J., Lubinski, J., Brodkiewicz, A., Jakubowska, A., Debski, R., Wysocki, M., Hiddemann, Wolfgang, editor, Haferlach, Torsten, editor, Unterhalt, Michael, editor, Büchner, Thomas, editor, and Ritter, Jörg, editor
Published: 2003
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29. Evaluation of Minimal Residual Disease (MRD) in Children with B-Cell Acute Lymphoblastic Leukemia During Maintenance of Remission

Author: Peregud-Pogorzelski, J., Lubinski, J., Brodkiewicz, A., Jakubowska, A., Swiatkiewicz, V., Kurylak, A., Hiddemann, Wolfgang, editor, Haferlach, Torsten, editor, Unterhalt, Michael, editor, Büchner, Thomas, editor, and Ritter, Jörg, editor
Published: 2003
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30. Evaluation of Minimal Residual Disease (MRD) in Children with T-Lineage Acute Lymphoblastic Leukemia

Author: Peregud-Pogorzelski, J., Lubinski, J., Brodkiewicz, A., Jakubowska, A., Debski, R., Wysocki, M., Hiddemann, Wolfgang, editor, Haferlach, Torsten, editor, Unterhalt, Michael, editor, Büchner, Thomas, editor, and Ritter, Jörg, editor
Published: 2003
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31. Frequency of Cytogenetic Aberrations and their Influence on Results of Treatment in Childhood Acute Lymphoblastic Leukemia (ALL)

Author: Peregud-Pogorzelski, J., Zajaczek, S., Lubinski, J., Brodkiewicz, A., Wysocki, M., Koltan, A., Hiddemann, Wolfgang, editor, Haferlach, Torsten, editor, Unterhalt, Michael, editor, Büchner, Thomas, editor, and Ritter, Jörg, editor
Published: 2003
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32. A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study.

Author: Bancroft E.K., Page E.C., Brook M.N., Thomas S., Taylor N., Pope J., McHugh J., Jones A.-B., Karlsson Q., Merson S., Ong K.R., Hoffman J., Huber C., Maehle L., Grindedal E.M., Stormorken A., Evans D.G., Rothwell J., Lalloo F., Brady A.F., Bartlett M., Snape K., Hanson H., James P., McKinley J., Mascarenhas L., Syngal S., Ukaegbu C., Side L., Thomas T., Barwell J., Teixeira M.R., Izatt L., Suri M., Macrae F.A., Poplawski N., Chen-Shtoyerman R., Ahmed M., Musgrave H., Nicolai N., Greenhalgh L., Brewer C., Pachter N., Spigelman A.D., Azzabi A., Helfand B.T., Halliday D., Buys S., Ramon Y Cajal T., Donaldson A., Cooney K.A., Harris M., McGrath J., Davidson R., Taylor A., Cooke P., Myhill K., Hogben M., Aaronson N.K., Ardern-Jones A., Bangma C.H., Castro E., Dearnaley D., Dias A., Dudderidge T., Eccles D.M., Green K., Eyfjord J., Falconer A., Foster C.S., Gronberg H., Hamdy F.C., Johannsson O., Khoo V., Lilja H., Lindeman G.J., Lubinski J., Axcrona K., Mikropoulos C., Mitra A.V., Moynihan C., Ni Raghallaigh H., Rennert G., Collier R., Offman J., Kote-Jarai Z., Eeles R.A., Bancroft E.K., Page E.C., Brook M.N., Thomas S., Taylor N., Pope J., McHugh J., Jones A.-B., Karlsson Q., Merson S., Ong K.R., Hoffman J., Huber C., Maehle L., Grindedal E.M., Stormorken A., Evans D.G., Rothwell J., Lalloo F., Brady A.F., Bartlett M., Snape K., Hanson H., James P., McKinley J., Mascarenhas L., Syngal S., Ukaegbu C., Side L., Thomas T., Barwell J., Teixeira M.R., Izatt L., Suri M., Macrae F.A., Poplawski N., Chen-Shtoyerman R., Ahmed M., Musgrave H., Nicolai N., Greenhalgh L., Brewer C., Pachter N., Spigelman A.D., Azzabi A., Helfand B.T., Halliday D., Buys S., Ramon Y Cajal T., Donaldson A., Cooney K.A., Harris M., McGrath J., Davidson R., Taylor A., Cooke P., Myhill K., Hogben M., Aaronson N.K., Ardern-Jones A., Bangma C.H., Castro E., Dearnaley D., Dias A., Dudderidge T., Eccles D.M., Green K., Eyfjord J., Falconer A., Foster C.S., Gronberg H., Hamdy F.C., Johannsson O., Khoo V., Lilja H., Lindeman G.J., Lubinski J., Axcrona K., Mikropoulos C., Mitra A.V., Moynihan C., Ni Raghallaigh H., Rennert G., Collier R., Offman J., Kote-Jarai Z., and Eeles R.A.
Abstract: BACKGROUND: Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants. METHOD(S): The IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3.0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This
Published: 2022

33. Germline MBD4 deficiency causes a multi-tumor predisposition syndrome

Author: Palles, C, West, HD, Chew, E, Galavotti, S, Flensburg, C, Grolleman, JE, Jansen, EAM, Curley, H, Chegwidden, L, Arbe-Barnes, EH, Lander, N, Truscott, R, Pagan, J, Bajel, A, Sherwood, K, Martin, L, Thomas, H, Georgiou, D, Fostira, F, Goldberg, Y, Adams, DJ, van der Biezen, SAM, Christie, M, Clendenning, M, Thomas, LE, Deltas, C, Dimovski, AJ, Dymerska, D, Lubinski, J, Mahmood, K, van der Post, RS, Sanders, M, Weitz, J, Taylor, JC, Turnbull, C, Vreede, L, van Wezel, T, Whalley, C, Arnedo-Pac, C, Caravagna, G, Cross, W, Chubb, D, Frangou, A, Gruber, AJ, Kinnersley, B, Noyvert, B, Church, D, Graham, T, Houlston, R, Lopez-Bigas, N, Sottoriva, A, Wedge, D, Jenkins, MA, Kuiper, RP, Roberts, AW, Cheadle, JP, Ligtenberg, MJL, Hoogerbrugge, N, Koelzer, VH, Rivas, AD, Winship, IM, Ponte, CR, Buchanan, DD, Power, DG, Green, A, Tomlinson, IPM, Sampson, JR, Majewski, IJ, de Voer, RM, Palles, C, West, HD, Chew, E, Galavotti, S, Flensburg, C, Grolleman, JE, Jansen, EAM, Curley, H, Chegwidden, L, Arbe-Barnes, EH, Lander, N, Truscott, R, Pagan, J, Bajel, A, Sherwood, K, Martin, L, Thomas, H, Georgiou, D, Fostira, F, Goldberg, Y, Adams, DJ, van der Biezen, SAM, Christie, M, Clendenning, M, Thomas, LE, Deltas, C, Dimovski, AJ, Dymerska, D, Lubinski, J, Mahmood, K, van der Post, RS, Sanders, M, Weitz, J, Taylor, JC, Turnbull, C, Vreede, L, van Wezel, T, Whalley, C, Arnedo-Pac, C, Caravagna, G, Cross, W, Chubb, D, Frangou, A, Gruber, AJ, Kinnersley, B, Noyvert, B, Church, D, Graham, T, Houlston, R, Lopez-Bigas, N, Sottoriva, A, Wedge, D, Jenkins, MA, Kuiper, RP, Roberts, AW, Cheadle, JP, Ligtenberg, MJL, Hoogerbrugge, N, Koelzer, VH, Rivas, AD, Winship, IM, Ponte, CR, Buchanan, DD, Power, DG, Green, A, Tomlinson, IPM, Sampson, JR, Majewski, IJ, and de Voer, RM
Abstract: We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER) gene MBD4. We identified five individuals with bi-allelic MBD4 variants within four families and these individuals had a personal and/or family history of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma. MBD4 encodes a glycosylase involved in repair of G:T mismatches resulting from deamination of 5'-methylcytosine. The colorectal adenomas from MBD4-deficient individuals showed a mutator phenotype attributable to mutational signature SBS1, consistent with the function of MBD4. MBD4-deficient polyps harbored somatic mutations in similar driver genes to sporadic colorectal tumors, although AMER1 mutations were more common and KRAS mutations less frequent. Our findings expand the role of BER deficiencies in tumor predisposition. Inclusion of MBD4 in genetic testing for polyposis and multi-tumor phenotypes is warranted to improve disease management.
Published: 2022

34. Pathology of Tumors Associated With Pathogenic Germline Variants in 9 Breast Cancer Susceptibility Genes

Author: Mavaddat, N, Dorling, L, Carvalho, S, Allen, J, Gonzalez-Neira, A, Keeman, R, Bolla, MK, Dennis, J, Wang, Q, Ahearn, TU, Andrulis, IL, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Blomqvist, C, Bogdanova, N, Bojesen, SE, Briceno, I, Bruning, T, Camp, NJ, Campbell, A, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Christiansen, H, Czene, K, Dork, T, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, JD, Flyger, H, Gabrielson, M, Gago-Dominguez, M, Geisler, J, Giles, GG, Guenel, P, Hadjisavvas, A, Hahnen, E, Hall, P, Hamann, U, Hartikainen, JM, Hartman, M, Hoppe, R, Howell, A, Jakubowska, A, Jung, A, Khusnutdinova, EK, Kristensen, VN, Li, J, Lim, SH, Lindblom, A, Loizidou, MA, Lophatananon, A, Lubinski, J, Madsen, MJ, Mannermaa, A, Manoochehri, M, Margolin, S, Mavroudis, D, Milne, RL, Taib, NAM, Morra, A, Muir, K, Obi, N, Osorio, A, Park-Simon, T-W, Peterlongo, P, Radice, P, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Shah, M, Sim, X, Southey, MC, Thorne, H, Tomlinson, I, Torres, D, Truong, T, Yip, CH, Spurdle, AB, Vreeswijk, MPG, Dunning, AM, Garcia-Closas, M, Pharoah, PDP, Kvist, A, Muranen, TA, Nevanlinna, H, Teo, SH, Devilee, P, Schmidt, MK, Easton, DF, Mavaddat, N, Dorling, L, Carvalho, S, Allen, J, Gonzalez-Neira, A, Keeman, R, Bolla, MK, Dennis, J, Wang, Q, Ahearn, TU, Andrulis, IL, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Blomqvist, C, Bogdanova, N, Bojesen, SE, Briceno, I, Bruning, T, Camp, NJ, Campbell, A, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Christiansen, H, Czene, K, Dork, T, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, JD, Flyger, H, Gabrielson, M, Gago-Dominguez, M, Geisler, J, Giles, GG, Guenel, P, Hadjisavvas, A, Hahnen, E, Hall, P, Hamann, U, Hartikainen, JM, Hartman, M, Hoppe, R, Howell, A, Jakubowska, A, Jung, A, Khusnutdinova, EK, Kristensen, VN, Li, J, Lim, SH, Lindblom, A, Loizidou, MA, Lophatananon, A, Lubinski, J, Madsen, MJ, Mannermaa, A, Manoochehri, M, Margolin, S, Mavroudis, D, Milne, RL, Taib, NAM, Morra, A, Muir, K, Obi, N, Osorio, A, Park-Simon, T-W, Peterlongo, P, Radice, P, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Shah, M, Sim, X, Southey, MC, Thorne, H, Tomlinson, I, Torres, D, Truong, T, Yip, CH, Spurdle, AB, Vreeswijk, MPG, Dunning, AM, Garcia-Closas, M, Pharoah, PDP, Kvist, A, Muranen, TA, Nevanlinna, H, Teo, SH, Devilee, P, Schmidt, MK, and Easton, DF
Abstract: IMPORTANCE: Rare germline genetic variants in several genes are associated with increased breast cancer (BC) risk, but their precise contributions to different disease subtypes are unclear. This information is relevant to guidelines for gene panel testing and risk prediction. OBJECTIVE: To characterize tumors associated with BC susceptibility genes in large-scale population- or hospital-based studies. DESIGN, SETTING, AND PARTICIPANTS: The multicenter, international case-control analysis of the BRIDGES study included 42 680 patients and 46 387 control participants, comprising women aged 18 to 79 years who were sampled independently of family history from 38 studies. Studies were conducted between 1991 and 2016. Sequencing and analysis took place between 2016 and 2021. EXPOSURES: Protein-truncating variants and likely pathogenic missense variants in ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53. MAIN OUTCOMES AND MEASURES: The intrinsic-like BC subtypes as defined by estrogen receptor, progesterone receptor, and ERBB2 (formerly known as HER2) status, and tumor grade; morphology; size; stage; lymph node involvement; subtype-specific odds ratios (ORs) for carrying protein-truncating variants and pathogenic missense variants in the 9 BC susceptibility genes. RESULTS: The mean (SD) ages at interview (control participants) and diagnosis (cases) were 55.1 (11.9) and 55.8 (10.6) years, respectively; all participants were of European or East Asian ethnicity. There was substantial heterogeneity in the distribution of intrinsic subtypes by gene. RAD51C, RAD51D, and BARD1 variants were associated mainly with triple-negative disease (OR, 6.19 [95% CI, 3.17-12.12]; OR, 6.19 [95% CI, 2.99-12.79]; and OR, 10.05 [95% CI, 5.27-19.19], respectively). CHEK2 variants were associated with all subtypes (with ORs ranging from 2.21-3.17) except for triple-negative disease. For ATM variants, the association was strongest for the hormone receptor (HR)+ERBB2- high-grade subt
Published: 2022

35. Germline MBD4 deficiency causes a multi-tumor predisposition syndrome

Author: Palles, C., West, H.D., Chew, E., Galavotti, S., Flensburg, C., Grolleman, J.E., Jansen, E.A.M., Curley, H., Chegwidden, L., Arbe-Barnes, E.H., Lander, N., Truscott, R., Pagan, J., Bajel, A., Sherwood, K., Martin, L., Thomas, H, Georgiou, D., Fostira, F., Goldberg, Y., Adams, D.J., Biezen, S.A.M. van der, Christie, M., Clendenning, M., Thomas, L.E., Deltas, C., Dimovski, A.J., Dymerska, D., Lubinski, J., Mahmood, K., Post, R.S. van der, Sanders, M., Weitz, J., Taylor, J.C., Turnbull, C., Vreede, L., Wezel, T. van, Whalley, C., Arnedo-Pac, C., Caravagna, G., Cross, W., Chubb, D., Frangou, A., Gruber, A.J., Kinnersley, B., Noyvert, B., Church, D., Graham, T., Houlston, R., Lopez-Bigas, N., Sottoriva, A., Wedge, D., Jenkins, Mark A., Kuiper, R.P., Roberts, A.W., Cheadle, J.P., Ligtenberg, M.J.L., Hoogerbrugge, N., Koelzer, V.H., Rivas, A.D., Winship, I.M., Ponte, C.R., Buchanan, D.D., Power, D.G., Green, A., Tomlinson, I.P., Sampson, J.R., Majewski, I.J., Voer, R.M. de, Palles, C., West, H.D., Chew, E., Galavotti, S., Flensburg, C., Grolleman, J.E., Jansen, E.A.M., Curley, H., Chegwidden, L., Arbe-Barnes, E.H., Lander, N., Truscott, R., Pagan, J., Bajel, A., Sherwood, K., Martin, L., Thomas, H, Georgiou, D., Fostira, F., Goldberg, Y., Adams, D.J., Biezen, S.A.M. van der, Christie, M., Clendenning, M., Thomas, L.E., Deltas, C., Dimovski, A.J., Dymerska, D., Lubinski, J., Mahmood, K., Post, R.S. van der, Sanders, M., Weitz, J., Taylor, J.C., Turnbull, C., Vreede, L., Wezel, T. van, Whalley, C., Arnedo-Pac, C., Caravagna, G., Cross, W., Chubb, D., Frangou, A., Gruber, A.J., Kinnersley, B., Noyvert, B., Church, D., Graham, T., Houlston, R., Lopez-Bigas, N., Sottoriva, A., Wedge, D., Jenkins, Mark A., Kuiper, R.P., Roberts, A.W., Cheadle, J.P., Ligtenberg, M.J.L., Hoogerbrugge, N., Koelzer, V.H., Rivas, A.D., Winship, I.M., Ponte, C.R., Buchanan, D.D., Power, D.G., Green, A., Tomlinson, I.P., Sampson, J.R., Majewski, I.J., and Voer, R.M. de
Abstract: Contains fulltext : 251996.pdf (Publisher’s version ) (Open Access), We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER) gene MBD4. We identified five individuals with bi-allelic MBD4 variants within four families and these individuals had a personal and/or family history of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma. MBD4 encodes a glycosylase involved in repair of G:T mismatches resulting from deamination of 5'-methylcytosine. The colorectal adenomas from MBD4-deficient individuals showed a mutator phenotype attributable to mutational signature SBS1, consistent with the function of MBD4. MBD4-deficient polyps harbored somatic mutations in similar driver genes to sporadic colorectal tumors, although AMER1 mutations were more common and KRAS mutations less frequent. Our findings expand the role of BER deficiencies in tumor predisposition. Inclusion of MBD4 in genetic testing for polyposis and multi-tumor phenotypes is warranted to improve disease management.
Published: 2022

36. Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes

Author: Meagher, NS, Gorringe, KL, Wakefield, M, Bolithon, A, Pang, CNI, Chiu, DS, Anglesio, MS, Mallitt, K-A, Doherty, JA, Harris, HR, Schildkraut, JM, Berchuck, A, Cushing-Haugen, KL, Chezar, K, Chou, A, Tan, A, Alsop, J, Barlow, E, Beckmann, MW, Boros, J, Bowtell, DDL, Brand, AH, Brenton, JD, Campbell, I, Cheasley, D, Cohen, J, Cybulski, C, Elishaev, E, Erber, R, Farrell, R, Fischer, A, Fu, Z, Gilks, B, Gill, AJ, Gourley, C, Grube, M, Harnett, PR, Hartmann, A, Hettiaratchi, A, Hogdall, CK, Huzarski, T, Jakubowska, A, Jimenez-Linan, M, Kennedy, CJ, Kim, B-G, Kim, J-W, Kim, J-H, Klett, K, Koziak, JM, Lai, T, Laslavic, A, Lester, J, Leung, Y, Li, N, Liauw, W, Lim, BWX, Linder, A, Lubinski, J, Mahale, S, Mateoiu, C, McInerny, S, Menkiszak, J, Minoo, P, Mittelstadt, S, Morris, D, Orsulic, S, Park, S-Y, Pearce, CL, Pearson, J, Pike, MC, Quinn, CM, Mohan, GR, Rao, J, Riggan, MJ, Ruebner, M, Salfinger, S, Scott, CL, Shah, M, Steed, H, Stewart, CJR, Subramanian, D, Sung, S, Tang, K, Timpson, P, Ward, RL, Wiedenhoefer, R, Thorne, H, Cohen, PA, Crowe, P, Fasching, PA, Gronwald, J, Hawkins, NJ, Hogdall, E, Huntsman, DG, James, PA, Karlan, BY, Kelemen, LE, Kommoss, S, Konecny, GE, Modugno, F, Park, SK, Staebler, A, Sundfeldt, K, Wu, AH, Talhouk, A, Pharoah, PDP, Anderson, L, DeFazio, A, Kobel, M, Friedlander, ML, Ramus, SJ, Meagher, NS, Gorringe, KL, Wakefield, M, Bolithon, A, Pang, CNI, Chiu, DS, Anglesio, MS, Mallitt, K-A, Doherty, JA, Harris, HR, Schildkraut, JM, Berchuck, A, Cushing-Haugen, KL, Chezar, K, Chou, A, Tan, A, Alsop, J, Barlow, E, Beckmann, MW, Boros, J, Bowtell, DDL, Brand, AH, Brenton, JD, Campbell, I, Cheasley, D, Cohen, J, Cybulski, C, Elishaev, E, Erber, R, Farrell, R, Fischer, A, Fu, Z, Gilks, B, Gill, AJ, Gourley, C, Grube, M, Harnett, PR, Hartmann, A, Hettiaratchi, A, Hogdall, CK, Huzarski, T, Jakubowska, A, Jimenez-Linan, M, Kennedy, CJ, Kim, B-G, Kim, J-W, Kim, J-H, Klett, K, Koziak, JM, Lai, T, Laslavic, A, Lester, J, Leung, Y, Li, N, Liauw, W, Lim, BWX, Linder, A, Lubinski, J, Mahale, S, Mateoiu, C, McInerny, S, Menkiszak, J, Minoo, P, Mittelstadt, S, Morris, D, Orsulic, S, Park, S-Y, Pearce, CL, Pearson, J, Pike, MC, Quinn, CM, Mohan, GR, Rao, J, Riggan, MJ, Ruebner, M, Salfinger, S, Scott, CL, Shah, M, Steed, H, Stewart, CJR, Subramanian, D, Sung, S, Tang, K, Timpson, P, Ward, RL, Wiedenhoefer, R, Thorne, H, Cohen, PA, Crowe, P, Fasching, PA, Gronwald, J, Hawkins, NJ, Hogdall, E, Huntsman, DG, James, PA, Karlan, BY, Kelemen, LE, Kommoss, S, Konecny, GE, Modugno, F, Park, SK, Staebler, A, Sundfeldt, K, Wu, AH, Talhouk, A, Pharoah, PDP, Anderson, L, DeFazio, A, Kobel, M, Friedlander, ML, and Ramus, SJ
Abstract: PURPOSE: Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features. EXPERIMENTAL DESIGN: Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55). RESULTS: Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95% confidence interval (CI), 1.04-7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04-1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01-1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%). CONCLUSIONS: An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.
Published: 2022

37. Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci

Author: DeVries, AA, Dennis, J, Tyrer, JP, Peng, P-C, Coetzee, SG, Reyes, AL, Plummer, JT, Davis, BD, Chen, SS, Dezem, FS, Aben, KKH, Anton-Culver, H, Antonenkova, NN, Beckmann, MW, Beeghly-Fadiel, A, Berchuck, A, Bogdanova, N, Bogdanova-Markov, N, Brenton, JD, Butzow, R, Campbell, I, Chang-Claude, J, Chenevix-Trench, G, Cook, LS, DeFazio, A, Doherty, JA, Dork, T, Eccles, DM, Eliassen, AH, Fasching, PA, Fortner, RT, Giles, GG, Goode, EL, Goodman, MT, Gronwald, J, Hakansson, N, Hildebrandt, MAT, Huff, C, Huntsman, DG, Jensen, A, Kar, S, Karlan, BY, Khusnutdinova, EK, Kiemeney, LA, Kjaer, SK, Kupryjanczyk, J, Labrie, M, Lambrechts, D, Le, ND, Lubinski, J, May, T, Menon, U, Milne, RL, Modugno, F, Monteiro, AN, Moysich, KB, Odunsi, K, Olsson, H, Pearce, CL, Pejovic, T, Ramus, SJ, Riboli, E, Riggan, MJ, Romieu, I, Sandler, DP, Schildkraut, JM, Setiawan, VW, Sieh, W, Song, H, Sutphen, R, Terry, KL, Thompson, PJ, Titus, L, Tworoger, SS, Van Nieuwenhuysen, E, Edwards, DV, Webb, PM, Wentzensen, N, Whittemore, AS, Wolk, A, Wu, AH, Ziogas, A, Freedman, ML, Lawrenson, K, Pharoah, PDP, Easton, DF, Gayther, SA, Jones, MR, DeVries, AA, Dennis, J, Tyrer, JP, Peng, P-C, Coetzee, SG, Reyes, AL, Plummer, JT, Davis, BD, Chen, SS, Dezem, FS, Aben, KKH, Anton-Culver, H, Antonenkova, NN, Beckmann, MW, Beeghly-Fadiel, A, Berchuck, A, Bogdanova, N, Bogdanova-Markov, N, Brenton, JD, Butzow, R, Campbell, I, Chang-Claude, J, Chenevix-Trench, G, Cook, LS, DeFazio, A, Doherty, JA, Dork, T, Eccles, DM, Eliassen, AH, Fasching, PA, Fortner, RT, Giles, GG, Goode, EL, Goodman, MT, Gronwald, J, Hakansson, N, Hildebrandt, MAT, Huff, C, Huntsman, DG, Jensen, A, Kar, S, Karlan, BY, Khusnutdinova, EK, Kiemeney, LA, Kjaer, SK, Kupryjanczyk, J, Labrie, M, Lambrechts, D, Le, ND, Lubinski, J, May, T, Menon, U, Milne, RL, Modugno, F, Monteiro, AN, Moysich, KB, Odunsi, K, Olsson, H, Pearce, CL, Pejovic, T, Ramus, SJ, Riboli, E, Riggan, MJ, Romieu, I, Sandler, DP, Schildkraut, JM, Setiawan, VW, Sieh, W, Song, H, Sutphen, R, Terry, KL, Thompson, PJ, Titus, L, Tworoger, SS, Van Nieuwenhuysen, E, Edwards, DV, Webb, PM, Wentzensen, N, Whittemore, AS, Wolk, A, Wu, AH, Ziogas, A, Freedman, ML, Lawrenson, K, Pharoah, PDP, Easton, DF, Gayther, SA, and Jones, MR
Abstract: BACKGROUND: Known risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort. METHODS: Single nucleotide polymorphism array data from 13 071 EOC cases and 17 306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer-related cell types. RESULTS: We identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (PEOC = 1.60E-21; OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4; odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4; ORHGSOC = 3.31 deletion). Four suggestive associations (P < .001) were identified for rare CNVs. Risk-associated CNVs were enriched (P < .05) at known EOC risk loci identified by genome-wide association study. Noncoding CNVs were enriched in active promoters and insulators in EOC-related cell types. CONCLUSIONS: CNVs in BRCA1 have been previously reported in smaller studies, but their observed frequency in this large population-based cohort, along with the CNVs observed at BRCA2 and RAD51C gene loci in EOC cases, suggests that these CNVs are potentially pathogenic and may contribute to the spectrum of disease-causing mutations in these genes. CNVs are likely to occur in a wider set of susceptibility regions, with potential implications for clinical genetic testing and disease prevention.
Published: 2022

38. Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium

Author: Moller, P, Seppala, T, Dowty, JG, Haupt, S, Dominguez-Valentin, M, Sunde, L, Bernstein, I, Engel, C, Aretz, S, Nielsen, M, Capella, G, Evans, DG, Burn, J, Holinski-Feder, E, Bertario, L, Bonanni, B, Lindblom, A, Levi, Z, Macrae, F, Winship, I, Plazzer, J-P, Sijmons, R, Laghi, L, Della Valle, A, Heinimann, K, Half, E, Lopez-Koestner, F, Alvarez-Valenzuela, K, Scott, RJ, Katz, L, Laish, I, Vainer, E, Vaccaro, CA, Carraro, DM, Gluck, N, Abu-Freha, N, Stakelum, A, Kennelly, R, Winter, D, Rossi, BM, Greenblatt, M, Bohorquez, M, Sheth, H, Tibiletti, MG, Lino-Silva, LS, Horisberger, K, Portenkirchner, C, Nascimento, I, Rossi, NT, da Silva, LA, Thomas, H, Zarand, A, Mecklin, J-P, Pylvanainen, K, Renkonen-Sinisalo, L, Lepisto, A, Peltomaki, P, Therkildsen, C, Lindberg, LJ, Thorlacius-Ussing, O, von Knebel Doeberitz, M, Loeffler, M, Rahner, N, Steinke-Lange, V, Schmiegel, W, Vangala, D, Perne, C, Hueneburg, R, de Vargas, AF, Latchford, A, Gerdes, A-M, Backman, A-S, Guillen-Ponce, C, Snyder, C, Lautrup, CK, Amor, D, Palmero, E, Stoffel, E, Duijkers, F, Hall, MJ, Hampel, H, Williams, H, Okkels, H, Lubinski, J, Reece, J, Ngeow, J, Guillem, JG, Arnold, J, Wadt, K, Monahan, K, Senter, L, Rasmussen, LJ, van Hest, LP, Ricciardiello, L, Kohonen-Corish, MRJ, Ligtenberg, MJL, Southey, M, Aronson, M, Zahary, MN, Samadder, NJ, Poplawski, N, Hoogerbrugge, N, Morrison, PJ, James, P, Lee, G, Chen-Shtoyerman, R, Ankathil, R, Pai, R, Ward, R, Parry, S, Debniak, T, John, T, van Overeem Hansen, T, Caldes, T, Yamaguchi, T, Barca-Tierno, V, Garre, P, Cavestro, GM, Weitz, J, Redler, S, Buettner, R, Heuveline, V, Hopper, JL, Win, AK, Lindor, N, Gallinger, S, Le Marchand, L, Newcomb, PA, Figueiredo, J, Buchanan, DD, Thibodeau, SN, ten Broeke, SW, Hovig, E, Nakken, S, Pineda, M, Duenas, N, Brunet, J, Green, K, Lalloo, F, Newton, K, Crosbie, EJ, Mints, M, Tjandra, D, Neffa, F, Esperon, P, Kariv, R, Rosner, G, Pavicic, WH, Kalfayan, P, Torrezan, GT, Bassaneze, T, Martin, C, Moslein, G, Ahadova, A, Kloor, M, Sampson, JR, Jenkins, MA, Moller, P, Seppala, T, Dowty, JG, Haupt, S, Dominguez-Valentin, M, Sunde, L, Bernstein, I, Engel, C, Aretz, S, Nielsen, M, Capella, G, Evans, DG, Burn, J, Holinski-Feder, E, Bertario, L, Bonanni, B, Lindblom, A, Levi, Z, Macrae, F, Winship, I, Plazzer, J-P, Sijmons, R, Laghi, L, Della Valle, A, Heinimann, K, Half, E, Lopez-Koestner, F, Alvarez-Valenzuela, K, Scott, RJ, Katz, L, Laish, I, Vainer, E, Vaccaro, CA, Carraro, DM, Gluck, N, Abu-Freha, N, Stakelum, A, Kennelly, R, Winter, D, Rossi, BM, Greenblatt, M, Bohorquez, M, Sheth, H, Tibiletti, MG, Lino-Silva, LS, Horisberger, K, Portenkirchner, C, Nascimento, I, Rossi, NT, da Silva, LA, Thomas, H, Zarand, A, Mecklin, J-P, Pylvanainen, K, Renkonen-Sinisalo, L, Lepisto, A, Peltomaki, P, Therkildsen, C, Lindberg, LJ, Thorlacius-Ussing, O, von Knebel Doeberitz, M, Loeffler, M, Rahner, N, Steinke-Lange, V, Schmiegel, W, Vangala, D, Perne, C, Hueneburg, R, de Vargas, AF, Latchford, A, Gerdes, A-M, Backman, A-S, Guillen-Ponce, C, Snyder, C, Lautrup, CK, Amor, D, Palmero, E, Stoffel, E, Duijkers, F, Hall, MJ, Hampel, H, Williams, H, Okkels, H, Lubinski, J, Reece, J, Ngeow, J, Guillem, JG, Arnold, J, Wadt, K, Monahan, K, Senter, L, Rasmussen, LJ, van Hest, LP, Ricciardiello, L, Kohonen-Corish, MRJ, Ligtenberg, MJL, Southey, M, Aronson, M, Zahary, MN, Samadder, NJ, Poplawski, N, Hoogerbrugge, N, Morrison, PJ, James, P, Lee, G, Chen-Shtoyerman, R, Ankathil, R, Pai, R, Ward, R, Parry, S, Debniak, T, John, T, van Overeem Hansen, T, Caldes, T, Yamaguchi, T, Barca-Tierno, V, Garre, P, Cavestro, GM, Weitz, J, Redler, S, Buettner, R, Heuveline, V, Hopper, JL, Win, AK, Lindor, N, Gallinger, S, Le Marchand, L, Newcomb, PA, Figueiredo, J, Buchanan, DD, Thibodeau, SN, ten Broeke, SW, Hovig, E, Nakken, S, Pineda, M, Duenas, N, Brunet, J, Green, K, Lalloo, F, Newton, K, Crosbie, EJ, Mints, M, Tjandra, D, Neffa, F, Esperon, P, Kariv, R, Rosner, G, Pavicic, WH, Kalfayan, P, Torrezan, GT, Bassaneze, T, Martin, C, Moslein, G, Ahadova, A, Kloor, M, Sampson, JR, and Jenkins, MA
Abstract: OBJECTIVE: To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants. METHODS: CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path_MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path_MMR carriers who were first- or second-degree relatives of Lynch syndrome probands. RESULTS: In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path_MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path_MSH2 50% and 39%; for path_MSH6 13% and 17% and for path_PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups. CONCLUSIONS: Prospectively observed CRC incidences (PLSD) in path_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so.
Published: 2022

39. Validated biomarker assays confirm that ARID1A loss is confounded with MMR deficiency, CD8(+) TIL infiltration, and provides no independent prognostic value in endometriosis-associated ovarian carcinomas

Author: Heinze, K, Nazeran, TM, Lee, S, Kramer, P, Cairns, ES, Chiu, DS, Leung, SCY, Kang, EY, Meagher, NS, Kennedy, CJ, Boros, J, Kommoss, F, Vollert, H-W, Heitze, F, du Bois, A, Harter, P, Grube, M, Kraemer, B, Staebler, A, Kommoss, FKF, Heublein, S, Sinn, H-P, Singh, N, Laslavic, A, Elishaev, E, Olawaiye, A, Moysich, K, Modugno, F, Sharma, R, Brand, AH, Harnett, PR, DeFazio, A, Fortner, RT, Lubinski, J, Lener, M, Toloczko-Grabarek, A, Cybulski, C, Gronwald, H, Gronwald, J, Coulson, P, El-Bahrawy, MA, Jones, ME, Schoemaker, MJ, Swerdlow, AJ, Gorringe, KL, Campbell, I, Cook, L, Gayther, SA, Carney, ME, Shvetsov, YB, Hernandez, BY, Wilkens, LR, Goodman, MT, Mateoiu, C, Linder, A, Sundfeldt, K, Kelemen, LE, Gentry-Maharaj, A, Widschwendter, M, Menon, U, Bolton, KL, Alsop, J, Shah, M, Jimenez-Linan, M, Pharoah, PDP, Brenton, JD, Cushing-Haugen, KL, Harris, HR, Doherty, JA, Gilks, B, Ghatage, P, Huntsman, DG, Nelson, GS, Tinker, A, Lee, C-H, Goode, EL, Nelson, BH, Ramus, SJ, Kommoss, S, Talhouk, A, Kobel, M, Anglesio, MS, Heinze, K, Nazeran, TM, Lee, S, Kramer, P, Cairns, ES, Chiu, DS, Leung, SCY, Kang, EY, Meagher, NS, Kennedy, CJ, Boros, J, Kommoss, F, Vollert, H-W, Heitze, F, du Bois, A, Harter, P, Grube, M, Kraemer, B, Staebler, A, Kommoss, FKF, Heublein, S, Sinn, H-P, Singh, N, Laslavic, A, Elishaev, E, Olawaiye, A, Moysich, K, Modugno, F, Sharma, R, Brand, AH, Harnett, PR, DeFazio, A, Fortner, RT, Lubinski, J, Lener, M, Toloczko-Grabarek, A, Cybulski, C, Gronwald, H, Gronwald, J, Coulson, P, El-Bahrawy, MA, Jones, ME, Schoemaker, MJ, Swerdlow, AJ, Gorringe, KL, Campbell, I, Cook, L, Gayther, SA, Carney, ME, Shvetsov, YB, Hernandez, BY, Wilkens, LR, Goodman, MT, Mateoiu, C, Linder, A, Sundfeldt, K, Kelemen, LE, Gentry-Maharaj, A, Widschwendter, M, Menon, U, Bolton, KL, Alsop, J, Shah, M, Jimenez-Linan, M, Pharoah, PDP, Brenton, JD, Cushing-Haugen, KL, Harris, HR, Doherty, JA, Gilks, B, Ghatage, P, Huntsman, DG, Nelson, GS, Tinker, A, Lee, C-H, Goode, EL, Nelson, BH, Ramus, SJ, Kommoss, S, Talhouk, A, Kobel, M, and Anglesio, MS
Published: 2022

40. PredictCBC-2.0: a contralateral breast cancer risk prediction model developed and validated in similar to 200,000 patients

Author: Giardiello, D, Hooning, MJ, Hauptmann, M, Keeman, R, Heemskerk-Gerritsen, BAM, Becher, H, Blomqvist, C, Bojesen, SE, Bolla, MK, Camp, NJ, Czene, K, Devilee, P, Eccles, DM, Fasching, PA, Figueroa, JD, Flyger, H, Garcia-Closas, M, Haiman, CA, Hamann, U, Hopper, JL, Jakubowska, A, Leeuwen, FE, Lindblom, A, Lubinski, J, Margolin, S, Martinez, ME, Nevanlinna, H, Nevelsteen, I, Pelders, S, Pharoah, PDP, Siesling, S, Southey, MC, van der Hout, AH, van Hest, LP, Chang-Claude, J, Hall, P, Easton, DF, Steyerberg, EW, Schmidt, MK, Giardiello, D, Hooning, MJ, Hauptmann, M, Keeman, R, Heemskerk-Gerritsen, BAM, Becher, H, Blomqvist, C, Bojesen, SE, Bolla, MK, Camp, NJ, Czene, K, Devilee, P, Eccles, DM, Fasching, PA, Figueroa, JD, Flyger, H, Garcia-Closas, M, Haiman, CA, Hamann, U, Hopper, JL, Jakubowska, A, Leeuwen, FE, Lindblom, A, Lubinski, J, Margolin, S, Martinez, ME, Nevanlinna, H, Nevelsteen, I, Pelders, S, Pharoah, PDP, Siesling, S, Southey, MC, van der Hout, AH, van Hest, LP, Chang-Claude, J, Hall, P, Easton, DF, Steyerberg, EW, and Schmidt, MK
Abstract: BACKGROUND: Prediction of contralateral breast cancer (CBC) risk is challenging due to moderate performances of the known risk factors. We aimed to improve our previous risk prediction model (PredictCBC) by updated follow-up and including additional risk factors. METHODS: We included data from 207,510 invasive breast cancer patients participating in 23 studies. In total, 8225 CBC events occurred over a median follow-up of 10.2 years. In addition to the previously included risk factors, PredictCBC-2.0 included CHEK2 c.1100delC, a 313 variant polygenic risk score (PRS-313), body mass index (BMI), and parity. Fine and Gray regression was used to fit the model. Calibration and a time-dependent area under the curve (AUC) at 5 and 10 years were assessed to determine the performance of the models. Decision curve analysis was performed to evaluate the net benefit of PredictCBC-2.0 and previous PredictCBC models. RESULTS: The discrimination of PredictCBC-2.0 at 10 years was higher than PredictCBC with an AUC of 0.65 (95% prediction intervals (PI) 0.56-0.74) versus 0.63 (95%PI 0.54-0.71). PredictCBC-2.0 was well calibrated with an observed/expected ratio at 10 years of 0.92 (95%PI 0.34-2.54). Decision curve analysis for contralateral preventive mastectomy (CPM) showed the potential clinical utility of PredictCBC-2.0 between thresholds of 4 and 12% 10-year CBC risk for BRCA1/2 mutation carriers and non-carriers. CONCLUSIONS: Additional genetic information beyond BRCA1/2 germline mutations improved CBC risk prediction and might help tailor clinical decision-making toward CPM or alternative preventive strategies. Identifying patients who benefit from CPM, especially in the general breast cancer population, remains challenging.
Published: 2022

41. Physical activity, sedentary time and breast cancer risk: a Mendelian randomisation study

Author: Dixon-Suen, SC, Lewis, SJ, Martin, RM, English, DR, Boyle, T, Giles, GG, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Lush, M, Ahearn, TU, Ambrosone, CB, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Augustinsson, A, Auvinen, P, Beane Freeman, LE, Becher, H, Beckmann, MW, Behrens, S, Bermisheva, M, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bonanni, B, Brenner, H, Bruening, T, Buys, SS, Camp, NJ, Campa, D, Canzian, F, Castelao, JE, Cessna, MH, Chang-Claude, J, Chanock, SJ, Clarke, CL, Conroy, DM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Doerk, T, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Fletcher, O, Flyger, H, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Garcia-Saenz, JA, Goldberg, MS, Guenel, P, Guendert, M, Hahnen, E, Haiman, CA, Haeberle, L, Hakansson, N, Hall, P, Hamann, U, Hart, SN, Harvie, M, Hillemanns, P, Hollestelle, A, Hooning, MJ, Hoppe, R, Hopper, J, Howell, A, Hunter, DJ, Jakubowska, A, Janni, W, John, EM, Jung, A, Kaaks, R, Keeman, R, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Lacey, J, Lambrechts, D, Le Marchand, L, Lindblom, A, Loibl, S, Lubinski, J, Mannermaa, A, Manoochehri, M, Margolin, S, Martinez, ME, Mavroudis, D, Menon, U, Mulligan, AM, Murphy, RA, Nevanlinna, H, Nevelsteen, I, Newman, WG, Offit, K, Olshan, AF, Olsson, H, Orr, N, Patel, A, Peto, J, Plaseska-Karanfilska, D, Presneau, N, Rack, B, Radice, P, Rees-Punia, E, Rennert, G, Rennert, HS, Romero, A, Saloustros, E, Sandler, DP, Schmidt, MK, Schmutzler, RK, Schwentner, L, Scott, C, Shah, M, Shu, X-O, Simard, J, Southey, MC, Stone, J, Surowy, H, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Tollenaar, RAEM, Troester, MA, Truong, T, Untch, M, Vachon, CM, Joseph, V, Wappenschmidt, B, Weinberg, CR, Wolk, A, Yannoukakos, D, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, PDP, Easton, DF, Milne, RL, Lynch, BM, Dixon-Suen, SC, Lewis, SJ, Martin, RM, English, DR, Boyle, T, Giles, GG, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Lush, M, Ahearn, TU, Ambrosone, CB, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Augustinsson, A, Auvinen, P, Beane Freeman, LE, Becher, H, Beckmann, MW, Behrens, S, Bermisheva, M, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bonanni, B, Brenner, H, Bruening, T, Buys, SS, Camp, NJ, Campa, D, Canzian, F, Castelao, JE, Cessna, MH, Chang-Claude, J, Chanock, SJ, Clarke, CL, Conroy, DM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Doerk, T, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Fletcher, O, Flyger, H, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Garcia-Saenz, JA, Goldberg, MS, Guenel, P, Guendert, M, Hahnen, E, Haiman, CA, Haeberle, L, Hakansson, N, Hall, P, Hamann, U, Hart, SN, Harvie, M, Hillemanns, P, Hollestelle, A, Hooning, MJ, Hoppe, R, Hopper, J, Howell, A, Hunter, DJ, Jakubowska, A, Janni, W, John, EM, Jung, A, Kaaks, R, Keeman, R, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Lacey, J, Lambrechts, D, Le Marchand, L, Lindblom, A, Loibl, S, Lubinski, J, Mannermaa, A, Manoochehri, M, Margolin, S, Martinez, ME, Mavroudis, D, Menon, U, Mulligan, AM, Murphy, RA, Nevanlinna, H, Nevelsteen, I, Newman, WG, Offit, K, Olshan, AF, Olsson, H, Orr, N, Patel, A, Peto, J, Plaseska-Karanfilska, D, Presneau, N, Rack, B, Radice, P, Rees-Punia, E, Rennert, G, Rennert, HS, Romero, A, Saloustros, E, Sandler, DP, Schmidt, MK, Schmutzler, RK, Schwentner, L, Scott, C, Shah, M, Shu, X-O, Simard, J, Southey, MC, Stone, J, Surowy, H, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Tollenaar, RAEM, Troester, MA, Truong, T, Untch, M, Vachon, CM, Joseph, V, Wappenschmidt, B, Weinberg, CR, Wolk, A, Yannoukakos, D, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, PDP, Easton, DF, Milne, RL, and Lynch, BM
Abstract: OBJECTIVES: Physical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics. METHODS: We performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105-377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (nsnps=5) or sedentary time (nsnps=6), or accelerometer-measured (nsnps=1) or self-reported (nsnps=5) vigorous physical activity. RESULTS: Greater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger). CONCLUSION: Our study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer r
Published: 2022

42. PredictCBC-2.0: a contralateral breast cancer risk prediction model developed and validated in similar to 200,000 patients (vol 24, 69, 2022)

Author: Giardiello, D, Hooning, MJ, Hauptmann, M, Keeman, R, Heemskerk-Gerritsen, BAM, Becher, H, Blomqvist, C, Bojesen, SE, Bolla, MK, Camp, NJ, Czene, K, Devilee, P, Eccles, DM, Fasching, PA, Figueroa, JD, Flyger, H, Garcia-Closas, M, Haiman, CA, Hamann, U, Hopper, JL, Jakubowska, A, Leeuwen, FE, Lindblom, A, Lubinski, J, Margolin, S, Martinez, ME, Nevanlinna, H, Nevelsteen, I, Pelders, S, Pharoah, PDP, Siesling, S, Southey, MC, van der Hout, AH, van Hest, LP, Chang-Claude, J, Hall, P, Easton, DF, Steyerberg, EW, Schmidt, MK, Giardiello, D, Hooning, MJ, Hauptmann, M, Keeman, R, Heemskerk-Gerritsen, BAM, Becher, H, Blomqvist, C, Bojesen, SE, Bolla, MK, Camp, NJ, Czene, K, Devilee, P, Eccles, DM, Fasching, PA, Figueroa, JD, Flyger, H, Garcia-Closas, M, Haiman, CA, Hamann, U, Hopper, JL, Jakubowska, A, Leeuwen, FE, Lindblom, A, Lubinski, J, Margolin, S, Martinez, ME, Nevanlinna, H, Nevelsteen, I, Pelders, S, Pharoah, PDP, Siesling, S, Southey, MC, van der Hout, AH, van Hest, LP, Chang-Claude, J, Hall, P, Easton, DF, Steyerberg, EW, and Schmidt, MK
Published: 2022

43. The impact of an expanded genetic testing program and selective oophorectomy on the incidence of ovarian cancer in West Pomerania

Author: Menkiszak, J., Sopik, V., Chudecka‐Głaz, A., Domagała, W., Urasińska, E., Symonowicz, H., Majdanik, E., Waloszczyk, P., Sycz, K., Świniarska, M., Huzarski, T., Cybulski, C., Debniak, T., Oszurek, O., Lubinski, J., Narod, S.A., and Gronwald, J.
Published: 2017
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44. Breast cancer risk after age 60 among BRCA1 and BRCA2 mutation carriers

Author: Stjepanovic N., Lubinski J., Moller P., Randall Armel S., Foulkes W. D., Tung N., Neuhausen S. L., Kotsopoulos J., Sun P., Sun S., Eisen A., Narod S. A., Senter L., Couch C. E. F., Fruscio R., Weitzel J. N., Olopade O., Singer C. F., Pal T., Huzarski T., Cybulski C., Sweet K., Zakalik D., Wood M., McKinnon W., Elser C., Wiesner G., Friedman E., Meschino W., Snyder C., Metcalfe K., Poll A., Warner E., Kim R., Demsky R., Ainsworth P., Steele L., Saal H., Serfas K., Panchal S., Cullinane C. A., Reilly R. E., Blum J. L., Kwong A., Rayson D., Cajal T. R., Dungan J., Yerushalmi R., Ginsburg O., Schraeder I., Cohen S., LemireLemire E., Zovato S., Rastelli A., Gronwald J., McCuaig J., Karlan B., Bordeleau L., Stjepanovic, N, Lubinski, J, Moller, P, Randall Armel, S, Foulkes, W, Tung, N, Neuhausen, S, Kotsopoulos, J, Sun, P, Sun, S, Eisen, A, Narod, S, Senter, L, Couch, C, Fruscio, R, Weitzel, J, Olopade, O, Singer, C, Pal, T, Huzarski, T, Cybulski, C, Sweet, K, Zakalik, D, Wood, M, Mckinnon, W, Elser, C, Wiesner, G, Friedman, E, Meschino, W, Snyder, C, Metcalfe, K, Poll, A, Warner, E, Kim, R, Demsky, R, Ainsworth, P, Steele, L, Saal, H, Serfas, K, Panchal, S, Cullinane, C, Reilly, R, Blum, J, Kwong, A, Rayson, D, Cajal, T, Dungan, J, Yerushalmi, R, Ginsburg, O, Schraeder, I, Cohen, S, Lemirelemire, E, Zovato, S, Rastelli, A, Gronwald, J, Mccuaig, J, Karlan, B, and Bordeleau, L
Subjects: 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Heterozygote, medicine.medical_treatment, Ovariectomy, Genes, BRCA2, Genes, BRCA1, Breast Neoplasms, 03 medical and health sciences, Breast cancer screening, 0302 clinical medicine, Breast cancer, Internal medicine, medicine, Humans, Cumulative incidence, Genetic Predisposition to Disease, Prospective Studies, skin and connective tissue diseases, Prospective cohort study, Mastectomy, Aged, Aged, 80 and over, BRCA2 Protein, medicine.diagnostic_test, business.industry, BRCA1 Protein, Incidence, Oophorectomy, Cancer, Hormone replacement therapy (menopause), Middle Aged, BRCA1, medicine.disease, BRCA2, Prophylactic Surgery, 3. Good health, Prospective, 030104 developmental biology, 030220 oncology & carcinogenesis, Mutation, Female, business
Abstract: Purpose: It is not known whether the risk of breast cancer among BRCA1 and BRCA2 mutation carriers after age 60 is high enough to justify intensive screening or prophylactic surgery. Thus, we conducted a prospective analysis of breast cancer risk in BRCA1 and BRCA2 mutation carriers from age 60 until age 80. Methods: Subjects had no history of cancer and both breasts intact at age 60 (n = 699). Women were followed until a breast cancer diagnosis, prophylactic bilateral mastectomy or death. We calculated the annual cancer rate and cumulative incidence of breast cancer (invasive and in situ) from age 60 to age 80. We assessed the associations between hormone replacement therapy, family history of breast cancer and bilateral oophorectomy and breast cancer risk. Results: Over a mean follow-up of 7.9years, 61 invasive and 20 in situ breast cancers were diagnosed in the cohort. The mean annual rate of invasive breast cancer was 1.8% for BRCA1 mutation carriers and 1.7% for BRCA2 mutation carriers. The cumulative risk of invasive breast cancer from age 60 to 80 was 20.1% for women with a BRCA1 mutation and was 17.3% for women with a BRCA2 mutation. Hormone replacement therapy, family history and oophorectomy were not associated with breast cancer risk. Conclusions: Findings from this large prospective study indicate that the risk of developing breast cancer remains high after age 60 in both BRCA1 and BRCA2 mutation carriers. These findings warrant further evaluation of the role of breast cancer screening in older mutation carriers.
Published: 2020

45. A mosaic PIK3CA variant in a young adult with diffuse gastric cancer: case report

Author: te Paske, I.B.A.W., Garcia-Pelaez, J., Sommer, A.K., Matalonga, L., Starzynska, T., Jakubowska, A., Valle, L., Capella, G., Aretz, S., Holinski-Feder, E., Steinke-Lange, V., Laner, A., Schröck, E., Rump, A., Ligtenberg, M., Hoischen, A., Geverink, N., Evans, D.G., Tischkowitz, M., Laurie, S., van der Post, R.S., Lubinski, J., Oliveira, C., Hoogerbrugge, N., de Voer, R.M., Sommer, Anna K [0000-0001-6850-9290], Starzynska, Teresa [0000-0001-5573-2397], Jakubowska, Anna [0000-0002-5650-0501], Hoogerbrugge, Nicoline [0000-0003-2393-8141], de Voer, Richarda M [0000-0002-8222-0343], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Adult, Somatic cell, Class I Phosphatidylinositol 3-Kinases, Mutation, Missense, Stomach Neoplasms/genetics, Brief Communication, Whole Exome Sequencing, Germline, CDH1, 03 medical and health sciences, 0302 clinical medicine, Stomach Neoplasms, Exome Sequencing, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Genetics, medicine, Cancer genomics, Missense mutation, Humans, Young adult, Genetics (clinical), Class I Phosphatidylinositol 3-Kinases/genetics, biology, business.industry, Mosaicism, Cancer, medicine.disease, Phenotype, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, biology.protein, Female, Hereditary diffuse gastric cancer, business, Gastric cancer
Abstract: Hereditary diffuse gastric cancer (HDGC) is associated with germline deleterious variants in CDH1 and CTNNA1. The majority of HDGC-suspected patients are still genetically unresolved, raising the need for identification of novel HDGC predisposing genes. Under the collaborative environment of the SOLVE-RD consortium, re-analysis of whole-exome sequencing data from unresolved gastric cancer cases (n = 83) identified a mosaic missense variant in PIK3CA in a 25-year-old female with diffuse gastric cancer (DGC) without familial history for cancer. The variant, c.3140A>G p.(His1047Arg), a known cancer-related somatic hotspot, was present at a low variant allele frequency (18%) in leukocyte-derived DNA. Somatic variants in PIK3CA are usually associated with overgrowth, a phenotype that was not observed in this patient. This report highlights mosaicism as a potential, and understudied, mechanism in the etiology of DGC. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. The research work at i3S/Ipatimup is supported by the European Regional Development Fund (ERDF) through COMPETE 2020 - Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT/ Ministério da Ciência, Tecnologia e Inovação in the framework of the project “Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274) and Project Ref. POCI-01-0145-FEDER-030164. Data was reanalysed using the RD‐Connect Genome‐Phenome Analysis Platform, which received funding from EU projects RD‐Connect, Solve-RD and EJP-RD (grant numbers FP7 305444, H2020 779257, H2020 825575), Instituto de Salud Carlos III (grant numbers PT13/0001/0044, PT17/0009/0019; Instituto Nacional de Bioinformática, INB) and ELIXIR Implementation Studies.
Published: 2021

46. Pathologic complete response to neoadjuvant cisplatin in BRCA1-positive breast cancer patients

Author: Byrski, T., Huzarski, T., Dent, R., Marczyk, E., Jasiowka, M., Gronwald, J., Jakubowicz, J., Cybulski, C., Wisniowski, R., Godlewski, D., Lubinski, J., and Narod, S. A.
Published: 2014
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47. Common variants of ZNF750, RPTOR and TRAF3IP2 genes and psoriasis risk

Author: Dębniak, T., Soczawa, E., Boer, M., Różewicka-Czabańska, M., Wiśniewska, J., Serrano-Fernandez, P., Mirecka, A., Paszkowska-Szczur, K., Lubinski, J., Krysztoforska, L., Adamski, Z., and Maleszka, R.
Published: 2014
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48. NOD2 variants and the risk of malignant melanoma

Author: Dȩbniak, T, Kurzawski, G, Huzarski, T, Byrski, T, Gronwald, J, Dȩbniak, B, Rozmiarek, A, Dziuba, I, Złowocka, E, Suchy, J, Górski, B, Cybulski, C, Mierzejewski, M, Masojć, B, Masoj, B, Mȩdrek, K, Oszurek, O, Oleg, O, and Lubiǹski, J
Published: 2005

49. Increased risk of breast cancer in relatives of malignant melanoma patients from families with strong cancer familial aggregation

Author: Dȩbniak, T, Górski, B, Cybulski, C, Jakubowska, A, Kurzawski, G, Kładny, J, Załuga, E, Fiedorowicz, J, Dȩbniak, B, and Lubiński, J
Published: 2003

50. Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element

Author: Baxter, J.S., Johnson, N., Tomczyk, K., Gillespie, A., Maguire, S., Brough, R., Fachal, L., Michailidou, K., Bolla, M.K., Wang, Q., Dennis, J., Ahearn, T.U., Andrulis, I.L., Anton-Culver, H., Antonenkova, N.N., Arndt, V., Aronson, K.J., Augustinsson, A., Becher, H., Beckmann, M.W., Behrens, S., Benitez, J., Bermisheva, M., Bogdanova, N.V., Bojesen, S.E., Brenner, H., Brucker, S.Y., Cai, Q.Y., Campa, D., Canzian, F., Castelao, J.E., Chan, T.L., Chang-Claude, J., Chanock, S.J., Chenevix-Trench, G., Choi, J.Y., Clarke, C.L., Collaborators, N., Colonna, S., Conroy, D.M., Couch, F.J., Cox, A., Cross, S.S., Czene, K., Daly, M.B., Devilee, P., Dork, T., Dossus, L., Dwek, M., Eccles, D.M., Ekici, A.B., Eliassen, A.H., Engel, C., Fasching, P.A., Figueroa, J., Flyger, H., Gago-Dominguez, M., Gao, C., Garcia-Closas, M., Garcia-Saenz, J.A., Ghoussaini, M., Giles, G.G., Goldberg, M.S., Gonzalez-Neira, A., Guenel, P., Gundert, M., Haeberle, L., Hahnen, E., Haiman, C.A., Hall, P., Hamann, U., Hartman, M., Hatse, S., Hauke, J., Hollestelle, A., Hoppe, R., Hopper, J.L., Hou, M.F., Ito, H., Iwasaki, M., Jager, A., Jakubowska, A., Janni, W., John, E.M., Joseph, V., Jung, A., Kaaks, R., Kang, D., Keeman, R., Khusnutdinova, E., Kim, S.W., Kosma, V.M., Kraft, P., Kristensen, V.N., Kubelka-Sabit, K., Kurian, A.W., Kwong, A., Lacey, J.V., Lambrechts, D., Larson, N.L., Larsson, S.C., Marchand, L. le, Lejbkowicz, F., Li, J.M., Long, J.R., Lophatananon, A., LubiNski, J., Mannermaa, A., Manoochehri, M., Manoukian, S., Margolin, S., Matsuo, K., Mavroudis, D., Mayes, R., Menon, U., Milne, R.L., Taib, N.A.M., Muir, K., Muranen, T.A., Murphy, R.A., Nevanlinna, H., O'Brien, K.M., Offit, K., Olson, J.E., Olsson, H., Park, S.K., Park-Simon, T.W., Patel, A.V., Peterlongo, P., Peto, J., Plaseska-Karanfilska, D., Presneau, N., Pylkas, K., Rack, B., Rennert, G., Romero, A., Ruebner, M., Rudiger, T., Saloustros, E., Sandler, D.P., Sawyer, E.J., Schmidt, M.K., Schmutzler, R.K., Schneeweiss, A., Schoemaker, M.J., Shah, M., Shen, C.Y., Shu, X.O., Simard, J., Southey, M.C., Stone, J., Surowy, H., Swerdlow, A.J., Tamimi, R.M., Tapper, W.J., Taylor, J.A., Teo, S.H., Teras, L.R., Terry, M.B., Toland, A.E., Tomlinson, I., Truong, T., Tseng, C.C., Untch, M., Vachon, C.M., Ouweland, A.M.W. van den, Wang, S.S., Weinberg, C.R., Wendt, C., Winham, S.J., Winqvist, R., Wolk, A., Wu, A.H., Yamaji, T., Zheng, W., Ziogas, A., Pharoah, P.D.P., Dunning, A.M., Easton, D.F., Pettitt, S.J., Lord, C.J., Haider, S., Orr, N., Fletcher, O., kConFab Investigators, ABCTB Investigators, Medical Oncology, Clinical Genetics, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, Biosciences, Dennis, Joe [0000-0003-4591-1214], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository
Subjects: Basic medicine, breast cancer risk, 0302 clinical medicine, Transcription (biology), Risk Factors, WIDE ASSOCIATION, TRANSCRIPTION, Promoter Regions, Genetic, Genetics (clinical), Sequence Deletion, Genetics, Genetics & Heredity, 0303 health sciences, Chromosome Mapping, 3. Good health, 030220 oncology & carcinogenesis, Chromosomes, Human, Pair 2, Pair 2, Female, Medical Genetics, Life Sciences & Biomedicine, Human, Tumor suppressor gene, SUSCEPTIBILITY LOCI, In silico, 3122 Cancers, Locus (genetics), Breast Neoplasms, Biology, Chromosomes, Article, Cell Line, RNAS, Promoter Regions, 03 medical and health sciences, functional annotation, risk locus, CRISPR-Cas Systems, Genetic Association Studies, Genetic Variation, Humans, Insulin-Like Growth Factor Binding Protein 5, Molecular Sequence Annotation, 11Q13, Genetic, SDG 3 - Good Health and Well-being, Enhancer, Transcription factor, 030304 developmental biology, Medicinsk genetik, Reporter gene, Science & Technology, IDENTIFICATION, Clinical medicine, Estrogen receptor alpha
Abstract: A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74-0.81, p = 3.1 × 10-31). ispartof: AMERICAN JOURNAL OF HUMAN GENETICS vol:108 issue:7 pages:1190-1203 ispartof: location:United States status: published
Published: 2021

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