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

Author

Barnes D.R., Silvestri V., Leslie G., McGuffog L., Dennis J., Yang X., Adlard J., Agnarsson B.A., Ahmed M., Aittomaki K., Andrulis I.L., Arason A., Arnold N., Auber B., Azzollini J., Balmana J., Barkardottir R.B., Barrowdale D., Barwell J., Belotti M., Benitez J., Berthet P., Boonen S.E., Borg A., Bozsik A., Brady A., Brennan P., Brewer C., Brunet J., Bucalo A., Buys S.S., Caldes T., Caligo M.A., Campbell I., Cassingham H., Lotte Christensen L., Cini G., Claes K.B.M., Cook J., Coppa A., Cortesi L., Damante G., Darder E., Davidson R., de la Hoya M., De Leeneer K., de Putter R., Del Valle J., Diez O., Chun Ding Y., Domchek S.M., Donaldson A., Eason J., Eeles R., Engel C., Gareth Evans D., Feliubadalo L., Fostira F., Frone M., Frost D., Gallagher D., Gehrig A., Giraud S., Glendon G., Godwin A.K., Goldgar D.E., Greene M.H., Gregory H., Gross E., Hahnen E., Hamann U., Hansen T.V.O., Hanson H., Hentschel J., Horvath J., Izatt L., Izquierdo A., James P.A., Janavicius R., Birk Jensen U., Johannsson O.T., John E.M., Kramer G., Kroeldrup L., Kruse T.A., Lautrup C., Lazaro C., Lesueur F., Lopez-Fernandez A., Mai P.L., Manoukian S., Matrai Z., Matricardi L., Maxwell K.N., Mebirouk N., Meindl A., Montagna M., Monteiro A.N., Morrison P.J., Muranen T.A., Murray A., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Nguyen-Dumont T., Niederacher D., Olah E., Olopade O.I., Palli D., Parsons M.T., Sokilde Pedersen I., Peissel B., Perez-Segura P., Peterlongo P., Petersen A.H., Pinto P., Porteous M.E., Pottinger C., Angel Pujana M., Radice P., Ramser J., Rantala J., Robson M., Rogers M.T., Ronlund K., Rump A., Maria Sanchez de Abajo A., Shah P.D., Sharif S., Side L.E., Singer C.F., Stadler Z., Steele L., Stoppa-Lyonnet D., Sutter C., Yen Tan Y., Teixeira M.R., Teule A., Thull D.L., Tischkowitz M., Toland A.E., Tommasi S., Toss A., Trainer A.H., Tripathi V., Valentini V., van Asperen C.J., Venturelli M., Viel A., Vijai J., Walker L., Wang-Gohrke S., Wappenschmidt B., Whaite A., Zanna I., Offit K., Thomassen M., Couch F.J., Schmutzler R.K., Simard J., Easton D.F., Chenevix-Trench G., Antoniou A.C., Ottini L., Barnes D.R., Silvestri V., Leslie G., McGuffog L., Dennis J., Yang X., Adlard J., Agnarsson B.A., Ahmed M., Aittomaki K., Andrulis I.L., Arason A., Arnold N., Auber B., Azzollini J., Balmana J., Barkardottir R.B., Barrowdale D., Barwell J., Belotti M., Benitez J., Berthet P., Boonen S.E., Borg A., Bozsik A., Brady A., Brennan P., Brewer C., Brunet J., Bucalo A., Buys S.S., Caldes T., Caligo M.A., Campbell I., Cassingham H., Lotte Christensen L., Cini G., Claes K.B.M., Cook J., Coppa A., Cortesi L., Damante G., Darder E., Davidson R., de la Hoya M., De Leeneer K., de Putter R., Del Valle J., Diez O., Chun Ding Y., Domchek S.M., Donaldson A., Eason J., Eeles R., Engel C., Gareth Evans D., Feliubadalo L., Fostira F., Frone M., Frost D., Gallagher D., Gehrig A., Giraud S., Glendon G., Godwin A.K., Goldgar D.E., Greene M.H., Gregory H., Gross E., Hahnen E., Hamann U., Hansen T.V.O., Hanson H., Hentschel J., Horvath J., Izatt L., Izquierdo A., James P.A., Janavicius R., Birk Jensen U., Johannsson O.T., John E.M., Kramer G., Kroeldrup L., Kruse T.A., Lautrup C., Lazaro C., Lesueur F., Lopez-Fernandez A., Mai P.L., Manoukian S., Matrai Z., Matricardi L., Maxwell K.N., Mebirouk N., Meindl A., Montagna M., Monteiro A.N., Morrison P.J., Muranen T.A., Murray A., Nathanson K.L., Neuhausen S.L., Nevanlinna H., Nguyen-Dumont T., Niederacher D., Olah E., Olopade O.I., Palli D., Parsons M.T., Sokilde Pedersen I., Peissel B., Perez-Segura P., Peterlongo P., Petersen A.H., Pinto P., Porteous M.E., Pottinger C., Angel Pujana M., Radice P., Ramser J., Rantala J., Robson M., Rogers M.T., Ronlund K., Rump A., Maria Sanchez de Abajo A., Shah P.D., Sharif S., Side L.E., Singer C.F., Stadler Z., Steele L., Stoppa-Lyonnet D., Sutter C., Yen Tan Y., Teixeira M.R., Teule A., Thull D.L., Tischkowitz M., Toland A.E., Tommasi S., Toss A., Trainer A.H., Tripathi V., Valentini V., van Asperen C.J., Venturelli M., Viel A., Vijai J., Walker L., Wang-Gohrke S., Wappenschmidt B., Whaite A., Zanna I., Offit K., Thomassen M., Couch F.J., Schmutzler R.K., Simard J., Easton D.F., Chenevix-Trench G., Antoniou A.C., and Ottini L.

Abstract

BACKGROUND: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers. METHOD(S): 483 BRCA1 and 1,318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were three versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen-receptor (ER) negative (PRSER-) or ER-positive (PRSER+) breast cancer risk. RESULT(S): PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07-1.83) for BRCA1 and 1.33 (95% CI=1.16-1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for both BRCA1 (OR=1.73, 95% CI=1.28-2.33) and BRCA2 (OR=1.60, 95% CI=1.34-1.91) carriers. The estimated breast cancer ORs were larger after adjusting for female relative breast cancer family history. By age 85years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions. CONCLUSION(S): Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and to inform clinical management.Copyright © The Author(s) 2021. Published by Oxford University Press.

Published
2021

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

Author

Patel, VL, Busch, EL, Friebel, TM, Cronin, A, Leslie, G, McGuffog, L, Adlard, J, Agata, S, Agnarsson, BA, Ahmed, M, Aittomaki, K, Alducci, E, Andrulis, IL, Arason, A, Arnold, N, Artioli, G, Arver, B, Auber, B, Azzollini, J, Balmana, J, Barkardottir, RB, Barnes, DR, Barroso, A, Barrowdale, D, Belotti, M, Benitez, J, Bertelsen, B, Blok, MJ, Bodrogi, I, Bonadona, V, Bonanni, B, Bondavalli, D, Boonen, SE, Borde, J, Borg, A, Bradbury, AR, Brady, A, Brewer, C, Brunet, J, Buecher, B, Buys, SS, Cabezas-Camarero, S, Caldes, T, Caliebe, A, Caligo, MA, Calvello, M, Campbell, IG, Carnevali, I, Carrasco, E, Chan, TL, Chu, ATW, Chung, WK, Claes, KBM, Cook, J, Cortesi, L, Couch, FJ, Daly, MB, Damante, G, Darder, E, Davidson, R, de la Hoya, M, Della Puppa, L, Dennis, J, Diez, O, Ding, YC, Ditsch, N, Domchek, SM, Donaldson, A, Dworniczak, B, Easton, DF, Eccles, DM, Eeles, RA, Ehrencrona, H, Ejlertsen, B, Engel, C, Evans, DG, Faivre, L, Faust, U, Feliubadalo, L, Foretova, L, Fostira, F, Fountzilas, G, Frost, D, Garcia-Barberan, V, Garre, P, Gauthier-Villars, M, Geczi, L, Gehrig, A, Gerdes, A-M, Gesta, P, Giannini, G, Glendon, G, Godwin, AK, Goldgar, DE, Greene, MH, Gutierrez-Barrera, AM, Hahnen, E, Hamann, U, Hauke, J, Herold, N, Hogervorst, FBL, Honisch, E, Hopper, JL, Hulick, PJ, Izatt, L, Jager, A, James, P, Janavicius, R, Jensen, UB, Jensen, TD, Johannsson, OT, John, EM, Joseph, V, Kang, E, Kast, K, Kiiski, J, Kim, S-W, Kim, Z, Ko, K-P, Konstantopoulou, I, Kramer, G, Krogh, L, Kruse, TA, Kwong, A, Larsen, M, Lasset, C, Lautrup, C, Lazaro, C, Lee, J, Lee, JW, Lee, MH, Lemke, J, Lesueur, F, Liljegren, A, Lindblom, A, Llovet, P, Lopez-Fernandez, A, Lopez-Perolio, I, Lorca, V, Loud, JT, Ma, ESK, Mai, PL, Manoukian, S, Mari, V, Martin, L, Matricardi, L, Mebirouk, N, Medici, V, Meijers-Heijboer, HEJ, Meindl, A, Mensenkamp, AR, Miller, C, Gomes, DM, Montagna, M, Mooij, TM, Moserle, L, Mouret-Fourme, E, Mulligan, AM, Nathanson, KL, Navratilova, M, Nevanlinna, H, Niederacher, D, Nielsen, FCC, Nikitina-Zake, L, Offit, K, Olah, E, Olopade, O, Ong, K-R, Osorio, A, Ott, C-E, Palli, D, Park, SK, Parsons, MT, Pedersen, IS, Peissel, B, Peixoto, A, Perez-Segura, P, Peterlongo, P, Petersen, AH, Porteous, ME, Angel Pujana, M, Radice, P, Ramser, J, Rantala, J, Rashid, MU, Rhiem, K, Rizzolo, P, Robson, ME, Rookus, MA, Rossing, CM, Ruddy, KJ, Santos, C, Saule, C, Scarpitta, R, Schmutzler, RK, Schuster, H, Senter, L, Seynaeve, CM, Shah, PD, Sharma, P, Shin, VY, Silvestri, V, Simard, J, Singer, CF, Skytte, A-B, Snape, K, Solano, AR, Soucy, P, Southey, MC, Spurdle, AB, Steele, L, Steinemann, D, Stoppa-Lyonnet, D, Stradella, A, Sunde, L, Sutter, C, Tan, YY, Teixeira, MR, Teo, SH, Thomassen, M, Tibiletti, MG, Tischkowitz, M, Tognazzo, S, Toland, AE, Tommasi, S, Torres, D, Toss, A, Trainer, AH, Tung, N, van Asperen, CJ, van der Baan, FH, van der Kolk, LE, van der Luijt, RB, van Hest, LP, Varesco, L, Varon-Mateeva, R, Viel, A, Vierstraete, J, Villa, R, von Wachenfeldt, A, Wagner, P, Wang-Gohrke, S, Wappenschmidt, B, Weitzel, JN, Wieme, G, Yadav, S, Yannoukakos, D, Yoon, S-Y, Zanzottera, C, Zorn, KK, D'Amico, A, Freedman, ML, Pomerantz, MM, Chenevix-Trench, G, Antoniou, AC, Neuhausen, SL, Ottini, L, Nielsen, HR, Rebbeck, TR, Patel, VL, Busch, EL, Friebel, TM, Cronin, A, Leslie, G, McGuffog, L, Adlard, J, Agata, S, Agnarsson, BA, Ahmed, M, Aittomaki, K, Alducci, E, Andrulis, IL, Arason, A, Arnold, N, Artioli, G, Arver, B, Auber, B, Azzollini, J, Balmana, J, Barkardottir, RB, Barnes, DR, Barroso, A, Barrowdale, D, Belotti, M, Benitez, J, Bertelsen, B, Blok, MJ, Bodrogi, I, Bonadona, V, Bonanni, B, Bondavalli, D, Boonen, SE, Borde, J, Borg, A, Bradbury, AR, Brady, A, Brewer, C, Brunet, J, Buecher, B, Buys, SS, Cabezas-Camarero, S, Caldes, T, Caliebe, A, Caligo, MA, Calvello, M, Campbell, IG, Carnevali, I, Carrasco, E, Chan, TL, Chu, ATW, Chung, WK, Claes, KBM, Cook, J, Cortesi, L, Couch, FJ, Daly, MB, Damante, G, Darder, E, Davidson, R, de la Hoya, M, Della Puppa, L, Dennis, J, Diez, O, Ding, YC, Ditsch, N, Domchek, SM, Donaldson, A, Dworniczak, B, Easton, DF, Eccles, DM, Eeles, RA, Ehrencrona, H, Ejlertsen, B, Engel, C, Evans, DG, Faivre, L, Faust, U, Feliubadalo, L, Foretova, L, Fostira, F, Fountzilas, G, Frost, D, Garcia-Barberan, V, Garre, P, Gauthier-Villars, M, Geczi, L, Gehrig, A, Gerdes, A-M, Gesta, P, Giannini, G, Glendon, G, Godwin, AK, Goldgar, DE, Greene, MH, Gutierrez-Barrera, AM, Hahnen, E, Hamann, U, Hauke, J, Herold, N, Hogervorst, FBL, Honisch, E, Hopper, JL, Hulick, PJ, Izatt, L, Jager, A, James, P, Janavicius, R, Jensen, UB, Jensen, TD, Johannsson, OT, John, EM, Joseph, V, Kang, E, Kast, K, Kiiski, J, Kim, S-W, Kim, Z, Ko, K-P, Konstantopoulou, I, Kramer, G, Krogh, L, Kruse, TA, Kwong, A, Larsen, M, Lasset, C, Lautrup, C, Lazaro, C, Lee, J, Lee, JW, Lee, MH, Lemke, J, Lesueur, F, Liljegren, A, Lindblom, A, Llovet, P, Lopez-Fernandez, A, Lopez-Perolio, I, Lorca, V, Loud, JT, Ma, ESK, Mai, PL, Manoukian, S, Mari, V, Martin, L, Matricardi, L, Mebirouk, N, Medici, V, Meijers-Heijboer, HEJ, Meindl, A, Mensenkamp, AR, Miller, C, Gomes, DM, Montagna, M, Mooij, TM, Moserle, L, Mouret-Fourme, E, Mulligan, AM, Nathanson, KL, Navratilova, M, Nevanlinna, H, Niederacher, D, Nielsen, FCC, Nikitina-Zake, L, Offit, K, Olah, E, Olopade, O, Ong, K-R, Osorio, A, Ott, C-E, Palli, D, Park, SK, Parsons, MT, Pedersen, IS, Peissel, B, Peixoto, A, Perez-Segura, P, Peterlongo, P, Petersen, AH, Porteous, ME, Angel Pujana, M, Radice, P, Ramser, J, Rantala, J, Rashid, MU, Rhiem, K, Rizzolo, P, Robson, ME, Rookus, MA, Rossing, CM, Ruddy, KJ, Santos, C, Saule, C, Scarpitta, R, Schmutzler, RK, Schuster, H, Senter, L, Seynaeve, CM, Shah, PD, Sharma, P, Shin, VY, Silvestri, V, Simard, J, Singer, CF, Skytte, A-B, Snape, K, Solano, AR, Soucy, P, Southey, MC, Spurdle, AB, Steele, L, Steinemann, D, Stoppa-Lyonnet, D, Stradella, A, Sunde, L, Sutter, C, Tan, YY, Teixeira, MR, Teo, SH, Thomassen, M, Tibiletti, MG, Tischkowitz, M, Tognazzo, S, Toland, AE, Tommasi, S, Torres, D, Toss, A, Trainer, AH, Tung, N, van Asperen, CJ, van der Baan, FH, van der Kolk, LE, van der Luijt, RB, van Hest, LP, Varesco, L, Varon-Mateeva, R, Viel, A, Vierstraete, J, Villa, R, von Wachenfeldt, A, Wagner, P, Wang-Gohrke, S, Wappenschmidt, B, Weitzel, JN, Wieme, G, Yadav, S, Yannoukakos, D, Yoon, S-Y, Zanzottera, C, Zorn, KK, D'Amico, A, Freedman, ML, Pomerantz, MM, Chenevix-Trench, G, Antoniou, AC, Neuhausen, SL, Ottini, L, Nielsen, HR, and Rebbeck, TR

Abstract

Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3' region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25-2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12-11.54; P = 0.0002). No genotype-phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. SIGNIFICANCE: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.

Published
2020

3. The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Author

Figlioli, G, Bogliolo, M, Catucci, I, Caleca, L, Viz Lasheras, S, Pujol, R, Kiiski, J, Muranen, TA, Barnes, DR, Dennis, J, Michailidou, K, Bolla, MK, Leslie, G, Aalfs, CM, Adank, MA, Adlard, J, Agata, S, Cadoo, K, Agnarsson, BA, Ahearn, T, Aittomaki, K, Ambrosone, CB, Andrews, L, Anton-Culver, H, Antonenkova, NN, Arndt, V, Arnold, N, Aronson, KJ, Arun, BK, Asseryanis, E, Auber, B, Auvinen, P, Azzollini, J, Balmana, J, Barkardottir, RB, Barrowdale, D, Barwell, J, Freeman, LEB, Beauparlant, CJ, Beckmann, MW, Behrens, S, Benitez, J, Berger, R, Bermisheva, M, Blanco, AM, Blomqvist, C, Bogdanova, N, Bojesen, A, Bojesen, SE, Bonanni, B, Borg, A, Brady, AF, Brauch, H, Brenner, H, Bruening, T, Burwinkel, B, Buys, SS, Caldes, T, Caliebe, A, Caligo, MA, Campa, D, Campbell, IG, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Claes, KBM, Clarke, CL, Collavoli, A, Conner, TA, Cox, DG, Cybulski, C, Czene, K, Daly, MB, de la Hoya, M, Devilee, P, Diez, O, Ding, YC, Dite, GS, Ditsch, N, Domchek, SM, Dorfling, CM, dos-Santos-Silva, I, Durda, K, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Ellberg, C, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Flyger, H, Foulkes, WD, Friebel, TM, Friedman, E, Gabrielson, M, Gaddam, P, Gago-Dominguez, M, Gao, C, Gapstur, SM, Garber, J, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Gayther, SA, Giles, GG, Glendon, G, Godwin, AK, Goldberg, MS, Goldgar, DE, Guenel, P, Gutierrez-Barrera, AM, Haeberle, L, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Harrington, PA, Hein, A, Heyworth, J, Hillemanns, P, Hollestelle, A, Hopper, JL, Hosgood, HD, Howell, A, Hu, C, Hulick, PJ, Hunter, DJ, Imyanitov, EN, Isaacs, C, Jakimovska, M, Jakubowska, A, James, P, Janavicius, R, Janni, W, John, EM, Jones, ME, Jung, A, Kaaks, R, Karlan, BY, Khusnutdinova, E, Kitahara, CM, Konstantopoulou, I, Koutros, S, Kraft, P, Lambrechts, D, Lazaro, C, Le Marchand, L, Lester, J, Lesueur, F, Lilyquist, J, Loud, JT, Lu, KH, Luben, RN, Lubinski, J, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martens, JWM, Maurer, T, Mavroudis, D, Mebirouk, N, Meindl, A, Menon, U, Miller, A, Montagna, M, Nathanson, KL, Neuhausen, SL, Newman, WG, Nguyen-Dumont, T, Nielsen, FC, Nielsen, S, Nikitina-Zake, L, Offit, K, Olah, E, Olopade, O, Olshan, AF, Olson, JE, Olsson, H, Osorio, A, Ottini, L, Peissel, B, Peixoto, A, Peto, J, Plaseska-Karanfilska, D, Pocza, T, Presneau, N, Angel Pujana, M, Punie, K, Rack, B, Rantala, J, Rashid, MU, Rau-Murthy, R, Rennert, G, Lejbkowicz, F, Rhenius, V, Romero, A, Rookus, MA, Ross, EA, Rossing, M, Rudaitis, V, Ruebner, M, Saloustros, E, Sanden, K, Santamarina, M, Scheuner, MT, Schmutzler, RK, Schneider, M, Scott, C, Senter, L, Shah, M, Sharma, P, Shu, X-O, Simard, J, Singer, CF, Sohn, C, Soucy, P, Southey, MC, Spinelli, JJ, Steele, L, Stoppa-Lyonnet, D, Tapper, WJ, Teixeira, MR, Terry, MB, Thomassen, M, Thompson, J, Thull, DL, Tischkowitz, M, Tollenaar, RAEM, Torres, D, Troester, MA, Truong, T, Tung, N, Untch, M, Vachon, CM, van Rensburg, EJ, van Veen, EM, Vega, A, Viel, A, Wappenschmidt, B, Weitzel, JN, Wendt, C, Wieme, G, Wolk, A, Yang, XR, Zheng, W, Ziogas, A, Zorn, KK, Dunning, AM, Lush, M, Wang, Q, McGuffog, L, Parsons, MT, Pharoah, PDP, Fostira, F, Toland, AE, Andrulis, IL, Ramus, SJ, Swerdlow, AJ, Greene, MH, Chung, WK, Milne, RL, Chenevix-Trench, G, Doerk, T, Schmidt, MK, Easton, DF, Radice, P, Hahnen, E, Antoniou, AC, Couch, FJ, Nevanlinna, H, Surralles, J, Peterlongo, P, Balleine, R, Baxter, R, Braye, S, Carpenter, J, Dahlstrom, J, Forbes, J, Lee, CS, Marsh, D, Morey, A, Pathmanathan, N, Scott, R, Simpson, P, Spigelman, A, Wilcken, N, Yip, D, Zeps, N, Belotti, M, Bertrand, O, Birot, A-M, Buecher, B, Caputo, S, Dupre, A, Fourme, E, Gauthier-Villars, M, Golmard, L, Le Mentec, M, Moncoutier, V, de Pauw, A, Saule, C, Boutry-Kryza, N, Calender, A, Giraud, S, Leone, M, Bressac-de-Paillerets, B, Caron, O, Guillaud-Bataille, M, Bignon, Y-J, Uhrhammer, N, Bonadona, V, Lasset, C, Berthet, P, Castera, L, Vaur, D, Bourdon, V, Nogues, C, Noguchi, T, Popovici, C, Remenieras, A, Sobol, H, Coupier, I, Pujol, P, Adenis, C, Dumont, A, Revillion, F, Muller, D, Barouk-Simonet, E, Bonnet, F, Bubien, V, Longy, M, Sevenet, N, Gladieff, L, Guimbaud, R, Feillel, V, Toulas, C, Dreyfus, H, Leroux, CD, Peysselon, M, Rebischung, C, Legrand, C, Baurand, A, Bertolone, G, Coron, F, Faivre, L, Jacquot, C, Lizard, S, Kientz, C, Lebrun, M, Prieur, F, Fert-Ferrer, S, Mari, V, Venat-Bouvet, L, Bezieau, S, Delnatte, C, Mortemousque, I, Colas, C, Coulet, F, Soubrier, F, Warcoin, M, Bronner, M, Sokolowska, J, Collonge-Rame, M-A, Damette, A, Gesta, P, Lallaoui, H, Chiesa, J, Molina-Gomes, D, Ingster, O, Manouvrier-Hanu, S, Lejeune, S, Aghmesheh, M, Greening, S, Amor, D, Gattas, M, Botes, L, Buckley, M, Friedlander, M, Koehler, J, Meiser, B, Saleh, M, Salisbury, E, Trainer, A, Tucker, K, Antill, Y, Dobrovic, A, Fellows, A, Fox, S, Harris, M, Nightingale, S, Phillips, K, Sambrook, J, Thorne, H, Armitage, S, Arnold, L, Kefford, R, Kirk, J, Rickard, E, Bastick, P, Beesley, J, Hayward, N, Spurdle, A, Walker, L, Beilby, J, Saunders, C, Bennett, I, Blackburn, A, Bogwitz, M, Gaff, C, Lindeman, G, Pachter, N, Sexton, A, Visvader, J, Taylor, J, Winship, I, Brennan, M, Brown, M, French, J, Edwards, S, Burgess, M, Burke, J, Patterson, B, Butow, P, Culling, B, Caldon, L, Callen, D, Chauhan, D, Eisenbruch, M, Heiniger, L, Chauhan, M, Christian, A, Dixon, J, Kidd, A, Cohen, P, Colley, A, Fenton, G, Crook, A, Dickson, R, Field, M, Cui, J, Cummings, M, Dawson, S-J, DeFazio, A, Delatycki, M, Dudding, T, Edkins, T, Farshid, G, Flanagan, J, Fong, P, Forrest, L, Gallego-Ortega, D, George, P, Gill, G, Kollias, J, Haan, E, Hart, S, Jenkins, M, Hunt, C, Lakhani, S, Lipton, L, Lobb, L, Mann, G, McLachlan, SA, O'Connell, S, O'Sullivan, S, Pieper, E, Robinson, B, Saunus, J, Scott, E, Shelling, A, Williams, R, Young, MA, Figlioli, G, Bogliolo, M, Catucci, I, Caleca, L, Viz Lasheras, S, Pujol, R, Kiiski, J, Muranen, TA, Barnes, DR, Dennis, J, Michailidou, K, Bolla, MK, Leslie, G, Aalfs, CM, Adank, MA, Adlard, J, Agata, S, Cadoo, K, Agnarsson, BA, Ahearn, T, Aittomaki, K, Ambrosone, CB, Andrews, L, Anton-Culver, H, Antonenkova, NN, Arndt, V, Arnold, N, Aronson, KJ, Arun, BK, Asseryanis, E, Auber, B, Auvinen, P, Azzollini, J, Balmana, J, Barkardottir, RB, Barrowdale, D, Barwell, J, Freeman, LEB, Beauparlant, CJ, Beckmann, MW, Behrens, S, Benitez, J, Berger, R, Bermisheva, M, Blanco, AM, Blomqvist, C, Bogdanova, N, Bojesen, A, Bojesen, SE, Bonanni, B, Borg, A, Brady, AF, Brauch, H, Brenner, H, Bruening, T, Burwinkel, B, Buys, SS, Caldes, T, Caliebe, A, Caligo, MA, Campa, D, Campbell, IG, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Claes, KBM, Clarke, CL, Collavoli, A, Conner, TA, Cox, DG, Cybulski, C, Czene, K, Daly, MB, de la Hoya, M, Devilee, P, Diez, O, Ding, YC, Dite, GS, Ditsch, N, Domchek, SM, Dorfling, CM, dos-Santos-Silva, I, Durda, K, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Ellberg, C, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Flyger, H, Foulkes, WD, Friebel, TM, Friedman, E, Gabrielson, M, Gaddam, P, Gago-Dominguez, M, Gao, C, Gapstur, SM, Garber, J, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Gayther, SA, Giles, GG, Glendon, G, Godwin, AK, Goldberg, MS, Goldgar, DE, Guenel, P, Gutierrez-Barrera, AM, Haeberle, L, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Harrington, PA, Hein, A, Heyworth, J, Hillemanns, P, Hollestelle, A, Hopper, JL, Hosgood, HD, Howell, A, Hu, C, Hulick, PJ, Hunter, DJ, Imyanitov, EN, Isaacs, C, Jakimovska, M, Jakubowska, A, James, P, Janavicius, R, Janni, W, John, EM, Jones, ME, Jung, A, Kaaks, R, Karlan, BY, Khusnutdinova, E, Kitahara, CM, Konstantopoulou, I, Koutros, S, Kraft, P, Lambrechts, D, Lazaro, C, Le Marchand, L, Lester, J, Lesueur, F, Lilyquist, J, Loud, JT, Lu, KH, Luben, RN, Lubinski, J, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martens, JWM, Maurer, T, Mavroudis, D, Mebirouk, N, Meindl, A, Menon, U, Miller, A, Montagna, M, Nathanson, KL, Neuhausen, SL, Newman, WG, Nguyen-Dumont, T, Nielsen, FC, Nielsen, S, Nikitina-Zake, L, Offit, K, Olah, E, Olopade, O, Olshan, AF, Olson, JE, Olsson, H, Osorio, A, Ottini, L, Peissel, B, Peixoto, A, Peto, J, Plaseska-Karanfilska, D, Pocza, T, Presneau, N, Angel Pujana, M, Punie, K, Rack, B, Rantala, J, Rashid, MU, Rau-Murthy, R, Rennert, G, Lejbkowicz, F, Rhenius, V, Romero, A, Rookus, MA, Ross, EA, Rossing, M, Rudaitis, V, Ruebner, M, Saloustros, E, Sanden, K, Santamarina, M, Scheuner, MT, Schmutzler, RK, Schneider, M, Scott, C, Senter, L, Shah, M, Sharma, P, Shu, X-O, Simard, J, Singer, CF, Sohn, C, Soucy, P, Southey, MC, Spinelli, JJ, Steele, L, Stoppa-Lyonnet, D, Tapper, WJ, Teixeira, MR, Terry, MB, Thomassen, M, Thompson, J, Thull, DL, Tischkowitz, M, Tollenaar, RAEM, Torres, D, Troester, MA, Truong, T, Tung, N, Untch, M, Vachon, CM, van Rensburg, EJ, van Veen, EM, Vega, A, Viel, A, Wappenschmidt, B, Weitzel, JN, Wendt, C, Wieme, G, Wolk, A, Yang, XR, Zheng, W, Ziogas, A, Zorn, KK, Dunning, AM, Lush, M, Wang, Q, McGuffog, L, Parsons, MT, Pharoah, PDP, Fostira, F, Toland, AE, Andrulis, IL, Ramus, SJ, Swerdlow, AJ, Greene, MH, Chung, WK, Milne, RL, Chenevix-Trench, G, Doerk, T, Schmidt, MK, Easton, DF, Radice, P, Hahnen, E, Antoniou, AC, Couch, FJ, Nevanlinna, H, Surralles, J, Peterlongo, P, Balleine, R, Baxter, R, Braye, S, Carpenter, J, Dahlstrom, J, Forbes, J, Lee, CS, Marsh, D, Morey, A, Pathmanathan, N, Scott, R, Simpson, P, Spigelman, A, Wilcken, N, Yip, D, Zeps, N, Belotti, M, Bertrand, O, Birot, A-M, Buecher, B, Caputo, S, Dupre, A, Fourme, E, Gauthier-Villars, M, Golmard, L, Le Mentec, M, Moncoutier, V, de Pauw, A, Saule, C, Boutry-Kryza, N, Calender, A, Giraud, S, Leone, M, Bressac-de-Paillerets, B, Caron, O, Guillaud-Bataille, M, Bignon, Y-J, Uhrhammer, N, Bonadona, V, Lasset, C, Berthet, P, Castera, L, Vaur, D, Bourdon, V, Nogues, C, Noguchi, T, Popovici, C, Remenieras, A, Sobol, H, Coupier, I, Pujol, P, Adenis, C, Dumont, A, Revillion, F, Muller, D, Barouk-Simonet, E, Bonnet, F, Bubien, V, Longy, M, Sevenet, N, Gladieff, L, Guimbaud, R, Feillel, V, Toulas, C, Dreyfus, H, Leroux, CD, Peysselon, M, Rebischung, C, Legrand, C, Baurand, A, Bertolone, G, Coron, F, Faivre, L, Jacquot, C, Lizard, S, Kientz, C, Lebrun, M, Prieur, F, Fert-Ferrer, S, Mari, V, Venat-Bouvet, L, Bezieau, S, Delnatte, C, Mortemousque, I, Colas, C, Coulet, F, Soubrier, F, Warcoin, M, Bronner, M, Sokolowska, J, Collonge-Rame, M-A, Damette, A, Gesta, P, Lallaoui, H, Chiesa, J, Molina-Gomes, D, Ingster, O, Manouvrier-Hanu, S, Lejeune, S, Aghmesheh, M, Greening, S, Amor, D, Gattas, M, Botes, L, Buckley, M, Friedlander, M, Koehler, J, Meiser, B, Saleh, M, Salisbury, E, Trainer, A, Tucker, K, Antill, Y, Dobrovic, A, Fellows, A, Fox, S, Harris, M, Nightingale, S, Phillips, K, Sambrook, J, Thorne, H, Armitage, S, Arnold, L, Kefford, R, Kirk, J, Rickard, E, Bastick, P, Beesley, J, Hayward, N, Spurdle, A, Walker, L, Beilby, J, Saunders, C, Bennett, I, Blackburn, A, Bogwitz, M, Gaff, C, Lindeman, G, Pachter, N, Sexton, A, Visvader, J, Taylor, J, Winship, I, Brennan, M, Brown, M, French, J, Edwards, S, Burgess, M, Burke, J, Patterson, B, Butow, P, Culling, B, Caldon, L, Callen, D, Chauhan, D, Eisenbruch, M, Heiniger, L, Chauhan, M, Christian, A, Dixon, J, Kidd, A, Cohen, P, Colley, A, Fenton, G, Crook, A, Dickson, R, Field, M, Cui, J, Cummings, M, Dawson, S-J, DeFazio, A, Delatycki, M, Dudding, T, Edkins, T, Farshid, G, Flanagan, J, Fong, P, Forrest, L, Gallego-Ortega, D, George, P, Gill, G, Kollias, J, Haan, E, Hart, S, Jenkins, M, Hunt, C, Lakhani, S, Lipton, L, Lobb, L, Mann, G, McLachlan, SA, O'Connell, S, O'Sullivan, S, Pieper, E, Robinson, B, Saunus, J, Scott, E, Shelling, A, Williams, R, and Young, MA

Abstract

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.

Published
2019

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

Author

Silvestri, V, Barrowdale, D, Mulligan, AM, Neuhausen, SL, Fox, S, Karlan, BY, Mitchell, G, James, P, Thull, DL, Zorn, KK, Carter, NJ, Nathanson, KL, Dornchek, SM, Rebbeck, TR, Ramus, SJ, Nussbaum, RL, Olopade, OI, Rantala, J, Yoon, S-Y, Caligo, MA, Spugnesi, L, Bojesen, A, Pedersen, IS, Thomassen, M, Jensen, UB, Toland, AE, Senter, L, Andrulis, IL, Glendon, G, Hulick, PJ, Irnyanitov, EN, Greene, MH, Mai, PL, Singer, CF, Rappaport-Fuerhauser, C, Kramer, G, Vijai, J, Offit, K, Robson, M, Lincoln, A, Jacobs, L, Machackova, E, Foretova, L, Navratilova, M, Vasickova, P, Couch, FJ, Hallberg, E, Ruddy, KJ, Sharma, P, Kim, S-W, Teixeira, MR, Pinte, P, Montagna, M, Matricardi, L, Arason, A, Johannsson, OT, Barkardottir, RB, Jakubowska, A, Lubinski, J, Izquierdo, A, Angel Pujana, M, Balmana, J, Diez, O, Ivady, G, Papp, J, Olah, E, Kwong, A, Nevanlinna, H, Aittomaki, K, Perez Segura, P, Caldes, T, Van Maerken, T, Poppe, B, Claes, KBM, Isaacs, C, Elan, C, Lasset, C, Stoppa-Lyonnet, D, Barjhoux, L, Belotti, M, Meindl, A, Gehrig, A, Sutter, C, Enger, C, Niederacher, D, Steinemann, D, Hahnen, E, Kast, K, Arnold, N, Varon-Mateeva, R, Wand, D, Godwin, AK, Evans, DG, Frost, D, Perkins, J, Adlard, J, Izatt, L, Platte, R, Eeles, R, Ellis, S, Hamann, U, Garber, J, Fostira, F, Fountzilas, G, Pasini, B, Giannini, G, Rizzolo, P, Russo, A, Cortesi, L, Papi, L, Varesco, L, Palli, D, Zanna, I, Savarese, A, Radice, P, Manoukian, S, Peissel, B, Barile, M, Bonanni, B, Viel, A, Pensotti, V, Tommasi, S, Peterlongo, P, Weitzel, JN, Osorio, A, Benitez, J, McGuffog, L, Healey, S, Gerdes, A-M, Ejlertsen, B, Hansen, TVO, Steele, L, Ding, YC, Tung, N, Janavicius, R, Goldgar, DE, Buys, SS, Daly, MB, Bane, A, Terry, MB, John, EM, Southey, M, Easton, DF, Chenevix-Trench, G, Antoniou, AC, Ottini, L, Silvestri, V, Barrowdale, D, Mulligan, AM, Neuhausen, SL, Fox, S, Karlan, BY, Mitchell, G, James, P, Thull, DL, Zorn, KK, Carter, NJ, Nathanson, KL, Dornchek, SM, Rebbeck, TR, Ramus, SJ, Nussbaum, RL, Olopade, OI, Rantala, J, Yoon, S-Y, Caligo, MA, Spugnesi, L, Bojesen, A, Pedersen, IS, Thomassen, M, Jensen, UB, Toland, AE, Senter, L, Andrulis, IL, Glendon, G, Hulick, PJ, Irnyanitov, EN, Greene, MH, Mai, PL, Singer, CF, Rappaport-Fuerhauser, C, Kramer, G, Vijai, J, Offit, K, Robson, M, Lincoln, A, Jacobs, L, Machackova, E, Foretova, L, Navratilova, M, Vasickova, P, Couch, FJ, Hallberg, E, Ruddy, KJ, Sharma, P, Kim, S-W, Teixeira, MR, Pinte, P, Montagna, M, Matricardi, L, Arason, A, Johannsson, OT, Barkardottir, RB, Jakubowska, A, Lubinski, J, Izquierdo, A, Angel Pujana, M, Balmana, J, Diez, O, Ivady, G, Papp, J, Olah, E, Kwong, A, Nevanlinna, H, Aittomaki, K, Perez Segura, P, Caldes, T, Van Maerken, T, Poppe, B, Claes, KBM, Isaacs, C, Elan, C, Lasset, C, Stoppa-Lyonnet, D, Barjhoux, L, Belotti, M, Meindl, A, Gehrig, A, Sutter, C, Enger, C, Niederacher, D, Steinemann, D, Hahnen, E, Kast, K, Arnold, N, Varon-Mateeva, R, Wand, D, Godwin, AK, Evans, DG, Frost, D, Perkins, J, Adlard, J, Izatt, L, Platte, R, Eeles, R, Ellis, S, Hamann, U, Garber, J, Fostira, F, Fountzilas, G, Pasini, B, Giannini, G, Rizzolo, P, Russo, A, Cortesi, L, Papi, L, Varesco, L, Palli, D, Zanna, I, Savarese, A, Radice, P, Manoukian, S, Peissel, B, Barile, M, Bonanni, B, Viel, A, Pensotti, V, Tommasi, S, Peterlongo, P, Weitzel, JN, Osorio, A, Benitez, J, McGuffog, L, Healey, S, Gerdes, A-M, Ejlertsen, B, Hansen, TVO, Steele, L, Ding, YC, Tung, N, Janavicius, R, Goldgar, DE, Buys, SS, Daly, MB, Bane, A, Terry, MB, John, EM, Southey, M, Easton, DF, Chenevix-Trench, G, Antoniou, AC, and Ottini, L

Abstract

BACKGROUND: BRCA1 and, more commonly, BRCA2 mutations are associated with increased risk of male breast cancer (MBC). However, only a paucity of data exists on the pathology of breast cancers (BCs) in men with BRCA1/2 mutations. Using the largest available dataset, we determined whether MBCs arising in BRCA1/2 mutation carriers display specific pathologic features and whether these features differ from those of BRCA1/2 female BCs (FBCs). METHODS: We characterised the pathologic features of 419 BRCA1/2 MBCs and, using logistic regression analysis, contrasted those with data from 9675 BRCA1/2 FBCs and with population-based data from 6351 MBCs in the Surveillance, Epidemiology, and End Results (SEER) database. RESULTS: Among BRCA2 MBCs, grade significantly decreased with increasing age at diagnosis (P = 0.005). Compared with BRCA2 FBCs, BRCA2 MBCs were of significantly higher stage (P for trend = 2 × 10(-5)) and higher grade (P for trend = 0.005) and were more likely to be oestrogen receptor-positive [odds ratio (OR) 10.59; 95 % confidence interval (CI) 5.15-21.80] and progesterone receptor-positive (OR 5.04; 95 % CI 3.17-8.04). With the exception of grade, similar patterns of associations emerged when we compared BRCA1 MBCs and FBCs. BRCA2 MBCs also presented with higher grade than MBCs from the SEER database (P for trend = 4 × 10(-12)). CONCLUSIONS: On the basis of the largest series analysed to date, our results show that BRCA1/2 MBCs display distinct pathologic characteristics compared with BRCA1/2 FBCs, and we identified a specific BRCA2-associated MBC phenotype characterised by a variable suggesting greater biological aggressiveness (i.e., high histologic grade). These findings could lead to the development of gender-specific risk prediction models and guide clinical strategies appropriate for MBC management.

Published
2016

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

Author

Kuchenbaecker, KB, Ramus, SJ, Tyrer, J, Lee, A, Shen, HC, Beesley, J, Lawrenson, K, McGuffog, L, Healey, S, Lee, JM, Spindler, TJ, Lin, YG, Pejovic, T, Bean, Y, Li, Q, Coetzee, S, Hazelett, D, Miron, A, Southey, M, Terry, MB, Goldgar, DE, Buys, SS, Janavicius, R, Dorfling, CM, van Rensburg, EJ, Neuhausen, SL, Ding, YC, Hansen, TVO, Jonson, L, Gerdes, A-M, Ejlertsen, B, Barrowdale, D, Dennis, J, Benitez, J, Osorio, A, Garcia, MJ, Komenaka, I, Weitzel, JN, Ganschow, P, Peterlongo, P, Bernard, L, Viel, A, Bonanni, B, Peissel, B, Manoukian, S, Radice, P, Papi, L, Ottini, L, Fostira, F, Konstantopoulou, I, Garber, J, Frost, D, Perkins, J, Platte, R, Ellis, S, Godwin, AK, Schmutzler, RK, Meindl, A, Engel, C, Sutter, C, Sinilnikova, OM, Damiola, F, Mazoyer, S, Stoppa-Lyonnet, D, Claes, K, De Leeneer, K, Kirk, J, Rodriguez, GC, Piedmonte, M, O'Malley, DM, de la Hoya, M, Caldes, T, Aittomaeki, K, Nevanlinna, H, Collee, JM, Rookus, MA, Oosterwijk, JC, Tihomirova, L, Tung, N, Hamann, U, Isaccs, C, Tischkowitz, M, Imyanitov, EN, Caligo, MA, Campbell, IG, Hogervorst, FBL, Olah, E, Diez, O, Blanco, I, Brunet, J, Lazaroso, C, Angel Pujana, M, Jakubowska, A, Gronwald, J, Lubinski, J, Sukiennicki, G, Barkardottir, RB, Plante, M, Simard, J, Soucy, P, Montagna, M, Tognazzo, S, Teixeira, MR, Pankratz, VS, Wang, X, Lindor, N, Szabo, CI, Kauff, N, Vijai, J, Aghajanian, CA, Pfeiler, G, Berger, A, Singer, CF, Tea, M-K, Phelan, CM, Greene, MH, Mai, PL, Rennert, G, Mulligan, AM, Tchatchou, S, Andrulis, IL, Glendon, G, Toland, AE, Jensen, UB, Kruse, TA, Thomassen, M, Bojesen, A, Zidan, J, Friedman, E, Laitman, Y, Soller, M, Liljegren, A, Arver, B, Einbeigi, Z, Stenmark-Askmalm, M, Olopade, OI, Nussbaum, RL, Rebbeck, TR, Nathanson, KL, Domchek, SM, Lu, KH, Karlan, BY, Walsh, C, Lester, J, Hein, A, Ekici, AB, Beckmann, MW, Fasching, PA, Lambrechts, D, Van Nieuwenhuysen, E, Vergote, I, Lambrechts, S, Dicks, E, Doherty, JA, Wicklund, KG, Rossing, MA, Rudolph, A, Chang-Claude, J, Wang-Gohrke, S, Eilber, U, Moysich, KB, Odunsi, K, Sucheston, L, Lele, S, Wilkens, LR, Goodman, MT, Thompson, PJ, Shvetsov, YB, Runnebaum, IB, Duerst, M, Hillemanns, P, Doerk, T, Antonenkova, N, Bogdanova, N, Leminen, A, Pelttari, LM, Butzow, R, Modugno, F, Kelley, JL, Edwards, RP, Ness, RB, du Bois, A, Heitz, F, Schwaab, I, Harter, P, Matsuo, K, Hosono, S, Orsulic, S, Jensen, A, Kjaer, SK, Hogdall, E, Hasmad, HN, Azmi, MAN, Teo, S-H, Woo, Y-L, Fridley, BL, Goode, EL, Cunningham, JM, Vierkant, RA, Bruinsma, F, Giles, GG, Liang, D, Hildebrandt, MAT, Wu, X, Levine, DA, Bisogna, M, Berchuck, A, Iversen, ES, Schildkraut, JM, Concannon, P, Weber, RP, Cramer, DW, Terry, KL, Poole, EM, Tworoger, SS, Bandera, EV, Orlow, I, Olson, SH, Krakstad, C, Salvesen, HB, Tangen, IL, Bjorge, L, van Altena, AM, Aben, KKH, Kiemeney, LA, Massuger, LFAG, Kellar, M, Brooks-Wilson, A, Kelemen, LE, Cook, LS, Le, ND, Cybulski, C, Yang, H, Lissowska, J, Brinton, LA, Wentzensen, N, Hogdall, C, Lundvall, L, Nedergaard, L, Baker, H, Song, H, Eccles, D, McNeish, I, Paul, J, Carty, K, Siddiqui, N, Glasspool, R, Whittemore, AS, Rothstein, JH, McGuire, V, Sieh, W, Ji, B-T, Zheng, W, Shu, X-O, Gao, Y-T, Rosen, B, Risch, HA, McLaughlin, JR, Narod, SA, Monteiro, AN, Chen, A, Lin, H-Y, Permuth-Wey, J, Sellers, TA, Tsai, Y-Y, Chen, Z, Ziogas, A, Anton-Culver, H, Gentry-Maharaj, A, Menon, U, Harrington, P, Lee, AW, Wu, AH, Pearce, CL, Coetzee, G, Pike, MC, Dansonka-Mieszkowska, A, Timorek, A, Rzepecka, IK, Kupryjanczyk, J, Freedman, M, Noushmehr, H, Easton, DF, Offit, K, Couch, FJ, Gayther, S, Pharoah, PP, Antoniou, AC, Chenevix-Trench, G, Kuchenbaecker, KB, Ramus, SJ, Tyrer, J, Lee, A, Shen, HC, Beesley, J, Lawrenson, K, McGuffog, L, Healey, S, Lee, JM, Spindler, TJ, Lin, YG, Pejovic, T, Bean, Y, Li, Q, Coetzee, S, Hazelett, D, Miron, A, Southey, M, Terry, MB, Goldgar, DE, Buys, SS, Janavicius, R, Dorfling, CM, van Rensburg, EJ, Neuhausen, SL, Ding, YC, Hansen, TVO, Jonson, L, Gerdes, A-M, Ejlertsen, B, Barrowdale, D, Dennis, J, Benitez, J, Osorio, A, Garcia, MJ, Komenaka, I, Weitzel, JN, Ganschow, P, Peterlongo, P, Bernard, L, Viel, A, Bonanni, B, Peissel, B, Manoukian, S, Radice, P, Papi, L, Ottini, L, Fostira, F, Konstantopoulou, I, Garber, J, Frost, D, Perkins, J, Platte, R, Ellis, S, Godwin, AK, Schmutzler, RK, Meindl, A, Engel, C, Sutter, C, Sinilnikova, OM, Damiola, F, Mazoyer, S, Stoppa-Lyonnet, D, Claes, K, De Leeneer, K, Kirk, J, Rodriguez, GC, Piedmonte, M, O'Malley, DM, de la Hoya, M, Caldes, T, Aittomaeki, K, Nevanlinna, H, Collee, JM, Rookus, MA, Oosterwijk, JC, Tihomirova, L, Tung, N, Hamann, U, Isaccs, C, Tischkowitz, M, Imyanitov, EN, Caligo, MA, Campbell, IG, Hogervorst, FBL, Olah, E, Diez, O, Blanco, I, Brunet, J, Lazaroso, C, Angel Pujana, M, Jakubowska, A, Gronwald, J, Lubinski, J, Sukiennicki, G, Barkardottir, RB, Plante, M, Simard, J, Soucy, P, Montagna, M, Tognazzo, S, Teixeira, MR, Pankratz, VS, Wang, X, Lindor, N, Szabo, CI, Kauff, N, Vijai, J, Aghajanian, CA, Pfeiler, G, Berger, A, Singer, CF, Tea, M-K, Phelan, CM, Greene, MH, Mai, PL, Rennert, G, Mulligan, AM, Tchatchou, S, Andrulis, IL, Glendon, G, Toland, AE, Jensen, UB, Kruse, TA, Thomassen, M, Bojesen, A, Zidan, J, Friedman, E, Laitman, Y, Soller, M, Liljegren, A, Arver, B, Einbeigi, Z, Stenmark-Askmalm, M, Olopade, OI, Nussbaum, RL, Rebbeck, TR, Nathanson, KL, Domchek, SM, Lu, KH, Karlan, BY, Walsh, C, Lester, J, Hein, A, Ekici, AB, Beckmann, MW, Fasching, PA, Lambrechts, D, Van Nieuwenhuysen, E, Vergote, I, Lambrechts, S, Dicks, E, Doherty, JA, Wicklund, KG, Rossing, MA, Rudolph, A, Chang-Claude, J, Wang-Gohrke, S, Eilber, U, Moysich, KB, Odunsi, K, Sucheston, L, Lele, S, Wilkens, LR, Goodman, MT, Thompson, PJ, Shvetsov, YB, Runnebaum, IB, Duerst, M, Hillemanns, P, Doerk, T, Antonenkova, N, Bogdanova, N, Leminen, A, Pelttari, LM, Butzow, R, Modugno, F, Kelley, JL, Edwards, RP, Ness, RB, du Bois, A, Heitz, F, Schwaab, I, Harter, P, Matsuo, K, Hosono, S, Orsulic, S, Jensen, A, Kjaer, SK, Hogdall, E, Hasmad, HN, Azmi, MAN, Teo, S-H, Woo, Y-L, Fridley, BL, Goode, EL, Cunningham, JM, Vierkant, RA, Bruinsma, F, Giles, GG, Liang, D, Hildebrandt, MAT, Wu, X, Levine, DA, Bisogna, M, Berchuck, A, Iversen, ES, Schildkraut, JM, Concannon, P, Weber, RP, Cramer, DW, Terry, KL, Poole, EM, Tworoger, SS, Bandera, EV, Orlow, I, Olson, SH, Krakstad, C, Salvesen, HB, Tangen, IL, Bjorge, L, van Altena, AM, Aben, KKH, Kiemeney, LA, Massuger, LFAG, Kellar, M, Brooks-Wilson, A, Kelemen, LE, Cook, LS, Le, ND, Cybulski, C, Yang, H, Lissowska, J, Brinton, LA, Wentzensen, N, Hogdall, C, Lundvall, L, Nedergaard, L, Baker, H, Song, H, Eccles, D, McNeish, I, Paul, J, Carty, K, Siddiqui, N, Glasspool, R, Whittemore, AS, Rothstein, JH, McGuire, V, Sieh, W, Ji, B-T, Zheng, W, Shu, X-O, Gao, Y-T, Rosen, B, Risch, HA, McLaughlin, JR, Narod, SA, Monteiro, AN, Chen, A, Lin, H-Y, Permuth-Wey, J, Sellers, TA, Tsai, Y-Y, Chen, Z, Ziogas, A, Anton-Culver, H, Gentry-Maharaj, A, Menon, U, Harrington, P, Lee, AW, Wu, AH, Pearce, CL, Coetzee, G, Pike, MC, Dansonka-Mieszkowska, A, Timorek, A, Rzepecka, IK, Kupryjanczyk, J, Freedman, M, Noushmehr, H, Easton, DF, Offit, K, Couch, FJ, Gayther, S, Pharoah, PP, Antoniou, AC, and Chenevix-Trench, G

Abstract

Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.

Published
2015

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

Author

Hunter, KW, Couch, FJ, Wang, X, McGuffog, L, Lee, A, Olswold, C, Kuchenbaecker, KB, Soucy, P, Fredericksen, Z, Barrowdale, D, Dennis, J, Gaudet, MM, Dicks, E, Kosel, M, Healey, S, Sinilnikova, OM, Bacot, F, Vincent, D, Hogervorst, FBL, Peock, S, Stoppa-Lyonnet, D, Jakubowska, A, Radice, P, Schmutzler, RK, Domchek, SM, Piedmonte, M, Singer, CF, Friedman, E, Thomassen, M, Hansen, TVO, Neuhausen, SL, Szabo, CI, Blanco, I, Greene, MH, Karlan, BY, Garber, J, Phelan, CM, Weitzel, JN, Montagna, M, Olah, E, Andrulis, IL, Godwin, AK, Yannoukakos, D, Goldgar, DE, Caldes, T, Nevanlinna, H, Osorio, A, Terry, MB, Daly, MB, van Rensburg, EJ, Hamann, U, Ramus, SJ, Toland, AE, Caligo, MA, Olopade, OI, Tung, N, Claes, K, Beattie, MS, Southey, MC, Imyanitov, EN, Tischkowitz, M, Janavicius, R, John, EM, Kwong, A, Diez, O, Balmana, J, Barkardottir, RB, Arun, BK, Rennert, G, Teo, S-H, Ganz, PA, Campbell, I, van der Hout, AH, van Deurzen, CHM, Seynaeve, C, Garcia, EBG, van Leeuwen, FE, Meijers-Heijboer, HEJ, Gille, JJP, Ausems, MGEM, Blok, MJ, Ligtenberg, MJL, Rookus, MA, Devilee, P, Verhoef, S, van Os, TAM, Wijnen, JT, Frost, D, Ellis, S, Fineberg, E, Platte, R, Evans, DG, Izatt, L, Eeles, RA, Adlard, J, Eccles, DM, Cook, J, Brewer, C, Douglas, F, Hodgson, S, Morrison, PJ, Side, LE, Donaldson, A, Houghton, C, Rogers, MT, Dorkins, H, Eason, J, Gregory, H, McCann, E, Murray, A, Calender, A, Hardouin, A, Berthet, P, Delnatte, C, Nogues, C, Lasset, C, Houdayer, C, Leroux, D, Rouleau, E, Prieur, F, Damiola, F, Sobol, H, Coupier, I, Venat-Bouvet, L, Castera, L, Gauthier-Villars, M, Leone, M, Pujol, P, Mazoyer, S, Bignon, Y-J, Zlowocka-Perlowska, E, Gronwald, J, Lubinski, J, Durda, K, Jaworska, K, Huzarski, T, Spurdle, AB, Viel, A, Peissel, B, Bonanni, B, Melloni, G, Ottini, L, Papi, L, Varesco, L, Tibiletti, MG, Peterlongo, P, Volorio, S, Manoukian, S, Pensotti, V, Arnold, N, Engel, C, Deissler, H, Gadzicki, D, Gehrig, A, Kast, K, Rhiem, K, Meindl, A, Niederacher, D, Ditsch, N, Plendl, H, Preisler-Adams, S, Engert, S, Sutter, C, Varon-Mateeva, R, Wappenschmidt, B, Weber, BHF, Arver, B, Stenmark-Askmalm, M, Loman, N, Rosenquist, R, Einbeigi, Z, Nathanson, KL, Rebbeck, TR, Blank, SV, Cohn, DE, Rodriguez, GC, Small, L, Friedlander, M, Bae-Jump, VL, Fink-Retter, A, Rappaport, C, Gschwantler-Kaulich, D, Pfeiler, G, Tea, M-K, Lindor, NM, Kaufman, B, Paluch, SS, Laitman, Y, Skytte, A-B, Gerdes, A-M, Pedersen, IS, Moeller, ST, Kruse, TA, Jensen, UB, Vijai, J, Sarrel, K, Robson, M, Kauff, N, Mulligan, AM, Glendon, G, Ozcelik, H, Ejlertsen, B, Nielsen, FC, Jonson, L, Andersen, MK, Ding, YC, Steele, L, Foretova, L, Teule, A, Lazaro, C, Brunet, J, Angel Pujana, M, Mai, PL, Loud, JT, Walsh, C, Lester, J, Orsulic, S, Narod, SA, Herzog, J, Sand, SR, Tognazzo, S, Agata, S, Vaszko, T, Weaver, J, Stavropoulou, AV, Buys, SS, Romero, A, de la Hoya, M, Aittomaki, K, Muranen, TA, Duran, M, Chung, WK, Lasa, A, Dorfling, CM, Miron, A, Benitez, J, Senter, L, Huo, D, Chan, SB, Sokolenko, AP, Chiquette, J, Tihomirova, L, Friebel, TM, Agnarsson, BA, Lu, KH, Lejbkowicz, F, James, PA, Hall, P, Dunning, AM, Tessier, D, Cunningham, J, Slager, SL, Wang, C, Hart, S, Stevens, K, Simard, J, Pastinen, T, Pankratz, VS, Offit, K, Easton, DF, Chenevix-Trench, G, Antoniou, AC, Hunter, KW, Couch, FJ, Wang, X, McGuffog, L, Lee, A, Olswold, C, Kuchenbaecker, KB, Soucy, P, Fredericksen, Z, Barrowdale, D, Dennis, J, Gaudet, MM, Dicks, E, Kosel, M, Healey, S, Sinilnikova, OM, Bacot, F, Vincent, D, Hogervorst, FBL, Peock, S, Stoppa-Lyonnet, D, Jakubowska, A, Radice, P, Schmutzler, RK, Domchek, SM, Piedmonte, M, Singer, CF, Friedman, E, Thomassen, M, Hansen, TVO, Neuhausen, SL, Szabo, CI, Blanco, I, Greene, MH, Karlan, BY, Garber, J, Phelan, CM, Weitzel, JN, Montagna, M, Olah, E, Andrulis, IL, Godwin, AK, Yannoukakos, D, Goldgar, DE, Caldes, T, Nevanlinna, H, Osorio, A, Terry, MB, Daly, MB, van Rensburg, EJ, Hamann, U, Ramus, SJ, Toland, AE, Caligo, MA, Olopade, OI, Tung, N, Claes, K, Beattie, MS, Southey, MC, Imyanitov, EN, Tischkowitz, M, Janavicius, R, John, EM, Kwong, A, Diez, O, Balmana, J, Barkardottir, RB, Arun, BK, Rennert, G, Teo, S-H, Ganz, PA, Campbell, I, van der Hout, AH, van Deurzen, CHM, Seynaeve, C, Garcia, EBG, van Leeuwen, FE, Meijers-Heijboer, HEJ, Gille, JJP, Ausems, MGEM, Blok, MJ, Ligtenberg, MJL, Rookus, MA, Devilee, P, Verhoef, S, van Os, TAM, Wijnen, JT, Frost, D, Ellis, S, Fineberg, E, Platte, R, Evans, DG, Izatt, L, Eeles, RA, Adlard, J, Eccles, DM, Cook, J, Brewer, C, Douglas, F, Hodgson, S, Morrison, PJ, Side, LE, Donaldson, A, Houghton, C, Rogers, MT, Dorkins, H, Eason, J, Gregory, H, McCann, E, Murray, A, Calender, A, Hardouin, A, Berthet, P, Delnatte, C, Nogues, C, Lasset, C, Houdayer, C, Leroux, D, Rouleau, E, Prieur, F, Damiola, F, Sobol, H, Coupier, I, Venat-Bouvet, L, Castera, L, Gauthier-Villars, M, Leone, M, Pujol, P, Mazoyer, S, Bignon, Y-J, Zlowocka-Perlowska, E, Gronwald, J, Lubinski, J, Durda, K, Jaworska, K, Huzarski, T, Spurdle, AB, Viel, A, Peissel, B, Bonanni, B, Melloni, G, Ottini, L, Papi, L, Varesco, L, Tibiletti, MG, Peterlongo, P, Volorio, S, Manoukian, S, Pensotti, V, Arnold, N, Engel, C, Deissler, H, Gadzicki, D, Gehrig, A, Kast, K, Rhiem, K, Meindl, A, Niederacher, D, Ditsch, N, Plendl, H, Preisler-Adams, S, Engert, S, Sutter, C, Varon-Mateeva, R, Wappenschmidt, B, Weber, BHF, Arver, B, Stenmark-Askmalm, M, Loman, N, Rosenquist, R, Einbeigi, Z, Nathanson, KL, Rebbeck, TR, Blank, SV, Cohn, DE, Rodriguez, GC, Small, L, Friedlander, M, Bae-Jump, VL, Fink-Retter, A, Rappaport, C, Gschwantler-Kaulich, D, Pfeiler, G, Tea, M-K, Lindor, NM, Kaufman, B, Paluch, SS, Laitman, Y, Skytte, A-B, Gerdes, A-M, Pedersen, IS, Moeller, ST, Kruse, TA, Jensen, UB, Vijai, J, Sarrel, K, Robson, M, Kauff, N, Mulligan, AM, Glendon, G, Ozcelik, H, Ejlertsen, B, Nielsen, FC, Jonson, L, Andersen, MK, Ding, YC, Steele, L, Foretova, L, Teule, A, Lazaro, C, Brunet, J, Angel Pujana, M, Mai, PL, Loud, JT, Walsh, C, Lester, J, Orsulic, S, Narod, SA, Herzog, J, Sand, SR, Tognazzo, S, Agata, S, Vaszko, T, Weaver, J, Stavropoulou, AV, Buys, SS, Romero, A, de la Hoya, M, Aittomaki, K, Muranen, TA, Duran, M, Chung, WK, Lasa, A, Dorfling, CM, Miron, A, Benitez, J, Senter, L, Huo, D, Chan, SB, Sokolenko, AP, Chiquette, J, Tihomirova, L, Friebel, TM, Agnarsson, BA, Lu, KH, Lejbkowicz, F, James, PA, Hall, P, Dunning, AM, Tessier, D, Cunningham, J, Slager, SL, Wang, C, Hart, S, Stevens, K, Simard, J, Pastinen, T, Pankratz, VS, Offit, K, Easton, DF, Chenevix-Trench, G, and Antoniou, AC

Abstract

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 × 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 × 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 × 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.

Published
2013

7. Interplay between BRCA1 and RHAMM Regulates Epithelial Apicobasal Polarization and May Influence Risk of Breast Cancer

Author

Ashworth, A, Maxwell, CA, Benitez, J, Gomez-Baldo, L, Osorio, A, Bonifaci, N, Fernandez-Ramires, R, Costes, SV, Guino, E, Chen, H, Evans, GJR, Mohan, P, Catala, I, Petit, A, Aguilar, H, Villanueva, A, Aytes, A, Serra-Musach, J, Rennert, G, Lejbkowicz, F, Peterlongo, P, Manoukian, S, Peissel, B, Ripamonti, CB, Bonanni, B, Viel, A, Allavena, A, Bernard, L, Radice, P, Friedman, E, Kaufman, B, Laitman, Y, Dubrovsky, M, Milgrom, R, Jakubowska, A, Cybulski, C, Gorski, B, Jaworska, K, Durda, K, Sukiennicki, G, Lubinski, J, Shugart, YY, Domchek, SM, Letrero, R, Weber, BL, Hogervorst, FBL, Rookus, MA, Collee, JM, Devilee, P, Ligtenberg, MJ, van der Luijt, RB, Aalfs, CM, Waisfisz, Q, Wijnen, J, van Roozendaal, CEP, Easton, DF, Peock, S, Cook, M, Oliver, C, Frost, D, Harrington, P, Evans, DG, Lalloo, F, Eeles, R, Izatt, L, Chu, C, Eccles, D, Douglas, F, Brewer, C, Nevanlinna, H, Heikkinen, T, Couch, FJ, Lindor, NM, Wang, X, Godwin, AK, Caligo, MA, Lombardi, G, Loman, N, Karlsson, P, Ehrencrona, H, von Wachenfeldt, A, Barkardottir, RB, Hamann, U, Rashid, MU, Lasa, A, Caldes, T, Andres, R, Schmitt, M, Assmann, V, Stevens, K, Offit, K, Curado, J, Tilgner, H, Guigo, R, Aiza, G, Brunet, J, Castellsague, J, Martrat, G, Urruticoechea, A, Blanco, I, Tihomirova, L, Goldgar, DE, Buys, S, John, EM, Miron, A, Southey, M, Daly, MB, Schmutzler, RK, Wappenschmidt, B, Meindl, A, Arnold, N, Deissler, H, Varon-Mateeva, R, Sutter, C, Niederacher, D, Imyamitov, E, Sinilnikova, OM, Stoppa-Lyonne, D, Mazoyer, S, Verny-Pierre, C, Castera, L, de Pauw, A, Bignon, Y-J, Uhrhammer, N, Peyrat, J-P, Vennin, P, Ferrer, SF, Collonge-Rame, M-A, Mortemousque, I, Spurdle, AB, Beesley, J, Chen, X, Healey, S, Barcellos-Hoff, MH, Vidal, M, Gruber, SB, Lazaro, C, Capella, G, McGuffog, L, Nathanson, KL, Antoniou, AC, Chenevix-Trench, G, Fleisch, MC, Moreno, V, Angel Pujana, M, Ashworth, A, Maxwell, CA, Benitez, J, Gomez-Baldo, L, Osorio, A, Bonifaci, N, Fernandez-Ramires, R, Costes, SV, Guino, E, Chen, H, Evans, GJR, Mohan, P, Catala, I, Petit, A, Aguilar, H, Villanueva, A, Aytes, A, Serra-Musach, J, Rennert, G, Lejbkowicz, F, Peterlongo, P, Manoukian, S, Peissel, B, Ripamonti, CB, Bonanni, B, Viel, A, Allavena, A, Bernard, L, Radice, P, Friedman, E, Kaufman, B, Laitman, Y, Dubrovsky, M, Milgrom, R, Jakubowska, A, Cybulski, C, Gorski, B, Jaworska, K, Durda, K, Sukiennicki, G, Lubinski, J, Shugart, YY, Domchek, SM, Letrero, R, Weber, BL, Hogervorst, FBL, Rookus, MA, Collee, JM, Devilee, P, Ligtenberg, MJ, van der Luijt, RB, Aalfs, CM, Waisfisz, Q, Wijnen, J, van Roozendaal, CEP, Easton, DF, Peock, S, Cook, M, Oliver, C, Frost, D, Harrington, P, Evans, DG, Lalloo, F, Eeles, R, Izatt, L, Chu, C, Eccles, D, Douglas, F, Brewer, C, Nevanlinna, H, Heikkinen, T, Couch, FJ, Lindor, NM, Wang, X, Godwin, AK, Caligo, MA, Lombardi, G, Loman, N, Karlsson, P, Ehrencrona, H, von Wachenfeldt, A, Barkardottir, RB, Hamann, U, Rashid, MU, Lasa, A, Caldes, T, Andres, R, Schmitt, M, Assmann, V, Stevens, K, Offit, K, Curado, J, Tilgner, H, Guigo, R, Aiza, G, Brunet, J, Castellsague, J, Martrat, G, Urruticoechea, A, Blanco, I, Tihomirova, L, Goldgar, DE, Buys, S, John, EM, Miron, A, Southey, M, Daly, MB, Schmutzler, RK, Wappenschmidt, B, Meindl, A, Arnold, N, Deissler, H, Varon-Mateeva, R, Sutter, C, Niederacher, D, Imyamitov, E, Sinilnikova, OM, Stoppa-Lyonne, D, Mazoyer, S, Verny-Pierre, C, Castera, L, de Pauw, A, Bignon, Y-J, Uhrhammer, N, Peyrat, J-P, Vennin, P, Ferrer, SF, Collonge-Rame, M-A, Mortemousque, I, Spurdle, AB, Beesley, J, Chen, X, Healey, S, Barcellos-Hoff, MH, Vidal, M, Gruber, SB, Lazaro, C, Capella, G, McGuffog, L, Nathanson, KL, Antoniou, AC, Chenevix-Trench, G, Fleisch, MC, Moreno, V, and Angel Pujana, M

Abstract

Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM) that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n = 7,584, weighted hazard ratio ((w)HR) = 1.09 (95% CI 1.02-1.16), p(trend) = 0.017; and n = 3,965, (w)HR = 1.04 (95% CI 0.94-1.16), p(trend) = 0.43; respectively. Subsequently, studies of MCF10A apicobasal polarization revealed a central role for BRCA1 and RHAMM, together with AURKA and TPX2, in essential reorganization of microtubules. Mechanistically, reorganization is facilitated by BRCA1 and impaired by AURKA, which is regulated by negative feedback involving RHAMM and TPX2. Taken together, our data provide fundamental insight into apicobasal polarization through BRCA1 function, which may explain the expanded cell subsets and characteristic tumor type accompanying BRCA1 mutation, while also linking this process to sporadic breast cancer through perturbation of HMMR/RHAMM.

Published
2011

8. Author Correction: Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis.

Author

Zhang X, Chiang HC, Wang Y, Zhang C, Smith S, Zhao X, Nair SJ, Michalek J, Jatoi I, Lautner M, Oliver B, Wang H, Petit A, Soler T, Brunet J, Mateo F, Angel Pujana M, Poggi E, Chaldekas K, Isaacs C, Peshkin BN, Ochoa O, Chedin F, Theoharis C, Sun LZ, Curiel TJ, Elledge R, Jin VX, Hu Y, and Li R

Abstract

This corrects the article DOI: 10.1038/ncomms15908.

Published
2018
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9. Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis.

Author

Zhang X, Chiang HC, Wang Y, Zhang C, Smith S, Zhao X, Nair SJ, Michalek J, Jatoi I, Lautner M, Oliver B, Wang H, Petit A, Soler T, Brunet J, Mateo F, Angel Pujana M, Poggi E, Chaldekas K, Isaacs C, Peshkin BN, Ochoa O, Chedin F, Theoharis C, Sun LZ, Curiel TJ, Elledge R, Jin VX, Hu Y, and Li R

Subjects
Animals, BRCA1 Protein metabolism, Breast enzymology, Breast Neoplasms genetics, Breast Neoplasms metabolism, Breast Neoplasms pathology, Carcinogenesis, Female, Humans, Mice, Mice, Knockout, Nuclear Proteins genetics, Nuclear Proteins metabolism, Nucleic Acid Conformation, Promoter Regions, Genetic, RNA Polymerase II genetics, RNA-Binding Proteins, Tumor Suppressor Proteins metabolism, BRCA1 Protein chemistry, BRCA1 Protein genetics, Breast Neoplasms enzymology, RNA Polymerase II metabolism, Tumor Suppressor Proteins chemistry, Tumor Suppressor Proteins genetics
Abstract

Most BRCA1-associated breast tumours are basal-like yet originate from luminal progenitors. BRCA1 is best known for its functions in double-strand break repair and resolution of DNA replication stress. However, it is unclear whether loss of these ubiquitously important functions fully explains the cell lineage-specific tumorigenesis. In vitro studies implicate BRCA1 in elimination of R-loops, DNA-RNA hybrid structures involved in transcription and genetic instability. Here we show that R-loops accumulate preferentially in breast luminal epithelial cells, not in basal epithelial or stromal cells, of BRCA1 mutation carriers. Furthermore, R-loops are enriched at the 5' end of those genes with promoter-proximal RNA polymerase II (Pol II) pausing. Genetic ablation of Cobra1, which encodes a Pol II-pausing and BRCA1-binding protein, ameliorates R-loop accumulation and reduces tumorigenesis in Brca1-knockout mouse mammary epithelium. Our studies show that Pol II pausing is an important contributor to BRCA1-associated R-loop accumulation and breast cancer development.

Published
2017
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