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Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women

Article scientifique 2016 Anglais

Résumé

BACKGROUND: Most BRCA1 or BRCA2 mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both BRCA1 and BRCA2 are rare, and the consequences of transheterozygosity are poorly understood. METHODS: From 32,295 female BRCA1/2 mutation carriers, we identified 93 TH (0.3 %). "Cases" were defined as TH, and "controls" were single mutations at BRCA1 (SH1) or BRCA2 (SH2). Matched SH1 "controls" carried a BRCA1 mutation found in the TH "case". Matched SH2 "controls" carried a BRCA2 mutation found in the TH "case". After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2. RESULTS: The majority of TH (45.2 %) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; p = 0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 (p = 0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 (p = 0.231), but was on average 4.5 years younger in TH than in SH2 (p < 0.001). BC in TH was more likely to be estrogen receptor (ER) positive (p = 0.010) or progesterone receptor (PR) positive (p = 0.013) than in SH1, but less likely to be ER positive (p < 0.001) or PR positive (p = 0.012) than SH2. Among 15 tumors from TH patients, there was no clear pattern of loss of heterozygosity (LOH) for BRCA1 or BRCA2 in either BC or OC. CONCLUSIONS: Our observations suggest that clinical TH phenotypes resemble SH1. However, TH breast tumor marker characteristics are phenotypically intermediate to SH1 and SH2.

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Rebbeck, T., Friebel, T., Mitra, N., Wan, F., Chen, S., Andrulis, I., Apostolou, P., Arnold, N., Arun, B., Barrowdale, D., Benı́tez, J., Berger, R., Berthet, P., Borg, Å., Buys, S., Caldés, T., Carter, J., Chiquette, J., Claes, K., Couch, F., Cybulski, C., Daly, M., Hoya, M., Dı́ez, O., Domchek, S., Nathanson, K., Durda, K., Evans, D., Foretová, L., Friedman, E., Frost, D., Ganz, P., Garber, J., Glendon, G., Godwin, A., Greene, M., Gronwald, J., Hahnen, E., Hallberg, E., Hamann, U., Hansen, T., Imyanitov, E., Isaacs, C., Jakubowska, A., Janavičius, R., Jaworska–Bieniek, K., John, E., Karlan, B., Kaufman, B., Investigators, k., Kwong, A., Laitman, Y., Lasset, C., Lázaro, C., Lester, J., Loman, N., Lubiński, J., Manoukian, S., Mitchell, G., Montagna, M., Neuhausen, S., Nevanlinna, H., Niederacher, D., Nussbaum, R., Offit, K., Oláh, E., Olopade, O., Park, S., Piedmonte, M., Radice, P., Rappaport, C., Rookus, M., Seynaeve, C., Simard, J., Singer, C., Soucy, P., Southey, M., Stoppa‐Lyonnet, D., Sukiennicki, G., Szabo, C., Tancredi, M., Teixeira, M., Teo, S., Terry, M., Thomassen, M., Tihomirova, L., Tischkowitz, M., Toland, A., Tołoczko‐Grabarek, A., Tung, N., Rensburg, E., Villano, D., Wang‐Gohrke, S., Wappenschmidt, B., Weitzel, J., Zidan, J., Zorn, K. (2016). Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women. https://doi.org/10.1186/s13058-016-0768-3

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Auteur(s)

Timothy R. Rebbeck Tara M. Friebel Nandita Mitra Fei Wan Stephanie Chen Irene L. Andrulis Paraskevi Apostolou Norbert Arnold Banu Arun Daniel Barrowdale Javier Benı́tez Raanan Berger Pascaline Berthet Åke Borg Saundra S. Buys Trinidad Caldés Jonathan Carter Jocelyne Chiquette Kathleen Claes Fergus J. Couch Cezary Cybulski Mary B. Daly Miguel de la Hoya Orland Dı́ez Susan M. Domchek Katherine L. Nathanson Katarzyna Durda D. Gareth Evans Lenka Foretová Eitan Friedman Debra Frost Patricia A. Ganz Judy E. Garber Gord Glendon Andrew K. Godwin Mark H. Greene Jacek Gronwald Eric Hahnen Emily Hallberg Ute Hamann Thomas van Overeem Hansen Evgeny N. Imyanitov Claudine Isaacs Anna Jakubowska Ramūnas Janavičius Katarzyna Jaworska–Bieniek Esther M. John Beth Y. Karlan Bella Kaufman kConFab Investigators Ava Kwong Yael Laitman Christine Lasset Conxi Lázaro Jenny Lester Niklas Loman Jan Lubiński Siranoush Manoukian Gillian Mitchell Marco Montagna Susan L. Neuhausen Heli Nevanlinna Dieter Niederacher Robert L. Nussbaum Kenneth Offit Edith Oláh Olufunmilayo I. Olopade Sue K. Park Marion Piedmonte Paolo Radice Christine Rappaport Matti A. Rookus Caroline Seynaeve Jacques Simard Christian F. Singer Penny Soucy Melissa C. Southey Dominique Stoppa‐Lyonnet Grzegorz Sukiennicki Csilla I. Szabo Mariella Tancredi Manuel R. Teixeira Soo‐Hwang Teo Mary Beth Terry Mads Thomassen Laima Tihomirova Marc Tischkowitz Amanda E. Toland Aleksandra Tołoczko‐Grabarek Nadine Tung Elizabeth J. van Rensburg Danylo Villano Shan Wang‐Gohrke Barbara Wappenschmidt Jeffrey N. Weitzel Jamal Zidan Kristin K. Zorn

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