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

IF 6.1 1区医学 Q1 ONCOLOGY

Breast Cancer Research Pub Date : 2016-11-11 DOI:10.1186/s13058-016-0768-3

Timothy R Rebbeck, Tara M Friebel, Nandita Mitra, Fei Wan, Stephanie Chen, Irene L Andrulis, Paraskevi Apostolou, Norbert Arnold, Banu K Arun, Daniel Barrowdale, Javier Benitez, Raanan Berger, Pascaline Berthet, Ake Borg, Saundra S Buys, Trinidad Caldes, Jonathan Carter, Jocelyne Chiquette, Kathleen B M Claes, Fergus J Couch, Cezary Cybulski, Mary B Daly, Miguel de la Hoya, Orland Diez, Susan M Domchek, Katherine L Nathanson, Katarzyna Durda, Steve Ellis, D Gareth Evans, Lenka Foretova, Eitan Friedman, Debra Frost, Patricia A Ganz, Judy Garber, Gord Glendon, Andrew K Godwin, Mark H Greene, Jacek Gronwald, Eric Hahnen, Emily Hallberg, Ute Hamann, Thomas V O Hansen, Evgeny N Imyanitov, Claudine Isaacs, Anna Jakubowska, Ramunas Janavicius, Katarzyna Jaworska-Bieniek, Esther M John, Beth Y Karlan, Bella Kaufman, KConFab Investigators, Ava Kwong, Yael Laitman, Christine Lasset, Conxi Lazaro, Jenny Lester, Niklas Loman, Jan Lubinski, Siranoush Manoukian, Gillian Mitchell, Marco Montagna, Susan L Neuhausen, Heli Nevanlinna, Dieter Niederacher, Robert L Nussbaum, Kenneth Offit, Edith Olah, Olufunmilayo I Olopade, Sue Kyung Park, Marion Piedmonte, Paolo Radice, Christine Rappaport-Fuerhauser, Matti A Rookus, Caroline Seynaeve, Jacques Simard, Christian F Singer, Penny Soucy, Melissa 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 Ewart Toland, Aleksandra Toloczko-Grabarek, Nadine Tung, Elizabeth J van Rensburg, Danylo Villano, Shan Wang-Gohrke, Barbara Wappenschmidt, Jeffrey N Weitzel, Jamal Zidan, Kristin K Zorn, Lesley McGuffog, Douglas Easton, Georgia Chenevix-Trench, Antonis C Antoniou, Susan J Ramus

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引用次数: 0

Abstract

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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在 32 295 位女性的国际样本中发现 BRCA1 和 BRCA2 的有害突变遗传。

背景：大多数 BRCA1 或 BRCA2 基因突变携带者只遗传了一个（杂合子）基因突变。同时遗传了 BRCA1 和 BRCA2 中有害突变的杂合子（Transheterozygotes，TH）非常罕见，人们对杂合子的后果知之甚少：从 32,295 名女性 BRCA1/2 基因突变携带者中，我们发现了 93 例 TH（0.3%）。"病例 "定义为 TH，"对照 "为 BRCA1（SH1）或 BRCA2（SH2）的单一突变。匹配的 SH1 "对照 "携带在 TH "病例 "中发现的 BRCA1 突变。匹配的 SH2 "对照 "携带在 TH "病例 "中发现的 BRCA2 突变。将 TH 携带者与 SH1 或 SH2 匹配后，91 例 TH 与 9316 例 SH1 匹配，89 例 TH 与 3370 例 SH2 匹配：大多数 TH（45.2%）涉及三种常见的犹太突变。与 SH1 和 SH2 妇女相比，TH 妇女更有可能被诊断出患有乳腺癌（BC；P = 0.002）。与 SH2（p = 0.017）相比，TH 妇女更有可能被诊断出患有卵巢癌（OC），而 SH1 妇女则没有这种可能。TH与SH1的BC诊断年龄相同（p = 0.231），但TH比SH2平均年轻4.5岁（p 结论：TH与SH1的BC诊断年龄相同（p = 0.231），但TH比SH2平均年轻4.5岁：我们的观察结果表明，TH 的临床表型与 SH1 相似。然而，TH 乳腺肿瘤标记物特征在表型上介于 SH1 和 SH2 之间。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Breast Cancer Research 医学-肿瘤学

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期刊介绍： Breast Cancer Research is an international, peer-reviewed online journal, publishing original research, reviews, editorials and reports. Open access research articles of exceptional interest are published in all areas of biology and medicine relevant to breast cancer, including normal mammary gland biology, with special emphasis on the genetic, biochemical, and cellular basis of breast cancer. In addition to basic research, the journal publishes preclinical, translational and clinical studies with a biological basis, including Phase I and Phase II trials.