编码生殖细胞变异对对侧乳腺癌风险和存活的影响。
The impact of coding germline variants on contralateral breast cancer risk and survival.
发表日期：2023 Feb 16
作者：
Anna Morra, Nasim Mavaddat, Taru A Muranen, Thomas U Ahearn, Jamie Allen, Irene L Andrulis, Päivi Auvinen, Heiko Becher, Sabine Behrens, Carl Blomqvist, Stig E Bojesen, Manjeet K Bolla, Hiltrud Brauch, Nicola J Camp, Sara Carvalho, Jose E Castelao, Melissa H Cessna, Jenny Chang-Claude, Georgia Chenevix-Trench, , Kamila Czene, Brennan Decker, Joe Dennis, Thilo Dörk, Leila Dorling, Alison M Dunning, Arif B Ekici, Mikael Eriksson, D Gareth Evans, Peter A Fasching, Jonine D Figueroa, Henrik Flyger, Manuela Gago-Dominguez, Montserrat García-Closas, Willemina R R Geurts-Giele, Graham G Giles, Pascal Guénel, Melanie Gündert, Eric Hahnen, Per Hall, Ute Hamann, Patricia A Harrington, Wei He, Päivi Heikkilä, Maartje J Hooning, Reiner Hoppe, Anthony Howell, Keith Humphreys, , Anna Jakubowska, Audrey Y Jung, Renske Keeman, Vessela N Kristensen, Jan Lubiński, Arto Mannermaa, Mehdi Manoochehri, Siranoush Manoukian, Sara Margolin, Dimitrios Mavroudis, Roger L Milne, Anna Marie Mulligan, William G Newman, Tjoung-Won Park-Simon, Paolo Peterlongo, Paul D P Pharoah, Valerie Rhenius, Emmanouil Saloustros, Elinor J Sawyer, Rita K Schmutzler, Mitul Shah, Amanda B Spurdle, Ian Tomlinson, Thérèse Truong, Elke M van Veen, Maaike P G Vreeswijk, Qin Wang, Camilla Wendt, Xiaohong R Yang, Heli Nevanlinna, Peter Devilee, Douglas F Easton, Marjanka K Schmidt
来源：
AMERICAN JOURNAL OF HUMAN GENETICS
摘要：
罹患了乳腺癌（BC）易感性基因（除BRCA1、BRCA2和CHEK2之外）中编码生殖细胞变异与对侧乳腺癌（CBC）风险和乳腺癌特异性生存（BCSS）相关的证据很少。本研究旨在评估9个已知基因（ATM、BARD1、BRCA1、BRCA2、CHEK2、PALB2、RAD51C、RAD51D和TP53）和25个可疑的BC易感性基因中的蛋白质截短变异（PTVs）和罕见错义变异（MSVs）与CBC风险和BCSS的关联。使用Cox回归模型估计了危险比（HR）和95%置信区间（CI）。分析包括34,401名欧洲血统的乳腺癌患者，包括676例CBC和3,449例乳腺癌死亡病例；中位随访时间为10.9年。亚型分析基于第一次乳腺癌的雌激素受体（ER）状态。BRCA1、BRCA2和TP53中的PTVs和致病性/可能致病性MSVs，以及CHEK2和PALB2中的PTVs与CBC风险增加相关【HR(95%CI)分别为：2.88(1.70-4.87)、2.31(1.39-3.85)、8.29(2.53-27.21)、2.25(1.55-3.27)和2.67(1.33-5.35)】。BRCA2（ER阳性BC）中的PTVs和致病性/可能致病性MSVs，以及TP53和CHEK2中的PTVs与BCSS的关联证据最为强劲【根据肿瘤特征和治疗调整后，HR(95%CI)分别为：1.53(1.13-2.07)、2.08(0.95-4.57)和1.39(1.13-1.72)】。当剔除CBC的影响时，HR基本没有变化，表明这些关联不完全因CBC风险、肿瘤特征或治疗而解释。对于25个可疑的BC基因，PTVs和/或罕见MSVs与CBC风险或BCSS的关联证据有限。CBC发现与治疗决策、随访和BC诊断后筛查相关。 版权所有 © 2023 The Authors。 Elsevier Inc.保留所有权利。
Evidence linking coding germline variants in breast cancer (BC)-susceptibility genes other than BRCA1, BRCA2, and CHEK2 with contralateral breast cancer (CBC) risk and breast cancer-specific survival (BCSS) is scarce. The aim of this study was to assess the association of protein-truncating variants (PTVs) and rare missense variants (MSVs) in nine known (ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53) and 25 suspected BC-susceptibility genes with CBC risk and BCSS. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated with Cox regression models. Analyses included 34,401 women of European ancestry diagnosed with BC, including 676 CBCs and 3,449 BC deaths; the median follow-up was 10.9 years. Subtype analyses were based on estrogen receptor (ER) status of the first BC. Combined PTVs and pathogenic/likely pathogenic MSVs in BRCA1, BRCA2, and TP53 and PTVs in CHEK2 and PALB2 were associated with increased CBC risk [HRs (95% CIs): 2.88 (1.70-4.87), 2.31 (1.39-3.85), 8.29 (2.53-27.21), 2.25 (1.55-3.27), and 2.67 (1.33-5.35), respectively]. The strongest evidence of association with BCSS was for PTVs and pathogenic/likely pathogenic MSVs in BRCA2 (ER-positive BC) and TP53 and PTVs in CHEK2 [HRs (95% CIs): 1.53 (1.13-2.07), 2.08 (0.95-4.57), and 1.39 (1.13-1.72), respectively, after adjusting for tumor characteristics and treatment]. HRs were essentially unchanged when censoring for CBC, suggesting that these associations are not completely explained by increased CBC risk, tumor characteristics, or treatment. There was limited evidence of associations of PTVs and/or rare MSVs with CBC risk or BCSS for the 25 suspected BC genes. The CBC findings are relevant to treatment decisions, follow-up, and screening after BC diagnosis.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.