伴随观察乳腺癌易感基因中的胚系致病变异：BRIDGES测序数据集分析结果

Co-observation of germline pathogenic variants in breast cancer predisposition genes: Results from analysis of the BRIDGES sequencing dataset

AMERICAN JOURNAL OF HUMAN GENETICS

影响因子:8.1

分区:生物学1区 Top / 遗传学1区

发表日期:2024 Sep 05

作者: Aimee L Davidson, Kyriaki Michailidou, Michael T Parsons, Cristina Fortuno, Manjeet K Bolla, Qin Wang, Joe Dennis, Marc Naven, Mustapha Abubakar, Thomas U Ahearn, M Rosario Alonso, Irene L Andrulis, Antonis C Antoniou, Päivi Auvinen, Sabine Behrens, Marina A Bermisheva, Natalia V Bogdanova, Stig E Bojesen, Thomas Brüning, Helen J Byers, Nicola J Camp, Archie Campbell, Jose E Castelao, Melissa H Cessna, Jenny Chang-Claude, Stephen J Chanock, Georgia Chenevix-Trench, , J Margriet Collée, Kamila Czene, Thilo Dörk, Mikael Eriksson, D Gareth Evans, Peter A Fasching, Jonine D Figueroa, Henrik Flyger, Manuela Gago-Dominguez, Montserrat García-Closas, Gord Glendon, Anna González-Neira, Felix Grassmann, Jacek Gronwald, Pascal Guénel, Andreas Hadjisavvas, Lothar Haeberle, Per Hall, Ute Hamann, Mikael Hartman, Peh Joo Ho, Maartje J Hooning, Reiner Hoppe, Anthony Howell, , Anna Jakubowska, Elza K Khusnutdinova, Vessela N Kristensen, Jingmei Li, Joanna Lim, Annika Lindblom, Jenny Liu, Artitaya Lophatananon, Arto Mannermaa, Dimitrios A Mavroudis, Arjen R Mensenkamp, Roger L Milne, Kenneth R Muir, William G Newman, Nadia Obi, Mihalis I Panayiotidis, Sue K Park, Tjoung-Won Park-Simon, Paolo Peterlongo, Paolo Radice, Muhammad U Rashid, Valerie Rhenius, Emmanouil Saloustros, Elinor J Sawyer, Marjanka K Schmidt, Petra Seibold, Mitul Shah, Melissa C Southey, Soo Hwang Teo, Ian Tomlinson, Diana Torres, Thérèse Truong, Irma van de Beek, Annemieke H van der Hout, Camilla C Wendt, Alison M Dunning, Paul D P Pharoah, Peter Devilee, Douglas F Easton, Paul A James, Amanda B Spurdle

DOI: 10.1016/j.ajhg.2024.07.004

摘要

伴随观察某一基因变异与另一基因中的致病变异共同存在，能解释疾病表现，在常用变异分类指南中被定义为反对致病性的证据。多个变异鉴定专家小组已一致认为，这种证据类型不适用于乳腺癌易感基因变异的分类。我们对BRIDGES测序项目中55,815名乳腺癌患者的序列数据进行了统计分析，以正式评估伴随观察数据在胚系变异分类中的作用。分析内容包括11个乳腺癌易感基因中的预期功能丧失变异和BRCA1、BRCA2及TP53中的致病错义变异。评估是否在两个不同基因中观察到的致病变异的伴随频率是否高于或低于独立假设下的预期。BRCA1、BRCA2和PALB2中与其他基因的致病变异伴随观察的频率均低于预期。这种耗竭的证据在调整年龄、研究设计（家族性与群体性）及国家后依然存在。BRCA1、BRCA2或PALB2中的不明意义变异与其他乳腺癌基因中的致病变异伴随观察，作为支持性证据反对其致病性，基于可能比值的似然比进行分级，并在BRIDGES中发现的BRCA1和BRCA2错义变异的再分类中显示出实用性。我们的方法在评估伴随观察作为其他临床背景中变异致病性预测因子的价值方面具有广泛应用，包括由ClinGen变异鉴定专家小组制定的基因特异性指南。

Abstract

Co-observation of a gene variant with a pathogenic variant in another gene that explains the disease presentation has been designated as evidence against pathogenicity for commonly used variant classification guidelines. Multiple variant curation expert panels have specified, from consensus opinion, that this evidence type is not applicable for the classification of breast cancer predisposition gene variants. Statistical analysis of sequence data for 55,815 individuals diagnosed with breast cancer from the BRIDGES sequencing project was undertaken to formally assess the utility of co-observation data for germline variant classification. Our analysis included expected loss-of-function variants in 11 breast cancer predisposition genes and pathogenic missense variants in BRCA1, BRCA2, and TP53. We assessed whether co-observation of pathogenic variants in two different genes occurred more or less often than expected under the assumption of independence. Co-observation of pathogenic variants in each of BRCA1, BRCA2, and PALB2 with the remaining genes was less frequent than expected. This evidence for depletion remained after adjustment for age at diagnosis, study design (familial versus population-based), and country. Co-observation of a variant of uncertain significance in BRCA1, BRCA2, or PALB2 with a pathogenic variant in another breast cancer gene equated to supporting evidence against pathogenicity following criterion strength assignment based on the likelihood ratio and showed utility in reclassification of missense BRCA1 and BRCA2 variants identified in BRIDGES. Our approach has applicability for assessing the value of co-observation as a predictor of variant pathogenicity in other clinical contexts, including for gene-specific guidelines developed by ClinGen Variant Curation Expert Panels.