乳腺癌易感基因种系致病变异的共同观察：桥梁测序数据集的分析结果
Co-observation of germline pathogenic variants in breast cancer predisposition genes: Results from analysis of the BRIDGES sequencing dataset
影响因子:8.10000
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
摘要
在另一个基因中具有致病性变异的基因变异的共同观察，该基因解释了疾病表现，已被指定为反对常用变体分类指南致病性的证据。从共识的意见中，多个变体策展专家小组指定了这种证据类型不适用于对乳腺癌倾向基因变异的分类。对从桥梁测序项目诊断为乳腺癌的55,815名个人的统计分析进行了正式评估对种系变异分类的共表观测数据的实用性。我们的分析包括预期的功能丧失变体，在BRCA1，BRCA2和TP53中的11种乳腺癌易感基因和致病错义变体中。我们评估了在独立性假设下，两个不同基因中的致病变异的共同观察是否比预期的频率更高。剩余基因的BRCA1，BRCA2和PALB2中每种病原变异的共同观察的频率不如预期。调整诊断，研究设计（家族性与基于人群）和国家的年龄调整后，这种耗竭的证据仍然存在。在另一个乳腺癌基因中具有致病性变异的BRCA1，BRCA2或PALB2在BRCA1，BRCA2或PALB2中具有不确定意义的变异的共同观察，等于在标准强度分配后基于可能性比率的致病性证据，并在基于BRCA1和BRCA2变体的重新分类中表现出效用。我们的方法适用于评估共同观察的价值作为在其他临床背景下变异致病性的预测指标，包括针对克林根变体策划专家面板开发的基因特异性准则。
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.