Expansion of Cancer Risk Profile for BRCA1 and BRCA2 Pathogenic Variants.
Expansion of Cancer Risk Profile for BRCA1 and BRCA2 Pathogenic Variants.
复制标题
DOI：
10.1001/jamaoncol.2022.0476
复制
发表时间：
2022-06-01
期刊：
影响因子：
28.4
通讯作者：
中科院分区：
文献类型：
--
作者：
除了乳腺癌、卵巢癌、前列腺癌和胰腺癌外，哪些癌症类型及其临床特征与BRCA1和BRCA2的致病变异有关？在这项病例对照研究中，63例BRCA828例患者(14种常见癌症类型)和37例 086对照组的致病基因变异分别与胆道癌、食道癌和胃癌有关。 /2与胃癌相关。研究结果表明，与BRCA1和BRCA2致病变异相关的癌症类型范围比先前分析确定的范围更广，这可能表明BRCA1/2基因测试具有更广泛的临床相关性。BRCA1和BRCA2基因检测在乳腺癌、卵巢癌、前列腺癌和胰腺癌中的临床重要性被广泛认识。然而，没有足够的证据将其他可能与BRCA1和BRCA2相关的癌症类型包括在临床管理指南中。[目的]探讨BRCA1和BRCA2致病基因变异与其他癌症类型及其临床特征的关系，并对14种癌症类型的10 0名 914个体进行研究。这项旨在确定与BRCA1和BRCA2致病变异相关的癌症类型和临床特征的病例对照分析包括2003年4月至2018年3月期间来自日本Biobank多机构医院登记的63名 828名患者的14种常见癌症类型和37名 086对照的DNA样本和临床信息。对2019年8月至2021年10月期间的数据进行了分析。以多重聚合酶链式反应为基础的靶序列分析方法鉴定了BRCA1和BRCA2基因编码区和2个碱基对侧翼内含子序列的种系致病变异。通过比较每种癌症类型患者和对照组之间的致病变异携带者频率来评估(可能的)致病变异与每种癌症类型的相关性。65例 患者(确诊时平均年龄64.1[11.6]岁；女性27531例(42.3%))和38153例对照(登记时平均年龄61.8[14.6]岁；17例 911(46.9%)女性)纳入本研究。共鉴定出315个独特的致病变异体。致病变异与P <； 1 × 10−4在胆道癌(OR，17.4；95%CI，5.8-51.9)、食道癌(OR，5.6；95%CI，2.9-11.0)、胃癌(OR，5.2；95%CI，2.6-10.5)相关。BRCA2的95%可信区间3.1-7.1)，以及已确定的4种癌症类型。我们还观察到BRCA1和BRCA2中分别有2种和4种其他癌症类型存在关联。根据亲属报告的癌症类型的增加，胆道癌、女性乳腺癌、卵巢癌和前列腺癌患者的携带者人数有所增加。这项基于登记的大规模病例对照研究结果表明，BRCA1和BRCA2的致病变异与7种癌症类型的风险相关。这些结果表明BRCA1和BRCA2基因检测具有更广泛的临床相关性。这项病例对照研究调查了14种癌症类型的100名 914名日本人中BRCA1和BRCA2致病变异与其他癌症类型及其临床特征的关系。
Which cancer types and their clinical characteristics are associated with pathogenic variants in BRCA1 and BRCA2 in addition to breast, ovarian, prostate, and pancreatic cancers? In this case-control study of 63 828 patients with 14 common cancer types and 37 086 controls, pathogenic variants in BRCA1 were associated with biliary tract cancer, in BRCA2 with esophageal cancer, and in BRCA1/2 with gastric cancer. The study results suggest that the range of cancer types associated with pathogenic variants in BRCA1 and BRCA2 is broader than that determined from previous analyses, potentially indicating the broader clinical relevance of BRCA1/2 genetic testing. The clinical importance of genetic testing of BRCA1 and BRCA2 in breast, ovarian, prostate, and pancreatic cancers is widely recognized. However, there is insufficient evidence to include other cancer types that are potentially associated with BRCA1 and BRCA2 in clinical management guidelines. To evaluate the association of BRCA1 and BRCA2 pathogenic variants with additional cancer types and their clinical characteristics in 100 914 individuals across 14 cancer types. This case-control analysis to identify cancer types and clinical characteristics associated with pathogenic variants in BRCA1 and BRCA2 included DNA samples and clinical information from 63 828 patients with 14 common cancer types and 37 086 controls that were sourced from a multi-institutional hospital-based registry, BioBank Japan, between April 2003 and March 2018. The data were analyzed between August 2019 and October 2021. Germline pathogenic variants in coding regions and 2 bp flanking intronic sequences in BRCA1 and BRCA2 were identified by a multiplex polymerase chain reaction–based target sequence method. Associations of (likely) pathogenic variants with each cancer type were assessed by comparing pathogenic variant carrier frequency between patients in each cancer type and controls. A total of 65 108 patients (mean [SD] age at diagnosis, 64.1 [11.6] years; 27 531 [42.3%] female) and 38 153 controls (mean [SD] age at registration, 61.8 [14.6] years; 17 911 [46.9%] female) were included in this study. A total of 315 unique pathogenic variants were identified. Pathogenic variants were associated with P < 1 × 10−4 with an odds ratio (OR) of greater than 4.0 in biliary tract cancer (OR, 17.4; 95% CI, 5.8-51.9) in BRCA1, esophageal cancer (OR, 5.6; 95% CI, 2.9-11.0) in BRCA2, and gastric cancer (OR, 5.2; 95% CI, 2.6-10.5) in BRCA1, and (OR, 4.7; 95% CI, 3.1-7.1) in BRCA2 in addition to the 4 established cancer types. We also observed an association with 2 and 4 other cancer types in BRCA1 and BRCA2, respectively. Biliary tract, female breast, ovarian, and prostate cancers showed enrichment of carrier patients according to the increased number of reported cancer types in relatives. The results of this large-scale registry-based case-control study suggest that pathogenic variants in BRCA1 and BRCA2 were associated with the risk of 7 cancer types. These results indicate broader clinical relevance of BRCA1 and BRCA2 genetic testing. This case-control study examines the association of BRCA1 and BRCA2 pathogenic variants with additional cancer types and their clinical characteristics in 100 914 Japanese individuals across 14 cancer types.