Table_1_Whole Exome Sequencing in BRCA1-2 Candidate Families: The Contribution of Other Cancer Susceptibility Genes.docx

Hereditary Breast and Ovarian Cancer (HBOC) syndrome is a condition in which the risk of breast and ovarian cancer is higher than in the general population. The prevalent pathogenesis is attributable to inactivating variants of the BRCA1-2 highly penetrant genes, however, other cancer susceptibility genes may also be involved. By Whole Exome Sequencing (WES) we analyzed a series of 200 individuals selected for genetic testing in BRCA1-2 genes according to the updated National Comprehensive Cancer Network (NCCN) guidelines. Analysis by MLPA was performed to detect large BRCA1-2 deletions/duplications. Focusing on BRCA1-2 genes, data analysis identified 11 cases with pathogenic variants (4 in BRCA1 and 7 in BRCA1-2) and 12 with uncertain variants (7 in BRCA1 and 5 in BRCA2). Only one case was found with a large BRCA1 deletion. Whole exome analysis allowed to characterize pathogenic variants in 21 additional genes: 10 genes more traditionally associated to breast and ovarian cancer (ATM, BRIP1, CDH1, PALB2, PTEN, RAD51C, and TP53) (5% diagnostic yield) and 11 in candidate cancer susceptibility genes (DPYD, ERBB3, ERCC2, MUTYH, NQO2, NTHL1, PARK2, RAD54L, and RNASEL). In conclusion, this study allowed a personalized risk assessment and clinical surveillance in an increased number of HBOC families and to broaden the spectrum of causative variants also to candidate “non-canonical” genes.

遗传性乳腺癌和卵巢癌综合征（Hereditary Breast and Ovarian Cancer, HBOC）是一类使个体罹患乳腺癌与卵巢癌的风险显著高于普通人群的疾病。其主流发病机制与BRCA1、BRCA2这两个高外显率基因的失活变异相关，但其他癌症易感基因也可能参与致病过程。本研究通过全外显子组测序（Whole Exome Sequencing, WES），对依据最新版美国国家综合癌症网络（National Comprehensive Cancer Network, NCCN）指南、针对BRCA1/2基因开展基因检测的200例受试者队列进行了分析。同时采用多重连接依赖性探针扩增（MLPA）技术检测BRCA1/2基因的大片段缺失/重复变异。针对BRCA1/2基因的数据分析显示，共检出11例致病性变异（其中BRCA1基因4例，BRCA2基因7例），12例意义未明的变异（BRCA1基因7例，BRCA2基因5例）；仅发现1例BRCA1基因大片段缺失的病例。全外显子组测序分析还在21个其他基因中鉴定出致病性变异：其中10个为传统上与乳腺癌和卵巢癌相关的基因（包括ATM、BRIP1、CDH1、PALB2、PTEN、RAD51C及TP53），诊断检出率为5%；另外11个为候选癌症易感基因（包括DPYD、ERBB3、ERCC2、MUTYH、NQO2、NTHL1、PARK2、RAD54L及RNASEL）。综上，本研究使更多遗传性乳腺癌和卵巢癌综合征家族能够获得个性化风险评估与临床监测，并将致病变异的谱范围拓展至候选“非经典”癌症易感基因。