Detection Of Susceptibility Genes For Hereditary Breast Cancer In A Chinese Population By Next-generation Sequencing

[Objective] The genetic etiology of hereditary breast cancer in the Chinese population has not been fully elucidated. Through this study, we hoped to obtain comprehensive results regarding the hereditary breast cancer susceptibility genes in the Chinese population and to lay a foundation for the development of breast cancer genetic counseling in China.[Methods] We selected 152 known genes associated with hereditary cancer and evaluated them using targeted capture and NGS in 99 breast cancer patients from families with cancer without limitation regarding the cancer type.[Results] Forty-two loss-of-function germline mutations were identified in 21 genes of 34 breast cancer patients, including 18 (18.2%) BRCA1 or BRCA2 mutations,3 (3%) TP53 mutations,5 (5.1%) DNA MMR gene mutations,1 (1%) CDH1 mutation, 6 (6.1%) FA pathway gene mutations and 9 (9.1%) mutations in other genes. Seven (7.1%) patients were found to carry mutations in more than one gene; among these patients, four were BRCA1/2 mutation carriers. Compared to patients with only BRCA1/2 mutations, the average age of onset was much younger for those carrying mutations in other genes in addition to BRCA1/2. MSH3 germline mutations were identified in three families and functional studies confirmed the association between MSH3 mutation and tumorigenesis. A family fulfilling the revised Bethesda criteria was identified to carry a single MSH3 mutation. However, in another family fulfilling the HBOCS criteria, both MSH3 and BRCA1 mutations were identified. Segregation analysis suggested antagonism between BRCA1 and MSH3. Two TP53 and three MMR gene mutations were detected in the families that did not fulfill the typical phenotypes of hereditary cancer syndromes listed in the NCCN guidelines.[Conclusions] Our study involved comprehensive genetic testing of all known genes associated with hereditary cancer in breast cancer probands, regardless of the cancer types of their blood relatives. Our findings demonstrated that a multi-gene analysis using NGS could compensate for the shortcomings of traditional genetic counseling. NGS has the advantages of high efficiency and low cost, which shows enormous superiority and feasibility.