Abstract
The data on the phenotypes associated with some rare germline mutations in Chinese breast cancer patients are limited. The difference in somatic mutation profiles in breast cancer patients with germline BRCA and non-BRCA mutations remains unexplored. We interrogated the germline and somatic mutational profile of 524 Chinese breast cancer patients with various stages unselected for predisposing factors using a panel consisting of 520 cancer-related genes including 62 cancer susceptibility genes. We divided the patients into three groups according to germline mutations: Germline-BRCA1/2, Germline-others (non-BRCA) and Others (non-carriers). A total of 58 patients (11.1%) carried 76 likely pathogenic or pathogenic (LP/P) germline variants in 15 cancer predisposition genes. Germline BRCA1/2 mutations were detected from 29 (5.53%) patients; with 11 (2.10%) BRCA1 carriers and 18 (3.44%) BRCA2 carriers. In addition, LP/P germline mutations were detected in other genes including MUTYH (n=4), PALB2 (n=4), ATM (n=3), BRIP1 (n=3), CDH1 (n=3), RAD51C (n=3), CHEK2 (n=2), FANCA (n=2), PMS2 (n=2), TP53 (n=2), FANCI (n=1), FANCL (n=1) and PTEN (n=1). At least one variant of uncertain significance (VUS) was identified in 490 (93.5%) patients. Young age (P=0.011), premenopausal status (P=0.013), and breast/ovarian cancer family history (P=0.001) were correlated with germline mutations. Germline-BRCA1/2 group was detected with more missense (P=0.02) and less copy-number amplification (P=0.04) than Germline-others group. Meanwhile, Germline-others group and Others group are very similar (P>0.05). The mutation rates of AKT1, CCND1, FGFR1, and PIK3CA were different among the three groups. By investigating all breast and ovarian cancer-related genes listed in the US genetic guidelines, we identified 15 cancer susceptibility genes frequently mutated in the germline of our population and must be included in cancer predisposition screening. Our study contributed a better understanding of the tumor characteristics of patients with LP/P germline mutations.
Highlights
It is estimated that familial susceptibility to breast cancer accounts for about 25% of all breast cancer cases [1]
Our study is the most comprehensive germline mutation study in unselected breast cancer patients in Southern China interrogating all breast or ovarian cancer-related genes listed in the US genetic guidelines
Our findings may be useful for selecting the subset of breast cancer patients to receive multigene panel testing
Summary
It is estimated that familial susceptibility to breast cancer accounts for about 25% of all breast cancer cases [1]. The testing for germline mutations in highpenetrance breast cancer predisposition genes has become standard practice for breast cancer patients [2]. Existing recommendations for germline mutation testing of other high-penetrance genes including CDH1, TP53 and PTEN are based on specific clinical features [4]. Numerous studies have associated mutations in moderate-penetrance genes, including PALB2, ATM, CHEK2, BRIP1, with increased breast cancer risk of two to four-fold compared to the 10% risk of the general population [5]. Germline mutations in DNA damage repair genes such as ATM and CHEK2 are associated with an increased risk of breast cancer [9, 10]. Despite mounting evidence suggesting the association of mutations in moderate-penetrance genes with increased breast cancer risk, the current guidelines still do not require the testing of these genes. No consensus exists on the number and the specific genes needed to be sequenced and analyzed for the assessment of genetic cancer predisposition [11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
