Comparison of BRCA versus non-BRCA germline mutations and associated somatic mutation profiles in patients with unselected breast cancer

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.

Keywords: BRCA; breast cancer; germline mutations; non-BRCA; somatic mutations.

Figure 1

Frequency and distribution of LP/P germline variants. LP/P mutations identified in 62 cancer susceptibility genes in 524 unselected breast cancer patients. The multiples of genes associated with breast cancer risk are listed on the histogram.

Figure 2

LP/P germline BRCA1/2 mutations detected in this cohort. (A) 11 LP/P mutations found in BRCA1. (B) 18 LP/P mutations found in BRCA2. Colored boxes depict the different functional domains along the gene. Small colored circles denote the type of mutation while the location of the circle specifies the mutation site. A patient is represented by a circle. The length of the lollipop represents the number of people of a specific variant.

Figure 3

Comprehensive somatic mutation spectrum of the 524 patients. Each column represents a patient and each row represents a gene. The number on the left represents the percentage of patients with mutations in a specific gene. The top plot represents the overall number of mutations detected in a patient. Different colors denote different types of mutation. The annotation at the bottom, with each color representing each group, depicts the germline mutations carried by the patients.

Figure 4

Characteristics of Somatic Mutations in Breast Cancer Patients with Germline Mutations. (A) Three groups according to germline mutations: Germline-BRCA1/2, Germline-others (non-BRCA) and Others (non-carriers). (B) Somatic mutation positive detection rate among the three groups. (C) The difference of the mutation type distribution among the three groups. (D) The difference of the mutation genes among the three groups. * P<0.05. (E). PIK3CA mutation spectrum in the three groups.