Prevalence and clinical significance of BRCA1/2 germline and somatic mutations in Taiwanese patients with ovarian cancer

Abstract

Germline and somatic BRCA1/2 mutations define a subset of patients with ovarian cancer who may benefit from treatment with poly (ADP-ribose) polymerase inhibitors. Unfortunately, data on the frequency of BRCA1/2 germline mutations in Taiwanese patients with ovarian cancer are scarce, with the prevalence of somatic mutations being unknown. We aim to investigate the occurrence of BRCA1/2 mutations in 99 Taiwanese patients with ovarian cancer which included serous (n = 46), endometrioid (n = 24), and clear cell (n = 29) carcinomas. BRCA1/2 mutations were identified using next-generation sequencing of formalin-fixed paraffin-embedded tumor samples. Pathogenic variants (BRCA1: n = 7; BRCA2: n = 6) were detected in 12.1% (12/99) of the study patients. Somatic and germline BRCA1/2 mutation rates in serous ovarian cancer are 4/46 (8.7%) and 8/46 (17%), respectively. All of the pathogenic BRCA1/2 mutations were identified in serous carcinoma samples (12/46; 26.1%). One-third (4/12) of the deleterious BRCA1/2 mutations occurred in tumor tissues only (somatic mutations). All of them coexisted with loss of heterozygosity, resulting in biallelic BRCA inactivation. Five novel pathogenic mutations were identified, including four somatic variants (BRCA1 p.S242fs, BRCA1 p.F989fs, BRCA1 p.G1738fs, and BRCA2 p.D1451fs) and a germline variant (BRCA2 p.E260fs). We also detected additional six novel mutations (three in BRCA1 and three in BRCA2) with pathogenic potentials. We conclude that BRCA1/2 mutations are common in Taiwanese patients with serous ovarian carcinoma and similar to mutation rates in other ethnic groups. The analysis of BRCA1/2 somatic mutations is crucial for guiding therapeutic decisions in ovarian cancer.

Keywords: BRCA1/2; germline mutations; ovarian cancer; somatic mutations.

Figure 1. BRCA1/2 genetic variants identified in the study cohort

Distribution of pathogenic BRCA1/2 mutations according to different histological subtypes. The recurrent BRCA2 VUS p.S1946P was deemed to be pathogenic owing to its occurrence in two sisters with ovarian cancer (one with clear cell carcinoma and the other with serous carcinoma).

Figure 2. Pathogenic BRCA1/2 variants identified in the study cohort according to their amino acid position

The recurrent BRCA2 VUS p.S1946P—deemed to be pathogenic owing to its occurrence in two sisters with ovarian cancer—is included. However, splice site mutations are not displayed.

Figure 3. Family tree of the two sisters with ovarian cancer harboring the BRCA2 VUS p.S1946P

The asterisks denote subjects who have been tested for the BRCA2 VUS p.S1946P. Subjects with and without the variant of interest are reported as E+ and E-, respectively.