Germline and Somatic BRCA1/2 Mutations in 172 Chinese Women With Epithelial Ovarian Cancer

Abstract

Objective: Despite several nationwide cohort studies of germline BRCA1/2 mutations and several small cohort studies of somatic BRCA1/2 mutations in Chinese epithelial ovarian cancer (EOC) patients, little is known about the impact of these findings on survival outcomes in this population. In this study of 172 retrospectively recruited Chinese EOC patients, germline and somatic BRCA1/2 mutations and their value for predicting survival outcomes were evaluated. Methods: Unselected patients who visited the study center from January 1, 2011, to January 1, 2015, were recruited and asked to provide peripheral blood samples for this study if they were pathologically confirmed to have primary EOC. All patients received staging surgeries or debulking surgeries involving systemic platinum-based chemotherapy, and the patients were then followed up to December 1, 2017. DNA was extracted from formalin-fixed, paraffin-embedded (FFPE) sections and peripheral blood and sequenced for somatic and germline testing, respectively. The demographic and clinicopathological characteristics of the patients were collected to analyze the distribution of BRCA mutations in subgroups. Survival outcomes were compared among various BRCA mutation statuses using univariate and multivariate models. Results: In 58 (33.7%) patients, 63 variants were identified, including variants of unknown significance (VUS) in 18 patients (10.5%) and pathogenic or likely pathogenic variants in a partially overlapping set of 41 patients (23.8%). Germline BRCA mutations, somatic BRCA mutations, BRCA1 mutations in general, and BRCA2 mutations in general were found in 35 (20.3%), 7 (4.1%), 28 (16.3%), and 13 (7.6%) patients, respectively. Five recurrent mutations were identified. Personal and family cancer histories as well as hereditary breast and ovarian cancer (HBOC) criteria were associated with deleterious BRCA mutations both overall and in the germline specifically, whereas only age at diagnosis of EOC was associated with somatic BRCA mutations. In univariate and Cox regression analyses, patients with BRCA1/2 mutations in general had significant improvements in progression-free survival (PFS) and overall survival (OS). You et al. Germline and Somatic BRCA1/2 Mutations in EOC Conclusions: In Chinese EOC patients, the distributions and risk factors associated with germline and somatic BRCA1/2 mutations were similar to those previously reported in international studies. Deleterious BRCA mutations in general were associated with improved survival outcomes in this cohort.

The Prognostic and Predictive Role of Somatic BRCA Mutations in Ovarian Cancer: Results from a Multicenter Cohort Study

“…Interestingly, in both the overall population and stage III and IV patients, sBRCA did not show any advantage in terms of PFS, PFS2, and OS as compared to wild-type patients. Overall, our results confirm the recent results of You and colleagues [ 27 ] and are apparently in contrast with previous works by Lesnock et al [ 24 ] and Hennessy et al [ 3 ]. Furthermore, no significant differences in PFS, PFS2, and OS were observed between SNVs/indels and CNVs, suggesting that these populations are homogeneous in terms of outcome, while they seem to differ from gBRCA patients.…”

“…A few small cohort studies have previously shown that, like gBRCA, pathogenic sBRCA variants have a similar positive impact on OS as well as platinum and PARP inhibitor sensitivity [ 3 , 24 , 25 , 26 ]. On the other hand, a more recent study found no significant impact of sBRCA mutations on progression-free survival (PFS) or OS [ 27 ]. Nevertheless, all these studies suffered from relevant shortcomings, particularly in terms of the copy number variation (CNV) analysis of BRCA genes.…”

Identification of Recurrent Variants in BRCA1 and BRCA2 across Multiple Cancers in the Chinese Population

“…Recently, You et al identified five recurrent variants in 172 Chinese women with epithelial ovarian cancer, including three pathogenic mutations (BRCA1 c.5470_5477delATTG GGCA and c.66dup and BRCA2 c.1963delC) and two VUS missense mutations (BRCA2 c.1568A>G and c.6325G>A) [29]. However, these potentially pathogenic mutations above were not validated in our current study.…”

“…To date, several studies have reported the BRCA1/2 pathogenic variants from breast or ovarian cancer in Chinese populations with diverse results. A meta-analysis collected 94 publications with 2128 BRCA1/2 variant records which showed several high-frequency variants but no potential founder variants were identified [26], for example, the two highest recurrent variants c.5470_5477delATTGGGCA [27][28][29] in BRCA1 and c.3109C>T in BRCA2 [25,30].…”

“…To date, several studies have reported the BRCA1/2 pathogenic variants from breast or ovarian cancer in Chinese populations with diverse results. A meta-analysis collected 94 publications with 2128 BRCA1/2 variant records which showed several high-frequency variants but no potential founder variants were identified [ 26 ], for example, the two highest recurrent variants c.5470_5477delATTGGGCA [ 27 – 29 ] in BRCA1 and c.3109C>T in BRCA2 [ 25 , 30 ]. Recently, You et al identified five recurrent variants in 172 Chinese women with epithelial ovarian cancer, including three pathogenic mutations ( BRCA1 c.5470_5477delATTGGGCA and c.66dup and BRCA2 c.1963delC) and two VUS missense mutations ( BRCA2 c.1568A>G and c.6325G>A) [ 29 ].…”