<p>Frequency of germline mutations in BRCA1 and BRCA2 in ovarian cancer patients and their effect on treatment outcome</p>

Abstract

Aim of work Reporting the incidence and the variants of BRCA1 /2 mutations in ovarian cancer patients exploring their effects on the treatment outcomes. Patients and methods In total, 104 patients with epithelial ovarian cancer were prospectively recruited to the study. Analysis consisted of the sequencing of all the translated exons and immediately adjacent intronic regions of the BRCA1/2 genes. Responses to multiple lines of chemotherapy were assessed, as well as the effect of BRCA gene mutations on progression-free survival (PFS) and overall survival (OS). Results Pathogenic BRCA1 / 2 mutations were found in 21.15% of the patients. BRCA1 mutations represented 68.2% of the total mutations. Two novel BRCA1 mutations were identified. Age at diagnosis was a strong predictor of the presence of a pathogenic BRCA1/2 mutation. Patients with a family history of cancer had a higher incidence of BRCA mutations ( P =0.005). As high as 72% of the patients with BRCA mutations were diagnosed at advanced stage. High-grade serous tumors have a higher incidence of pathogenic mutation ( P =0.07). Response to neoadjuvant chemotherapy was high (93.9%). All patients underwent surgery which was optimal in 73.1% of the patients. As high as 85.6% of the patients received adjuvant chemotherapy. Relapse rate was 45.2%. Visceral metastasis was more often in BRCA carriers ( P =0.01). Patients carrying pathogenic BRCA1/2 mutations had a longer median PFS of 42.43 months (95% CI 32.04–52.83) compared to 22.24 months (95% CI 14.83–29.58) for non-carriers ( P =0.08). OS was 64.32 months (95% CI 38.09–90.06) for BRCA mutation patients versus 56.63 months (95% CI 50.05–63.21) ( P =0.04) for non-carriers. In multivariate analysis, early stage at diagnosis and optimal debulking were the only independent predictors of better PFS and OS. Conclusion We documented a number of pathogenic BRCA1 and 2 mutations in this patients cohort; two novel mutations were detected. BRCA status seemed to affect survival in ovarian cancer patients.

Germline and tumor BRCA1/2 mutations in Chinese high grade serous ovarian cancer patients

“…In general, the BRCA1/2 mutation frequencies in Asian countries seems to be higher than that in Western countries. The deleterious germline BRCA1/2 mutant rate in our study was similar to some of the above work (13,16). In addition, we identified 4.3% germline BRCA1 mutation as LGRs, which suggests LGRs detection should be considered in mutation screening and genetic counseling in HGSOC patients, especially for young patients without SNV and indel.…”

“…One study on germline BRCA1/2 mutation in 1915 unselected ovarian carcinomas was conducted in the United States, they found the deleterious mutation frequency including SNV, indel and LGRs in 1498 HGSOC patients was 16.0% by targeted capture (11), while another study from the United States showed that 98 out of 433 (22.6%) HGSOC patients were identified with germline BRCA1/2 mutation (SNV, indel and LGRs) by sequencing and MLPA (12). In a prospectively study mainly focused on the Arab population, a prevalence of 25.7% deleterious germline BRCA1/2 mutation (SNV and indel) was found in 74 HGSOC patients by sequencing (13). Among Asian countries, a relatively small number screening LGRs) and the result was consistent with a respective study in Japan that reported 28.5% of germline BRCA1/2 mutation (SNV and indel) by NGS testing (14,15).…”

“…Common mutation types include single-nucleotide variants (SNV), insertion/deletion (indel) and large genomic rearrangement (LRG) and can occur in both germ cells and somatic cells. To our knowledge, due to the insufficient precision of bioinformatics algorithm on copy number variation in next-generation sequencing (NGS) method, previous studies on the prevalence of BRCA1/2 mutation in ovarian cancer mainly evaluated germline SNV and indel, but usually lacked LGR detection (11)(12)(13)(14)(15)(16)(17). Besides that, studies on tumor BRCA1/2 mutation are still limited for the relatively lower prevalence and more complex detection workflow (4,18,19).…”

A comprehensive analysis of somatic alterations in Chinese ovarian cancer patients

“…Patients' age, tumor stage, and histological subtype are the most important prognostic factors 29 . Based on 104 patients with epithelial ovarian cancer, Ashour et al showed that 86.4% of patients harboring BRCA1/2 mutations were younger than 50 years old, suggesting that the age at diagnosis was a strong predictor of the presence of pathogenic BRCA1/2 mutations 30 . In another study of stage II-IV high-grade epithelial ovarian cancer, deleterious germline BRCA mutations were detected and patients' mean age at diagnosis was younger for patients harboring BRCA1 mutations than patients harboring BRCA2 mutations (52 years vs. 57 years, respectively, P = 0.06) 31 .…”

A Comprehensive Screening Strategy of Breast Cancer Based on Different Penetrance Susceptibility Genes in Healthy Han Chinese Females

“…For example, overall, BRCA2 mutations appear to be more common than BRCA1 mutations in the East Asian population in contrast to white populations, in which BRCA1 mutations may be as common as or more frequent than BRCA2 mutations [24]. To refine BC risk stratification, it is essential to validate these single nucleotide polymorphisms (SNPs) in specific ethnic groups before assessing the polygenic risk scores [25].…”