Germline <em>BRCA1</em> and <em>BRCA2</em> deleterious mutations and variants of unknown clinical significance associated with breast/ovarian cancer: a report from North India

Abstract

BackgroundThe spectrum of BRCA mutations that predispose to development of breast/ovarian cancer in Indian population remains unexplored. We report incidence and various types of pathogenic, likely pathogenic and variants of unknown significance (VUS) mutations in BRCA1 and BRCA2 genes observed at a tertiary cancer center in North India.Materials and methodsA total of 206 unrelated breast and/or ovarian cancer patients, who met the National Comprehensive Cancer Network (NCCN) guidelines for genetic testing, were screened for germline BRCA1/BRCA 2 mutations on high-throughput sequencing platform; large genomic rearrangements were assessed by multiple ligation probe assay. Mutations were mined in mutational databases, PubMed, and discerned into classes. Furthermore, the clinicopathological correlation of BRCA mutation status with prognostic markers in breast cancer and tumor histology in ovarian cancer was performed.ResultsIn total, 45/206 and 17/206 cases showed positivity for BRCA1 and BRCA2 mutations, respectively, whereas 1/206 was positive for a mutation in both the genes. Altogether, 33 distinct BRCA1 mutations were observed, among which 27 were deleterious (12 frameshifts, 8 nonsense, 1 missense, 3 splice-site variants, 2 big deletions and 1 large duplication) and 6 were VUS. Five novel BRCA1 mutations (c.541G>T, c.1681delT, c.2295delG, c.4915C>T and exon 23 deletion) were identified. Seven mutations (c.2214_2215insT, c.2295delG, c.3607C>T,c.4158_4162delCTCTC, c.4571C>A, splicesite_3 (C>T) and exon 21–23 duplication) occurred more than once, whereas 16 distinct BRCA2 mutations were noted – 9 were lethal (6 frameshifts, 2 nonsense and 1 big deletion) and 7 VUS. One unique pathogenic BRCA2 mutation (c.932_933insT) was recognized. Two mutations (c.9976A>T and c.10089A>G) recurred twice. No significant difference in hormone receptor status was observed among BRCA1 carriers, BRCA2 carriers and noncarriers.ConclusionWe have documented various pathogenic and VUS mutations in BRCA1 and BRCA2 genes observed in the cohort. Six novel mutations were identified. The knowledge shared would assist genetic testing in enabling more focused site-specific screening for mutations in biological relatives.

Prevalence of BRCA1 and BRCA2 Mutations Among Patients With Ovarian, Primary Peritoneal, and Fallopian Tube Cancer in India: A Multicenter Cross-Sectional Study

“…8 - 10 Inherited mutations in the key tumor suppressor genes, the breast cancer susceptibility gene 1 or 2 ( BRCA1 or BRCA2 ), are prevalent in 3%-27% of patients with ovarian cancer who are not selected on the basis of clinical features like family history. 11 , 12 By age 70 years, ovarian cancer risk is 40% in BRCA1 and 18% in BRCA2 mutation carriers. 13 Germline mutations in BRCA genes also confer high risk for the development of fallopian tube carcinoma and primary papillary serous carcinoma of the peritoneum.…”

“…22 - 26 For example, the recent National Comprehensive Cancer Network guidelines (version 1, 2020) recommend genetic testing for BRCA1 / 2 mutations along with other panels of mutations like CDH1 , PALB2 , PTEN , and TP53 in patients with breast cancer, ovarian cancer, and pancreatic cancer on the basis of their family history, ethnicity, age, and tumor histology. 27 Although a few regional studies have been reported, 11 , 28 , 29 these have included patients with breast and/or ovarian cancer who were chosen because of clinical features like suggestive family history or young age, with pathogenic or likely pathogenic mutation being reported in 25.5%-30.1% of them. Hence, this multicenter Indian study was undertaken in patients with ovarian cancer not selected for any predisposing clinical features, who were evaluated for prevalence of germline BRCA mutations and its association with clinical and pathologic characteristics.…”

Correlation between the number of false positive variants and the quality of results using Ion Torrent PGM™ sequencing to screen BRCA genes

“…In our study, BRCA2 variants ch13:32906547 (c.937_938insT) and chr13:32906565 (c.956_957insA) were confirmed as FP. Mehta et al (2018) reported these variants as true germline mutations in Indian patients with breast cancer and the coverage data and Sanger validation were not reported (14).…”

The Response of Second Line Chemotherapy Platinum Resistant Ovarian Cancer in Sudan: 2013-2017

“…Many factors can contribute in the etiology of ovarian tumors, and these may include genetic mutation such as Breast Cancer (BRCA) mutation (44)(45)(46)(47), postmenopausal stage (48), talcum powder (49) and hormonal change in advance age (50). Generally this type of cancer is considered to be one of the most devastating tumors, due to the lack of specific clinical symptoms related to it, until to be spread beyond level of the primary site and become difficult to treat (50).…”