Germline mutations of BRCA1 gene exon 11 are not associated with platinum response neither with survival advantage in patients with primary ovarian cancer: understanding the clinical importance of one of the biggest human exons. A study of the Tumor Bank Ovarian Cancer (TOC) Consortium

Abstract

Germline mutations in BRCA1 gene have been reported in up to 20 % of epithelial ovarian cancer (EOC) patients. Distinct clinical characteristics have been attributed to this special EOC population. We hypothesized that mutations in different BRCA1 gene exons may differently affect the clinical course of the disease. The aim of this study was to analyze, in a large cohort of primary EOCs, the clinical impact of mutations in BRCA1 gene exon 11, the largest exon of the gene sequence encoding the 60 % of BRCA1 protein. Two hundred sixty-three primary EOC patients, treated between 2000 and 2008 at Charité University Hospital of Berlin, were included. Patients' blood samples were obtained from the Tumor Ovarian Cancer (TOC) Network ( www.toc-network.de ). Direct sequencing of BRCA1 gene exon 11 was performed for each patient to detect mutations. Based on their BRCA1 exon 11 mutational status, patients were compared regarding clinico-pathological variables and survival. Mutations in BRCA1 exon 11 were found in 18 out of 263 patients (6.8 %). Further 10/263 (3.8 %) cases showed variants of uncertain significance (VUS). All exon 11 BRCA1-positive tumors (100 %) were Type 2 ovarian carcinomas (p = 0.05). Age at diagnosis was significantly younger in Type 2 exon 11 mutated patients (p = 0.01). On multivariate analysis, BRCA1 exon 11 mutational status was not found to be an independent predictive factor for optimal cytoreduction, platinum response, or survival. Mutations in BRCA1 gene exon 11 seem to predispose women to exclusively develop a Type 2 ovarian cancer at younger age. Exon 11 BRCA1-mutated EOC patients showed distinct clinico-pathological features but similar clinical outcome with respect to sporadic EOC patients.

Distinct implications of different BRCA mutations: efficacy of cytotoxic chemotherapy, PARP inhibition and clinical outcome in ovarian cancer

“…The study by Dimitrova et al73 of BRCA1 exon 11-associated OC revealed no 5-year OS benefit in this population versus the wild-type population, suggesting that all BRCA1 mutations are not equal in conveying survival advantage.…”

“…Growing data suggest that BRCA1 E11mut cells display a distinct partially platinum- and PARP inhibitor-resistant phenotype, and OC patients harboring BRCA1 mutations in exon 11 may not experience a BRCAness survival benefit 72,73. Similarly, BRCA1 mutations affecting RING domain function may also not display hypersensitivity to platinum or PARP inhibition 74,75.…”

Genetic Versus Epigenetic BRCA1 Silencing Pathways

“…On the contrary, they did not observe a significant earlier disease onset among hypermethylated patients, but our finding is in accordance with our previous report carried out on a smaller sample population. 21,22 Regarding the tumor dissemination pattern, to our knowledge, this is the first study in which a detailed comparison between GMB or HMB and BWT OC patients' tumor spread has been analyzed. No difference in cancer distribution was observed between the groups, and this might also justify the absence of significant differences in optimal tumor debulking rates among the 3 cohorts.…”

“…21,22 All detected mutations were compared with the Breast Core Information Database (https://research.nhgri.nih.gov/bic/) for describing the gene alterations. When a mutation was found, a second sequencing reaction with the reverse primer was performed to confirm the results.…”

Family-Specific Variants and the Limits of Human Genetics

“…Some missense variants in highly conserved functional domains alter protein function, and others do not (Jeyasekharan et al, 2013, Starita et al, 2015). Some gene domains tolerate variants and others do not (Dimitrova et al, 2016, Wang et al, 2016). Some splice-site variants cause exon skipping, but others do not or cause alternate splicing that does not substantially change protein function (de la Hoya et al, 2016).…”