The clinicopathological parameters of 36 EOC patients carrying germline BRCA1/2 DM were compared to high-grade serous EOC women of the COEUR cohort with known germline BRCA1/BRCA2 mutation carrier status (n = 376 non-carriers, n = 65 BRCA1 and n = 38 BRCA2).
These genes are associated with an estimated lifetime risk of EOC of 13% to 60% for BRCA1 variants and 10% to 25% for BRCA2 variants, with lower risks associated with remaining genes.
Our findings provide a novel mechanism underlying PARPi resistance in BRCA2 mutated EOC cells, and suggest that inhibition of ALDH1A1 could be exploited for preventing and overcoming PARPi resistance in EOC patients carrying BRCA2 mutation.
Epithelial ovarian cancer is composed of distinct histological subtypes with unique genomic characteristics, which are improving the precision and effectiveness of therapy, allowing discovery of predictors of response such as mutations in breast cancer susceptibility genes BRCA1 and BRCA2, and homologous recombination deficiency for DNA damage response pathway inhibitors or resistance (cyclin E1).
Germline BRCA1 or BRCA2 mutations (mtBRCA1 and mtBRCA2) increase risk for high-grade serous ovarian cancer (HGSOC), the most commonly diagnosed epithelial ovarian cancer histotype.
In conclusion, lncRNA RP11-552M11.4 correlates with worse prognosis, and promotes cell proliferation, migration, invasion, and inhibits cell apoptosis by down-regulating BRCA2 in EOC.
Currently, somatic or germinal mutations on BRCA1 and BRCA2 genes are the most important biomarkers in epithelial ovarian cancer having prognostic and predictive value.
To evaluate the long-term cost-effectiveness of germline BRCA1 and BRCA2 (collectively termed "BRCA") testing in women with epithelial ovarian cancer, and testing for the relevant mutation in first- and second-degree relatives of BRCA mutation-positive individuals, compared with no testing.
Mutations in BRCA1 and BRCA2 account for hereditary breast and ovarian cancer syndrome in a majority of families and 14% of epithelial ovarian cancer cases.
We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC.
Recent studies revealed frequent somatic mutations of BRCA1/BRCA2 and hypermethylation of the promoter of BRCA1 in EOC, in addition to germline mutations.
The key recommendations highlighted are: All women with high grade non-mucinous epithelial ovarian cancer should be offered at least BRCA1 and BRCA2 genetic testing.
After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis.
High percentage of BRCA2 methylation and correlation of BRCA2 expression with overall survival in epithelial ovarian cancer cases may lead to development of treatment modalities specifically to target methylation of BRCA genes.
Loss of function of the second allele causes complete loss of the corresponding protein and facilitates the development of a malignancy.The Association of Gynecologic Oncology recommends that testing for a germline mutation in BRCA1 or BRCA2 should be offered to all patients with epithelial ovarian cancer.
These results confirm that RAD51C and RAD51D are moderate ovarian cancer susceptibility genes and suggest that they confer levels of risk of EOC that may warrant their use alongside BRCA1 and BRCA2 in routine clinical genetic testing.