Unlike the presence of mutations, promoter hypermethylation of homologous recombination DNA repair (HRR)–associated genes is not associated with improved survival in ovarian carcinoma, according to a study presented at the 2017 Society of Gynecologic Oncology Annual Meeting.1

Mutations in genes that code for proteins involved in HRR, such as BRCA1 and RAD51C, are associated with improved survival among patients with ovarian carcinoma. The purpose of this study was to determine if promoter hypermethylation of these genes—another mechanism to decrease gene expression—is also associated with improved survival in this population.

The study evaluated samples of 332 primary ovarian carcinomas for promoter hypermethylation as well as germline and somatic mutations in 16 genes involved in the HRR.

Hypermethylation was present in BRCA1 and RAD51C in 6.6% and 2.7% of samples, respectively. Germline mutations were more common, affecting HRR-associated genes in 29% of samples.

Patients with BRCA1 promoter hypermethylation or mutations were younger, with a mean age of 57.7 and 54.1 years, respectively, compared with those with wild-type BRCA1, with a mean age of 63.3 (P = .029 and < .0001, respectively). High-grade serous histology and TP53 mutations were significantly associated with methylation (P = .045 and P = .012, respectively) and germline mutations (P = .001 and P = .004, respectively) in BRCA1.

Greater sensitivity to platinum chemotherapy was associated with BRCA1 mutations (P = .034), but not with promoter methylation. Hypermethylation of other HRR-associated genes was also not associated with improved survival.

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The authors suggested that “methylation is more readily reversed than mutation allowing more rapid development of platinum resistance.”

Reference

  1. Bernards SS, Pennington K, Harrell MI, Agnew KJ, Norquist BM, Swisher EM. Overall survival in BRCA1 or RAD51C methylated vs mutated ovarian carcinoma following primary treatment with platinum chemotherapy. Paper presented at: 48th Annual Meeting of the Society of Gynecologic Oncology; March 12-15, 2017; National Harbor, MD.