Unlike mutation, methylation of homologous recombination DNA repair pathway genes was not linked to longer survival or platinum sensitivity in high-grade serous ovarian cancer, according to molecular and clinical analyses of 332 patients.
“Methylation may be more readily reversed than mutation, allowing more rapid development of platinum resistance and negating any impact on overall survival,” said Sarah Bernards, a second-year medical student at the University of Washington, Seattle, who presented the findings at the annual meeting of the Society of Gynecologic Oncology.
The homologous recombination (HR) DNA repair pathway is critical for repairing cross-linking and double-strand breaks, Ms. Bernards noted. Genes such as BRCA1, BRCA2, and RAD51C are important in this pathway, and inherited and sporadic mutations of these genes can lead to ovarian carcinoma. Importantly, ovarian cancers with HR gene mutations are more sensitive to platinum and radiation therapy and are associated with longer progression-free survival and overall survival compared with ovarian cancers without these mutations.
Methylation of the promoter regions of BRCA1 and RAD51C reduces expression of these genes and has been found to be associated with high-grade serous ovarian cancer, Ms. Bernards explained. One previous study found promoter methylations of BRCA1 and RAD51C in 11.5% and 3% of such tumors, respectively ().
To further characterize HR gene methylations, Ms. Bernards and her associates used methylation-sensitive PCR to analyze ovarian carcinomas from patients who underwent primary debulking surgery and were enrolled in the University of Washington gynecologic oncology tissue bank. They also tested for damaging germline and somatic mutations in 16 HR DNA repair genes.
In all, 28% of cases had mutations in HR repair pathway genes, 7% had a BRCA1 methylation, and 3% had RAD51C methylation. BRCA1 and RAD51C methylation never overlapped with mutation (P = .001), and almost never overlapped with mutations in other HR DNA repair pathway genes, Ms. Bernards said.
Fully two-thirds of BRCA1 mutated cases were sensitive to chemotherapy, compared with 59% of BRCA1 methylated cases and 53% of wild-type BRCA1 cases (P = .03). Mutations of any HR DNA repair gene were associated with improved overall survival (hazard ratio, 0.7; 95% confidence interval, 0.5-0.9; P = .02), but methylation of RAD51C and BRCA1 was not (P = .3). Patients with HR gene mutations survived a median of 66 months after diagnosis, compared with 41 months for patients with RAD51C methylation and 43 months for patients with BRCA1 methylation.
Median age at diagnosis was 53 years for BRCA1 mutated cases (P less than .0001) and 55 years for BRCA1 methylated cases (P = .03), significantly lower than the 63-year median age for diagnosis of wild-type BRCA1 cases. High-grade histology characterized 71% of wild-type BRCA1 cases, compared with 82% of BRCA1 mutated cases (P = .001) and 91% of BRCA1 methylated cases (P = .05). Somatic TP53 mutations occurred in 67% of wild-type cases, 89% of mutated cases (P = .004), and 82% of methylated cases (P = .01).
To sum up, both methylation and mutation of BRCA1 were associated with younger age at diagnosis, high-grade histology, and TP53 mutations, but only BRCA1 mutation was tied to improved overall survival or platinum sensitivity, Ms. Bernards said.
The work was supported by a grant from the University of Washington School of Medicine Medical Student Research Training Program. Ms. Bernards conducted the work under Elizabeth Swisher, MD, a medical oncologist and head of the Swisher Lab at the University of Washington, Seattle. Ms. Bernards reported having no conflicts of interest.
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