The clinical importance of BRCAness in a population-based cohort of Danish epithelial ovarian cancer.

OBJECTIVE

Germline mutations in genes predict improved survival and sensitivity to treatment with poly(adenosine-diphosphate-ribose) polymerase inhibitors in epithelial ovarian carcinoma. The prognostic importance of other genetic alterations leading to homologous recombination deficiency, collectively BRCAness phenotype, is unresolved. The aim was to analyze the distribution of homologous recombination deficiency in epithelial ovarian carcinoma caused by mutations in a panel of homologous recombination genes (including ) or epigenetic alterations. A further aim was to investigate the prognostic importance of homologous recombination deficiency, the BRCAness phenotype.

METHODS

We assessed 380 patient specimens from a Danish population-based epithelial ovarian carcinoma cohort for germline and somatic mutations in 18 different homologous recombination genes, including and , using next generation sequencing. Epigenetic alteration due to hypermethylation was assessed by pyrosequencing and BRCA1 protein expression was evaluated by immunohistochemistry.

RESULTS

Seventeen percent of patients with epithelial ovarian carcinoma carried a germline (9.8%) and/or somatic (6.3%) mutation in 12 (, , , , , , , , , , ) of 18 sequenced homologous recombination genes. The homologous recombination mutation rate was similar among the different histologic subtypes, however the type of mutation ( and other homologous recombination mutations) differed, p=4×10. hypermethylation was present in 7.4% of patient specimens for a total BRCAness phenotype of 23.9%. The BRCAness phenotype was associated with improved overall survival in the high-grade serous carcinoma subgroup with a median overall survival of 4.4 years (95% CI 3.0 to 5.3) versus 2.2 years (95% CI 1.9 to 2.4) in BRCAness wildtype, p=0.0002. Multivariate analysis confirmed an independent prognostic value of the BRCAness phenotype among the high-grade serous carcinoma subgroup, hazard ratio 0.65 (95% CI 0.47 to 0.92), p=0.014.

CONCLUSIONS

The BRCAness phenotype is present in almost one-fourth of epithelial ovarian carcinoma and holds important prognostic information. The implications of our findings in relation to poly(adenosine-diphosphate-ribose) polymerase inhibitor treatment call for further investigation.