Germline and somatic mutations in homologous recombination genes among Chinese ovarian cancer patients detected using next-generation sequencing

Abstract

Objective: To define genetic profiling of homologous recombination (HR) deficiency in Chinese ovarian cancer patients.

Methods: we have applied next-generation sequencing to detect deleterious mutations through all exons in 31 core HR genes. Paired whole blood and frozen tumor samples from 50 Chinese women diagnosed with epithelial ovarian carcinomas were tested to identify both germline and somatic variants.

Results: Deleterious germline HR-mutations were identified in 36% of the ovarian cancer patients. Another 5 patients had only somatic mutations. BRCA2 was most frequently mutated. Three out of the 5 somatic mutations were in RAD genes and a wider distribution of other HR genes was involved in non-serous carcinomas. BRCA1/2-mutation carriers had favorable platinum sensitivity (relative risk, 1.57, p<0.05), resulting in a 100% remission probability and survival rate. In contrast, mutations in other HR genes predicted poor prognosis. However, multivariate analysis demonstrated that platinum sensitivity and optimal cytoreduction were the independent impact factors influencing survival (hazards ratio, 0.053) and relapse (hazards ratio, 0.247), respectively.

Conclusion: our results suggest that a more comprehensive profiling of HR defect than merely BRCA1/2 could help elucidate tumor heterogeneity and lead to better stratification of ovarian cancer patients for individualized clinical management.

Keywords: BRCA 1; BRCA 2; Epithelial Ovarian Cancer; Homologous Recombination; Next-generation Sequencing.

Fig. 1

(A) Overall pathogenic mutations in HR genes. (B) Gene distribution of germline HR mutations. (C) Gene distribution of somatic HR mutations. Values are presented as number (%). HR, homologous recombination.

Fig. 2

The association between HR mutations and (A) platinum sensitivity; (B) remission rate. HR, homologous recombination.

Fig. 3

Overall survival impacted by (A) HR mutations and (B) platinum sensitivity. HR, homologous recombination.

Fig. 4

PFS impacted by (A) HR mutations and (B) residual tumor. HR, homologous recombination; PFS, progression-free survival.