Genomic characteristics of homologous recombination deficiency in ovarian cancer.

Abstract

e17575 Background: HRD score correlates with sensitivity to PARP inhibitors (PARPi). BRCA1/2 mutations are well-known causes of HRD, but other genetic abnormalities of the homologous recombination repair (HRR) pathway could also cause HRD, although no consensus has been reached. We aimed to analyze HRD score and its relationship with genetic characteristics in ovarian cancer, particularly the HRR-related genes mutations. Methods: Matched tumor/normal DNA from Chinese patients with ovarian cancer (N = 181) were analyzed by Acornmed panel with 98 cancer-related genes. The HRD score is the sum of these scar signature scores, namely, the loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST). HRR genes mutations and clinical outcomes from the TCGA cohort were included. Results: In our cohort, 44.2% patients exhibited HRR genes mutations, yielded an increment of 12.2% than BRCA mutants. The most frequently mutated HRR genes were BRCA1 (25.0%), BRCA2 (8.0%), CDK12 (4.0%), and RAD51D (4.0%). Chinese cohort contained frequently somatic mutation of HRR genes compared with TCGA cohort (22.7% vs 13.6%, p < 0.010). Germline mutations of HRR genes and non-HRR genes occurred in 21.5% and 2.8% of cases detected, respectively. HRD score in HRR-related genes wildtype was lower than tumors with BRCA1/2 mutation and HRR genes mutation without BRCA1/2 carriers (median HRD score 33, 72 and 64; p < 0.001). Interestingly, no difference was observed in HRD scores between patients with somatic BRCA-mut and germline- BRCA mutants. The median HRD score in our cohort was 65 (range from 0 to 96), and 58.6% patients were HRD-high with the cutoff of HRD score ≥ 42. The HRD-high patients covered 89.7% of the BRCA-positive cases, besides, approximately 77.3% of the BRCA-wt/HRR-mut patients also harbored high HRD scores. Six mutated genes were significantly different between HRD-high and HRD-low group. ARID1A was frequently mutated in patients with HRD-low, while significantly more mutations in TP53 were identified among HRD-high patients. Interestingly, in the TCGA cohort, patients with TP53-mut (p = 0.024) and individuals without ARID1A mutation (p < 0.001) had remarkably high survival rates, as compared with the rest of these patients.Furthermore, tumors with HRD-high had a bit higher TMB (median TMB 4.56 vs 2.91, p = 0.018). Conclusions: Our data suggest that HRR genes mutations strongly affect HRD score, which may increase the number of patients who may benefit from PARPi treatment, and combining gene mutations and HRD score could optimize prognosis stratification in ovarian cancer. In addition, the molecular features of HRD provide new opportunities to predict the tumor response to multiple treatments.