Analysis of multiple genomic-factors affecting the homologous recombination deficiency (HRD) in Chinese ovarian cancer.

Abstract

88 Background: A large proportion of (but not all) ovarian cancers with high homologous recombination deficiency (HRD) scores are sensitive to Poly (ADP-ribose) polymerase inhibitors (PARPi). This study aimed to identify multiple genomic factors that could increase HRD scores, helped us understand the potential causes for high HRD scores, and thus make therapy decisions. Methods: A total of 370 Chinese ovarian cancer patients were retrospectively obtained from ovarian patients for HRD status and HRR gene alterations from October, 2021 to January, 2023. Patient information including age, gender, pathology type was collected. All specimens were detected by OncoDrug-SeqTM603-gene panel assay through next-generation sequencing (NGS) using Illumina NovaSeq 6000. The interaction between genomic alternation and its overall instability was analyzed to look for multi-factors affecting HRD. Results: Of 370 patients, there were 296 (80.08%) patients with over 50 years, 225(76.01%) with positive HRD, and 48 (16.2%) patients with BRCA1/2 mutations. The top ten commonly mutated genes were TP53 (54.05%), BRCA1 (8.1%), BRCA2 (8.11%), KRAS (8.11%), PDE1C (8.11%), ARID1A (5.41%), BRAF (5.41%), CDK12 (5.41%), CHEK2 (5.41%), and MSH2 (5.41%).Among of them, there were 24.32% of patients with both HRR and TP53 mutations, and 13.51% of patients had both BRCA1/2 and TP53 mutations. Furthermore, in the trio negative of BRCA1/2, TP53, and HRD groups, KRAS mutations were found in 30 (50%)patients. The mutations in TP53, BRAC1/2, and other HRR genes had positive correlations with HRD scores. Importantly, BRCA1/2-negative patients with mutant TP53 other than wild type had a significantly high HRD score (p<0.05). Although it did not hold true for other HRR gene (excluding BRCA) negative patients (p>0.05), an increasing trend in HRD score was still observed. Conclusions: Alterations of multiple genes including TP53, BRAC1/2, and other HRR genes are correlated with higher HRD scores. In this Chinese cohort, a large number of BRCA1/2-negative patients with TP53 mutations tend to have higher HRD scores. Whether this specific subgroup of Chinese ovarian cancers can benefit from PARPi is in question, although they present high HRD scores.