Abstract 366: Identification of a clinically significant pan-cancer biomarker for homologous recombination deficiency

Abstract

Abstract [Background] Genomic alterations in BRCA1/2 and the ‘genomic scar' signatures are associated with homologous recombination DNA repair deficiency (HRD) and serve as therapeutic biomarkers for sensitivity to platinum and PARP inhibitors in breast and ovarian cancers. However, the clinical significance of these biomarkers in other homologous recombination repair (HRR) pathway genes or in other cancer types is not fully understood. [Method] From the TCGA and the AACR GENIE project databases, we obtained clinical and genomic data of patients with multiple solid cancers, evaluated both locus-specific LOH in HRR pathway gene mutations and two genomic scar signature scores (HRD score and mutational signature 3), identified potential HRD cases, and examined the efficacy of DNA-damaging drugs in these HRD cases. [Results] Germline and somatic gene mutations in the HRR pathway genes with locus-specific LOH were significantly enriched in cases having high genomic scar scores, whereas those without the LOH were not enriched. Somatic mutations without the LOH were remarkably enriched in hypermutated cases and considered to be passenger mutations. The mutation rate and frequency with LOH in the HRR pathway genes varied widely by cancer type. When stratifying patients by gender and presence of TP53 mutation, the correlation between the two genomic scar scores and the resulting optimal cutoff values for biallelic HRR pathway gene alterations differed greatly. The potential HRD cases that were selected by the two genomic scar cutoffs and biallelic HRR pathway gene alterations showed significantly high gene expression-based HRD scores. In Cox proportional hazard multivariate analyses with covariates of age, stage, gender, HRD, and TP53 mutation, HRD was a good prognostic factor in the group with DNA-damaging agents, but a poor one in the group without the agents. [Conclusion] Increased attention on locus-specific LOH in HRR pathway gene alterations and the differences in genomic scar signatures stratified by gender and TP53 mutation is newly warranted in order to properly assess HRD in a pan-cancer manner. The results in the present study proved the clinical significance of HRD across cancer types and may contribute to the development of personalized medicine based on HRD. Citation Format: Shiro Takamatsu, JB Brown, Koji Yamanoi, Ken Yamaguchi, Junzo Hamanishi, Takashi Kobayashi, Masaki Mandai, Noriomi Matsumura. Identification of a clinically significant pan-cancer biomarker for homologous recombination deficiency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 366.