Utility of Homologous Recombination Dificiency Biomarkers Across Cancer Types

PURPOSE Homologous recombination DNA repair deficiency (HRD) is associated with sensitivity to platinum and poly (ADP-ribose) polymerase inhibitors in certain cancer types, including breast, ovarian, pancreatic, and prostate. In these cancers, BRCA1/2 alterations and genomic scar signatures are useful indicators for assessing HRD. However, alterations in other homologous recombination repair (HRR)-related genes and their clinical significance in other cancer types have not been adequately and systematically investigated. METHODS We obtained data sets of all solid tumors in The Cancer Genome Atlas and Cancer Cell Line Encyclopedia, and comprehensively analyzed HRR pathway gene alterations, their loss-of-heterozygosity status, and per-sample genomic scar scores, that is, the HRD score and mutational signature 3 ratio, DNA methylation profiles, gene expression profiles, somatic TP53 mutations, sex, and clinical or in vitro response to chemical exposure. RESULTS Biallelic alterations in HRR genes other than BRCA1/2 were also associated with elevated genomic scar scores. The association between HRR-related gene alterations and genomic scar scores differed significantly by sex and the presence of somatic TP53 mutations. HRD tumors determined by a combination of indices also showed HRD features in gene expression analysis and exhibited significantly higher sensitivity to DNA-damaging agents than non-HRD cases in both clinical samples and cell lines. CONCLUSION This study provides evidence for the usefulness of HRD analysis in all cancer types, improves chemotherapy decision making and its efficacy in clinical settings, and represents a substantial advancement in precision oncology. (C) 2021 by American Society of Clinical Oncology

Automated summary

Biallelic alterations in HRR genes other than BRCA1/2 are associated with elevated genomic scar scores, and this association varies significantly by sex and the presence of somatic TP53 mutations. Tumors with HRD features in gene expression analysis due to a combination of indices show significantly higher sensitivity to DNA-damaging agents, both in clinical samples and cell lines. This study supports the utility of HRD analysis in all cancer types and enhances chemotherapy decision making and efficacy in clinical settings, marking a significant advancement in precision oncology.