Utility of Homologous Recombination Deficiency Biomarkers Across Cancer Types.

Abstract

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, <i>BRCA1</i>/<i>2</i> 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. We obtained data sets of all solid tumors in The Cancer Genome Atlas and comprehensively analyzed HRR pathway gene alterations, their loss-of-heterozygosity status, per-sample genomic scar scores, ie, the HRD score and mutational signature 3 ratio, DNA methylation profiles, gene expression profiles, somatic <i>TP53</i> mutations, sex, and clinical information including chemotherapeutic regimens. Biallelic alterations in HRR genes other than <i>BRCA1</i>/<i>2</i> 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 <i>TP53</i> mutations. HRD cases determined by a combination of these indices also showed HRD features in gene expression analysis and were associated with better survival when treated with DNA-damaging agents. 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.