Utility of Homologous Recombination Deficiency Biomarkers Across Cancer Types. (25th May 2022)

• Record Type: Journal Article
• Authors: Takamatsu, Shiro; Brown, J.B.; Yamaguchi, Ken; Hamanishi, Junzo; Yamanoi, Koji; Takaya, Hisamitsu; Kaneyasu, Tomoko; Mori, Seiichi; Mandai, Masaki; Matsumura, Noriomi
• Is Part Of: JCO precision oncology. Volume 6(2022)
• Publication Date: 2022-05-25
• Subjects: Precision Medicine; Neoplasms; Pharmacogenetics; Molecular Targeted Therapy; Personalized medicine; Oncology; Pharmacogenomics; Periodical; Periodicals; 616.994
• DOI: 10.1200/PO.22.00085
• Languages: English
• ISSNs: 2473-4284

Abstract

Abstract : 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 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 TP53 mutations, sex, and clinical information including chemotherapeutic regimens. 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 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. 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. Abstract :