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Landscape of homologous recombination deficiencies in solid tumours: Analyses of two independent genomic datasets

DNA repair deficiencies are characteristic of cancer and homologous recombination deficiency (HRD) is the most common. HRD sensitizes tumour cells to PARP inhibitors so it is important to understand the landscape of HRD across diferent solid tumour types. Methods: Germline and somatic BRCA mu | Lai et al. BMC Cancer 2022 22 13 https doi.org 10.1186 s12885-021-09082-y RESEARCH Open Access Landscape of homologous recombination deficiencies in solid tumours analyses of two independent genomic datasets Zhongwu Lai1 Matthew Brosnan2 Ethan S. Sokol2 Mingchao Xie1 Jonathan R. Dry1 3 Elizabeth A. Harrington4 J. Carl Barrett1 and Darren Hodgson1 This study was presented in part at the 2019 Annual Meeting of the American Association for Cancer Research AACR abstract number 1747 . Abstract Background DNA repair deficiencies are characteristic of cancer and homologous recombination deficiency HRD is the most common. HRD sensitizes tumour cells to PARP inhibitors so it is important to understand the landscape of HRD across different solid tumour types. Methods Germline and somatic BRCA mutations in breast and ovarian cancers were evaluated using sequencing data from The Cancer Genome Atlas TCGA database. Secondly a larger independent genomic dataset was analysed to validate the TCGA results and determine the frequency of germline and somatic mutations across 15 different can- didate homologous recombination repair HRR genes and their relationship with the genetic events of bi-allelic loss loss of heterozygosity LOH and tumour mutation burden TMB . Results Approximately one-third of breast and ovarian cancer BRCA mutations were somatic. These showed a similar degree of bi-allelic loss and clinical outcomes to germline mutations identifying potentially 50 more patients that may benefit from precision treatments. HRR mutations were present in sizable proportions in all tumour types analysed and were associated with high TMB and LOH scores. We also identified numerous BRCA reversion mutations across all tumour types. Conclusions Our results will facilitate future research into the efficacy of precision oncology treatments including PARP and immune checkpoint inhibitors. Keywords Homologous recombination deficiency Homologous recombination repair Genomic loss of .