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

BMC Cancer

Mingchao Xie¹  J. Carl Barrett¹  Zhongwu Lai¹  Darren Hodgson¹  Jonathan R. Dry²  Elizabeth A. Harrington³  Matthew Brosnan⁴  Ethan S. Sokol⁴ 

[1] AstraZeneca, 02451, Waltham, MA, USA;AstraZeneca, 02451, Waltham, MA, USA;Present Address: Tempus Labs Inc., Boston, MA, USA;AstraZeneca, Cambridge, UK;Foundation Medicine Inc., Cambridge, MA, USA;

关键词: Homologous recombination deficiency;    Homologous recombination repair;    Genomic loss of heterozygosity;    Loss of function;    cancer;    Breast;    Ovarian;    Germline;    Somatic;    PARP inhibitors;    Immune checkpoint inhibitors;   

DOI  :  10.1186/s12885-021-09082-y

来源: Springer

【 摘 要 】

BackgroundDNA 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.MethodsGermline 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 candidate 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).ResultsApproximately 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.ConclusionsOur results will facilitate future research into the efficacy of precision oncology treatments, including PARP and immune checkpoint inhibitors.

【 授权许可】

CC BY