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

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 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).

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

Fig. 1

Kaplan-Meier estimates of a progression-free survival and b overall survival by BRCA status in the TCGA ovarian cancer cohort

Fig. 2

HRD-LOH scores by BRCA mutation in Foundation Medicine ovarian and breast cancer cohorts a germline versus somatic versus wild-type, b heterozygous (mono-allelic loss without LOH) versus homozygous (bi-allelic loss of function with LOH) versus compound heterozygous (bi-allelic loss of function without LOH) (observed in breast cancer cohort only) versus wild-type. Comphet, compound heterozygous; Het, heterozygous; Hom, homozygous

Fig. 3

a HRR gene mutation prevalence in the Foundation Medicine dataset across six tumour types and b bi-allelic loss of function rates of HRR gene mutations in the Foundation Medicine dataset across six tumour types. To prevent multiple counting of a patient so that they are not over-estimated in samples that have a mutation in multiple genes only, one was chosen for representation based upon biological significance, for example, when BRCA is present, it will be called BRCA, even though an ATM is also detected

Fig. 4

Likely BRCA1 and BRCA2 reversion mutations found in the cohort. For each gene, the boxes in the middle indicate protein and domain structures. Numbers below indicate amino acid numbering for the protein. Above the protein structure are the sensitizing mutations and below are candidate reversion mutations. Triangle indicates that the mutation is an indel resulting in frameshift, circle indicates SNV, and rectangle indicates in-frame deletion. Each colour represents a unique sample. The bar below indicates the location of exon 11, the largest exon for BRCA1 and BRCA2