BACKGROUND: Homologous recombination deficiency (HRD) impacts cancer treatment strategies, particularly effective utilization of PARP inhibitors. However, the variability of different HRD assays has hampered the selection of oncology patients who may benefit from these therapies. Our study aims to use the whole genome landscape to better define HRD in a pan-cancer cohort.

METHODS: We employed a whole genome sequencing HRD classifier that includes genome-wide signatures associated with HRD to analyze 580 tumor/normal paired samples. The HRD phenotype was correlated with genomic variants in BRCA1/2 and other homologous recombination repair genes.

RESULTS: In this paper we show that the HRD phenotype is identified in various cancers including breast (21%), pancreaticobiliary (20%), gynecological (17%), prostate (9%), upper gastrointestinal (GI) (2%), and other cancers (1%). HRD cases are not confined to BRCA1/2 mutations; 24% of HRD cases are BRCA1/2 wild-type. A diverse range of gene alterations involved in HRD are elucidated, including biallelic mutations in FANCF, XRCC2, and FANCC, and deleterious structural variants. In a subset of cases, the whole genome sequencing-based classifier offers more insights and a better correlation to treatment response when compared to other assays.

CONCLUSIONS: Although HRD is a biomarker used to determine which cancer patients would benefit from PARP inhibitors, a lack of harmonization of tests to determine HRD status makes it challenging to interpret their results. Our study highlights the use of comprehensive whole genome sequencing analysis to better predict HRD and elucidates genomic mechanisms associated with this phenotype.