Whole Genome Analysis Identifies Homologous Recombination Deficiency in Cancers with BRCA1/2 Wild-Type and BRCA1/2 Structural Variants

Purpose 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 novel whole genome sequencing (WGS) 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. The results were compared to other assays and, in a subset, with commercial HRD tests, correlating them with treatment responses. Results HRD phenotype was identified in various cancers including breast (21%), pancreaticobiliary (20%), gynecological (17%), prostate (9%), upper gastrointestinal (GI) (2%), and other cancers (1%). HRD cases were not confined to BRCA1/2 mutations; 24% of HRD cases were BRCA1/2 wild-type. A diverse range of gene alterations involved in HRD were elucidated, including biallelic mutations in FANCF, XRCC2 , and FANCC , and deleterious structural variants. In a subset of 15 cases, the WGS-based classifier offered more insights and a better correlation to treatment response when compared to other assays. Conclusion HRD is a biomarker used to determine which cancer patients would benefit from PARP inhibitors. However, a lack of harmonization of tests to determine HRD status makes it challenging to interpret their results. Our study highlights the use of comprehensive WGS analysis to better predict HRD and elucidates new genomic mechanisms associated with this phenotype.