Whole genome sequencing approach to assess homologous recombination deficiency in a pan-cancer cohort

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. 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. 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. 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. Homologous recombination deficiency is a condition in which a cancer cell cannot repair certain types of DNA damage. It causes genetic instability and is often due to changes in parts of the DNA called genes, such as BRCA1 and BRCA2. Cancers with this deficiency can be more readily killed by certain drugs that prevent DNA repair. Some of these drugs are approved for the treatment of several types of cancer, including ovarian, breast, pancreatic, and prostate cancers. To better identify tumors with this deficiency, we characterize the whole genome of cancer samples. We find that a comprehensive analysis of the entire genome improves the detection of homologous recombination deficiency. This type of analysis may provide a more accurate way to guide treatment decisions for people with cancer. Assaad, Hadi and Levine et al. develop a whole-genome sequencing classifier to improve the detection of homologous recombination deficiency (HRD) across a pan cancer cohort. The classifier detects HRD beyond BRCA1/2 mutations, reveals HRD-related genomic events, and correlates with treatment response in a subset of patients.