Colorectal cancer (CRC) heritability has been estimated to be around 30%. However, mutations in the known CRC susceptibility genes explain CRC risk in under 10% of the cases. Germline mutations in DNA-repair genes (DRGs) have recently been reported in CRC but their contribution to CRC risk is largely unknown. We evaluated the gene-level germline mutation enrichment of 40 DRGs in 680 unselected CRC individuals compared to 27728 ancestry-matched cancer-free adults. Significant findings were then examined in independent cohorts of 1661 unselected CRC cases and 1456 early-onset CRC cases. Of 680 individuals in the discovery set, 31 (4.56%) individuals harbored germline pathogenic mutations in known CRC susceptibility genes while another 33 (4.85%) individuals had DRG mutations that have not been previously associated with CRC risk. Germline pathogenic mutations in ATM and PALB2 were enriched in both the discovery (OR= 2.81; P= 0.035 and OR= 4.91; P= 0.024, respectively) and validation sets (OR= 2.97; Adjusted P= 0.0013 and OR= 3.42; Adjusted P= 0.034, for ATM and PALB2 respectively). Biallelic loss of ATM was evident in all cases with matched tumor profiling. CRC cases also had higher rates of actionable mutations in the HR pathway that can substantially increase the risk of developing cancers other than CRC. Our analysis provides evidence for ATM and PALB2 as CRC risk genes, underscoring the importance of the homologous recombination pathway in CRC. In addition, we identified frequent complete homologous recombination deficiency in CRC tumors, representing a unique opportunity to explore targeted therapeutic interventions such as PARPi.

Inherited DNA Repair Defects in Colorectal Cancer