Inherited DNA-Repair Defects in Colorectal Cancer.

Am J Hum Genet

Colorectal cancer (CRC) heritability has been estimated to be around 30%. However, mutations in the known CRC-susceptibility genes explain CRC risk in fewer than 10% of affected individuals. 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 and 27,728 ancestry-matched cancer-free adults. Significant findings were then examined in independent cohorts of 1,661 unselected CRC individuals and 1,456 individuals with early-onset CRC. Of the 680 individuals in the discovery set, 31 (4.56%) individuals harbored germline pathogenic mutations in known CRC-susceptibility genes, and 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 and p = 0.035 for ATM and OR = 4.91 and p = 0.024 for PALB2) and validation (OR = 2.97 and adjusted p = 0.0013 for ATM and OR = 3.42 and adjusted p = 0.034 for PALB2) sets. Biallelic loss of ATM was evident in all individuals with matched tumor profiling. CRC individuals also had higher rates of actionable mutations in the HR pathway, which 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 poly-ADP ribose polymerase inhibitor (PARPi).

Year of Publication
Am J Hum Genet
Date Published
2018 03 01
PubMed ID
PubMed Central ID
Grant list
KL2 TR001100 / TR / NCATS NIH HHS / United States
R35 CA197735 / CA / NCI NIH HHS / United States
R01 CA118553 / CA / NCI NIH HHS / United States
P01 CA087969 / CA / NCI NIH HHS / United States
P01 CA055075 / CA / NCI NIH HHS / United States
K08 CA188615 / CA / NCI NIH HHS / United States
UM1 CA186107 / CA / NCI NIH HHS / United States
R01 CA169141 / CA / NCI NIH HHS / United States
UM1 CA167552 / CA / NCI NIH HHS / United States
UL1 TR001102 / TR / NCATS NIH HHS / United States
R37 CA222574 / CA / NCI NIH HHS / United States
U01 HG006492 / HG / NHGRI NIH HHS / United States