Inherited DNA-Repair Defects in Colorectal Cancer

Abstract

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).

Keywords: ATM mutations; CRC; DNA-repair deficiency; PALB2 mutations; actionable mutations; cancer heritability; colorectal cancer genetics; germline genetics; homologous recombination.

Figure 1

Germline Pathogenic Mutations in the Known CRC-Predisposition Genes and Additional DRGs (A) Proportions of individuals with germline pathogenic mutations in the CRC-risk genes in 680 CRC individuals in the discovery set and 1,661 CRC individuals in the validation set. (B) Number and class of the detected germline pathogenic mutations in the DRGs in the discovery set (n = 680). DRGs where no mutations were detected (n = 19) are not shown here. (C) Enrichment of germline pathogenic DRG mutations in 680 CRC individuals in the discovery set. Fisher’s exact test was used to calculate the ORs and 95% CIs. A two-sided binomial test was used to calculate the p values. (D) A total of 18 germline pathogenic ATM mutations were seen in the discovery and validation sets in our study. This included seven (38.9%) nonsense mutations, six (33.3%) frameshift mutations, three (16.6%) splice-site mutations, one (5.6%) known pathogenic in-frame deletion, and one (5.6%) known pathogenic missense mutation.

Figure 2

Enrichment of DRG Mutations in Various Cohorts (A) Inherited pathogenic germline mutations in ATM were more commonly seen in individuals with CRC in the discovery (n = 680), validation (n = 1,661), and early-onset-CRC (1,456) sets than in cancer-free individuals. (B) Germline pathogenic mutations in PALB2 were significantly enriched in unselected CRC individuals from the discovery and validation sets. However, no significant enrichment was seen in the individuals with early-onset CRC. (C) A secondary analysis of the HR pathway showed significant enrichment of germline HR gene mutations, as an aggregate, in all CRC cohorts. (D) Individuals with CRC were also almost twice as likely to carry a clinically actionable mutation for which screening recommendations exist, which can greatly affect the clinical care offered to these individuals and their families.

Figure 3

Clinical and Molecular Characteristics of All Individuals with Germline Pathogenic Mutations in CRC-Risk Genes and DRGs in the CRC Discovery Set All individuals with germline pathogenic mutations in ATM had somatic LOH in their tumor samples. Two of these individuals had large deletions that affected the wild-type ATM allele, whereas three had truncating point mutations leading to the loss of the ATM wild-type allele as well. Abbreviations are as follows: AC-TC, ascending colon to transverse colon; SF-SC, splenic flexure to sigmoid colon; MSI, microsatellite instability; MSS, microsatellite stable; CIMP, CpG island methylator phenotype-specific promoter; and LOH, loss of heterozygosity.