Rare disruptive mutations and their contribution to the heritable risk of colorectal cancer

Abstract

Colorectal cancer (CRC) displays a complex pattern of inheritance. It is postulated that much of the missing heritability of CRC is enshrined in high-impact rare alleles, which are mechanistically and clinically important. In this study, we assay the impact of rare germline mutations on CRC, analysing high-coverage exome sequencing data on 1,006 early-onset familial CRC cases and 1,609 healthy controls, with additional sequencing and array data on up to 5,552 cases and 6,792 controls. We identify highly penetrant rare mutations in 16% of familial CRC. Although the majority of these reside in known genes, we identify POT1, POLE2 and MRE11 as candidate CRC genes. We did not identify any coding low-frequency alleles (1–5%) with moderate effect. Our study clarifies the genetic architecture of CRC and probably discounts the existence of further major high-penetrance susceptibility genes, which individually account for >1% of the familial risk. Our results inform future study design and provide a resource for contextualizing the impact of new CRC genes.

Updates on the Molecular Genetics of Colorectal Cancer

“…A mutation in POLE2 leads to polymerase proofreading-associated polyposis [15]. MRE11 is a nuclease involved in double strand break repair and it is active in mismatch repair-deficient cancer [15]. The findings in this study support DNA replication and repair defects as a basis for inherited CRC.…”

“…CRC (< 55 years) who also had a first-degree relative with CRC [15]. 16% of these patients were noted to have rare germline mutations in known CRC genes compared to healthy controls.…”

“…However, POT1, POLE2, and MRE11 were newly identified in this study. POT1 works in maintaining telomere length, and three disruptive mutations were noted in the CRC group [15]. POLE2 is a component of the polymerase epsilon enzyme complex.…”

“…POLE2 is a component of the polymerase epsilon enzyme complex. A mutation in POLE2 leads to polymerase proofreading-associated polyposis [15]. MRE11 is a nuclease involved in double strand break repair and it is active in mismatch repair-deficient cancer [15].…”

Germ line mutations in shelterin complex genes are associated with familial chronic lymphocytic leukemia

“…These findings are consistent with the evidence of linkage of familial CLL to chromosomes 7q31.32-q33 and 16q12.2-q23.1 that we previously observed (supplemental Figure 5). 43 Germ line disruptive variants within shelterin genes have recently been implicated in predisposition to familial melanoma, 39,40 cardiac angiosarcoma, 44 glioma, 45 and colorectal cancer, 46 whereas somatic mutations of POT1 are detectable in 3.5% of all CLL and 9% of encoding immunoglobulin heavy chain variable-unmutated CLL, 37 and were also identified in 10% of patients with cutaneous T-cell lymphoma.…”