Genetic Diagnosis by Exome Sequencing Feasible for Familial Colorectal Cancer


Key Points

  • Mismatch repair gene mutations were found in 10.9% of cases and mutations in other established colorectal cancer genes in 3.3%.
  • POLE/POLD1 exonuclease domain mutations were found in three patients.

In a study reported in the Journal of Clinical Oncology, Chubb et al found that genetic diagnosis of high-penetrance susceptibility to colorectal cancer can be achieved in a sizeable proportion of familial colorectal cancer cases via exome sequencing for germline mutations.

Study Details

The study involved sequencing of mismatch repair genes APC, MUTYH, and SMAD4/BMPR1A in 626 early-onset familial colorectal cancer cases from a population-based United Kingdom national registry and evaluation of the impact of exonuclease domain mutations in the POLE and POLD1 genes that have been associated with colorectal cancer risk.

Frequency of Mutations

Pathogenic or likely pathogenic mutations in mismatch repair genes were identified in 68 patients (10.9%), including 59 unique mutations. Mutations in other established colorectal cancer genes accounted for 3.3% of cases. POLE/POLD1 exonuclease domain mutations were found in three patients with family histories consistent with dominant transmission of colorectal cancer. Overall, mutations in the known genes accounted for 89 of the 626 cases (14.2%, 95% confidence interval = 11.5%–17.2%). No high-penetrance mutation in known colorectal cancer genes was found in 76% of patients; these patients tended to be diagnosed with colorectal cancer at a later age than known gene carriers.

The investigators concluded: “A genetic diagnosis is feasible in a high proportion of familial [colorectal cancer]. Mainstreaming such analysis in clinical practice should enable the medical management of patients and their families to be optimized. Findings suggest [colorectal cancer] screening of POLE and POLD1 mutation carriers should be comparable to that afforded to those at risk of [hereditary nonpolyposis colorectal cancer]. Although the risk of [colorectal cancer] associated with unexplained familial [colorectal cancer] is in general moderate, in some families the risk is substantive and likely to be the consequence of unidentified genes, as exemplified by POLE and POLD1. Our findings have utility in the design of genetic analyses to identify such novel [colorectal cancer] risk genes.”

Richard S. Houlston, MD, PhD, of The Institute of Cancer Research, London, is the corresponding author for the Journal of Clinical Oncology article.

The study was supported by grants from Cancer Research UK and the European Union and by Systems Biology of Colorectal Cancer. The study authors reported no potential conflicts of interest.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.