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Cellular Oncology
Published in: Cellular Oncology 6/2016

Open Access 01-12-2016 | Review

The genetic heterogeneity of colorectal cancer predisposition - guidelines for gene discovery

Authors: M. M. Hahn, R. M. de Voer, N. Hoogerbrugge, M. J. L. Ligtenberg, R. P. Kuiper, A. Geurts van Kessel

Published in: Cellular Oncology | Issue 6/2016

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Abstract

Background

Colorectal cancer (CRC) is a cumulative term applied to a clinically and genetically heterogeneous group of neoplasms that occur in the bowel. Based on twin studies, up to 45 % of the CRC cases may involve a heritable component. Yet, only in 5–10 % of these cases high-penetrant germline mutations are found (e.g. mutations in APC and DNA mismatch repair genes) that result in a familial aggregation and/or an early onset of the disease. Genome-wide association studies have revealed that another ~5 % of the CRC cases may be explained by a cumulative effect of low-penetrant risk factors. Recent attempts to identify novel genetic factors using whole exome and whole genome sequencing has proven to be difficult since the remaining, yet to be discovered, high penetrant CRC predisposing genes appear to be rare. In addition, most of the moderately penetrant candidate genes identified so far have not been confirmed in independent cohorts. Based on literature examples, we here discuss how careful patient and cohort selection, candidate gene and variant selection, and corroborative evidence may be employed to facilitate the discovery of novel CRC predisposing genes.

Conclusions

The picture emerges that the genetic predisposition to CRC is heterogeneous, involving complex interplays between common and rare (inter)genic variants with different penetrances. It is anticipated, however, that the use of large clinically well-defined patient and control datasets, together with improved functional and technical possibilities, will yield enough power to unravel this complex interplay and to generate accurate individualized estimates for the risk to develop CRC.
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Metadata
Title
The genetic heterogeneity of colorectal cancer predisposition - guidelines for gene discovery
Authors
M. M. Hahn
R. M. de Voer
N. Hoogerbrugge
M. J. L. Ligtenberg
R. P. Kuiper
A. Geurts van Kessel
Publication date
01-12-2016
Publisher
Springer Netherlands
Published in
Cellular Oncology / Issue 6/2016
Print ISSN: 2211-3428
Electronic ISSN: 2211-3436
DOI
https://doi.org/10.1007/s13402-016-0284-6

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