The genetic heterogeneity of colorectal cancer predisposition - guidelines for gene discovery.
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.
Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
M M
MM
Hahn
Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
R M
RM
de Voer
Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
N
N
Hoogerbrugge
Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
M J L
MJ
Ligtenberg
Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands. roland.kuiper@radboudumc.nl.
R P
RP
Kuiper
Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
A Geurts
AG
van Kessel
D000818:Animals; D015179:Colorectal Neoplasms / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans
Candidate gene identification; Colorectal cancer; Genetic predisposition; Next generation sequencing