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Cancer Genet. 2015 Jan-Feb;208(1-2):35-40. doi: 10.1016/j.cancergen.2014.12.004. Epub 2014 Dec 31.

Systematic search for rare variants in Finnish early-onset colorectal cancer patients.

Author information

1
Department of Medical Genetics, Genome-Scale Biology Program, University of Helsinki, Biomedicum, Helsinki, Finland.
2
Genome-Scale Biology Program, Institute of Biomedicine, University of Helsinki, Biomedicum, Helsinki, Finland; Science for Life Center, Department of Biosciences and Nutrition, Karolinska Institute, Huddinge, Sweden.
3
Department of Medical Genetics, Genome-Scale Biology Program, University of Helsinki, Biomedicum, Helsinki, Finland; Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland.
4
Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland.
5
Department of Surgery, Jyväskylä Central Hospital, University of Eastern Finland, Jyväskylä, Finland.
6
Department of Medical Genetics, Genome-Scale Biology Program, University of Helsinki, Biomedicum, Helsinki, Finland. Electronic address: lauri.aaltonen@helsinki.fi.

Abstract

The heritability of colorectal cancer (CRC) is incompletely understood, and the contribution of undiscovered rare variants may be important. In search of rare disease-causing variants, we exome sequenced 22 CRC patients who were diagnosed before the age of 40 years. Exome sequencing data from 95 familial CRC patients were available as a validation set. Cases with known CRC syndromes were excluded. All patients were from Finland, a country known for its genetically homogenous population. We searched for rare nonsynonymous variants with allele frequencies below 0.1% in 3,374 Finnish and 58,112 non-Finnish controls. In addition, homozygous and compound heterozygous variants were studied. No genes with rare loss-of-function variants were present in more than one early-onset CRC patient. Three genes (ADAMTS4, CYTL1, and SYNE1) harbored rare loss-of-function variants in both early-onset and familial CRC cases. Five genes with homozygous variants in early-onset CRC cases were found (MCTP2, ARHGAP12, ATM, DONSON, and ROS1), including one gene (MCTP2) with a homozygous splice site variant. All discovered homozygous variants were exclusive to one early-onset CRC case. Independent replication is required to associate the discovered variants with CRC. These findings, together with a lack of family history in 19 of 22 (86%) early-onset patients, suggest genetic heterogeneity in unexplained early-onset CRC patients, thus emphasizing the requirement for large sample sizes and careful study designs to elucidate the role of rare variants in CRC susceptibility.

KEYWORDS:

Genetic predisposition to disease; age of onset; colorectal neoplasms; exome sequencing

PMID:
25749350
DOI:
10.1016/j.cancergen.2014.12.004
[Indexed for MEDLINE]

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