Systematic search for rare variants in Finnish early-onset colorectal cancer patients.
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.
Department of Medical Genetics, Genome-Scale Biology Program, University of Helsinki, Biomedicum, Helsinki, Finland.
Tomas
T
Tanskanen
Department of Medical Genetics, Genome-Scale Biology Program, University of Helsinki, Biomedicum, Helsinki, Finland.
Alexandra E
AE
Gylfe
Department of Medical Genetics, Genome-Scale Biology Program, University of Helsinki, Biomedicum, Helsinki, Finland.
Riku
R
Katainen
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.
Minna
M
Taipale
Department of Medical Genetics, Genome-Scale Biology Program, University of Helsinki, Biomedicum, Helsinki, Finland; Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland.
Laura
L
Renkonen-Sinisalo
Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland.
Heikki
H
Järvinen
Department of Surgery, Jyväskylä Central Hospital, University of Eastern Finland, Jyväskylä, Finland.
Jukka-Pekka
JP
Mecklin
Department of Surgery, Jyväskylä Central Hospital, University of Eastern Finland, Jyväskylä, Finland.
Jan
J
Böhm
Department of Medical Genetics, Genome-Scale Biology Program, University of Helsinki, Biomedicum, Helsinki, Finland.
Outi
O
Kilpivaara
Department of Medical Genetics, Genome-Scale Biology Program, University of Helsinki, Biomedicum, Helsinki, Finland.
Esa
E
Pitkänen
Department of Medical Genetics, Genome-Scale Biology Program, University of Helsinki, Biomedicum, Helsinki, Finland.
Kimmo
K
Palin
Department of Medical Genetics, Genome-Scale Biology Program, University of Helsinki, Biomedicum, Helsinki, Finland.
Pia
P
Vahteristo
Department of Medical Genetics, Genome-Scale Biology Program, University of Helsinki, Biomedicum, Helsinki, Finland.
Sari
S
Tuupanen
Department of Medical Genetics, Genome-Scale Biology Program, University of Helsinki, Biomedicum, Helsinki, Finland. Electronic address: lauri.aaltonen@helsinki.fi.
Lauri A
LA
Aaltonen
D000328:Adult; D017668:Age of Onset; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005192:Family Health; D005387:Finland / Q000453:epidemiology; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D009154:Mutation; D017422:Sequence Analysis, DNA / Q000379:methods; D055815:Young Adult
Genetic predisposition to disease; age of onset; colorectal neoplasms; exome sequencing