title: Eleven candidate susceptibility genes for common familial colorectal cancer.
abstract: Hereditary factors are presumed to play a role in one third of colorectal cancer (CRC) cases. However, in the majority of familial CRC cases the genetic basis of predisposition remains unexplained. This is particularly true for families with few affected individuals. To identify susceptibility genes for this common phenotype, we examined familial cases derived from a consecutive series of 1514 Finnish CRC patients. Ninety-six familial CRC patients with no previous diagnosis of a hereditary CRC syndrome were included in the analysis. Eighty-six patients had one affected first-degree relative, and ten patients had two or more. Exome sequencing was utilized to search for genes harboring putative loss-of-function variants, because such alterations are likely candidates for disease-causing mutations. Eleven genes with rare truncating variants in two or three familial CRC cases were identified: UACA, SFXN4, TWSG1, PSPH, NUDT7, ZNF490, PRSS37, CCDC18, PRADC1, MRPL3, and AKR1C4. Loss of heterozygosity was examined in all respective cancer samples, and was detected in seven occasions involving four of the candidate genes. In all seven occasions the wild-type allele was lost (P = 0.0078) providing additional evidence that these eleven genes are likely to include true culprits. The study provides a set of candidate predisposition genes which may explain a subset of common familial CRC. Additional genetic validation in other populations is required to provide firm evidence for causality, as well as to characterize the natural history of the respective phenotypes.
authors.affiliation: Department of Medical Genetics, Genome-Scale Biology Research Program, University of Helsinki, Helsinki, Finland.
authors.forename: Alexandra E
authors.initials: AE
authors.lastname: Gylfe
authors.forename: Riku
authors.initials: R
authors.lastname: Katainen
authors.forename: Johanna
authors.initials: J
authors.lastname: Kondelin
authors.forename: Tomas
authors.initials: T
authors.lastname: Tanskanen
authors.forename: Tatiana
authors.initials: T
authors.lastname: Cajuso
authors.forename: Ulrika
authors.initials: U
authors.lastname: Hänninen
authors.forename: Jussi
authors.initials: J
authors.lastname: Taipale
authors.forename: Minna
authors.initials: M
authors.lastname: Taipale
authors.forename: Laura
authors.initials: L
authors.lastname: Renkonen-Sinisalo
authors.forename: Heikki
authors.initials: H
authors.lastname: Järvinen
authors.forename: Jukka-Pekka
authors.initials: JP
authors.lastname: Mecklin
authors.forename: Outi
authors.initials: O
authors.lastname: Kilpivaara
authors.forename: Esa
authors.initials: E
authors.lastname: Pitkänen
authors.forename: Pia
authors.initials: P
authors.lastname: Vahteristo
authors.forename: Sari
authors.initials: S
authors.lastname: Tuupanen
authors.forename: Auli
authors.initials: A
authors.lastname: Karhu
authors.forename: Lauri A
authors.initials: LA
authors.lastname: Aaltonen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D015179:Colorectal Neoplasms / Q000235:genetics*; D059472:Exome; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D019656:Loss of Heterozygosity / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010375:Pedigree