title: Somatic mutations and germline sequence variants in patients with familial colorectal cancer.
abstract: It is estimated that up to 35% of colorectal cancers (CRC) can be explained by hereditary factors. However, genes predisposing to highly penetrant CRC syndromes account for only a small fraction of all cases. Thus, most CRCs still remain molecularly unexplained. A recent systematic sequencing study on well-annotated human protein coding genes identified 280 somatically mutated candidate cancer genes (CAN genes) in breast and colorectal cancer. It is estimated that 8% of all reported cancer genes show both somatic and germline mutations. Therefore, the identified CAN genes serve as a distinct set of candidates for being involved in hereditary susceptibility. The aim of this study was to evaluate the role of colorectal CAN genes in familial CRC. Samples from 45 familial CRCs without known cancer predisposing mutations were screened for somatic and germline variants in 15 top-ranked CAN genes. Six of the genes were found to be somatically mutated in our tumor series. We identified 22 nonsynonymous somatic mutations of which the majority was of missense type. In germline, three novel nonsynonymous variants were identified in the following genes: CSMD3, EPHB6 and C10orf137, and none of the variants were present in 890 population-matched healthy controls. It is possible that the identified germline variants modulate predisposition to CRC. Functional validation and larger sample sets, however, will be required to clarify the role of the identified germline variants in CRC susceptibility.
authors.affiliation: Department of Medical Genetics, Genome-Scale Biology Research Program, Biomedicum Helsinki, University of Helsinki, Finland.
authors.forename: Alexandra E
authors.initials: AE
authors.lastname: Gylfe
authors.forename: Johanna
authors.initials: J
authors.lastname: Sirkiä
authors.forename: Manuel
authors.initials: M
authors.lastname: Ahlsten
authors.forename: Heikki
authors.initials: H
authors.lastname: Järvinen
authors.forename: Jukka-Pekka
authors.initials: JP
authors.lastname: Mecklin
authors.forename: Auli
authors.initials: A
authors.lastname: Karhu
authors.forename: Lauri A
authors.initials: LA
authors.lastname: Aaltonen
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D003106:Colon / Q000378:metabolism / Q000473:pathology; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics* / Q000473:pathology; D004273:DNA, Neoplasm / Q000235:genetics*; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D010375:Pedigree; D011379:Prognosis; D011446:Prospective Studies; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D036081:Receptors, Eph Family; D012007:Rectum / Q000378:metabolism / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; C477878:CSMD3 protein, human; D004273:DNA, Neoplasm; D008565:Membrane Proteins; C106797:EPHB6 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D036081:Receptors, Eph Family