title: Undefined familial colorectal cancer and the role of pleiotropism in cancer susceptibility genes.
abstract: Although family history is a major risk factor for colorectal cancer (CRC) a genetic diagnosis cannot be obtained in over 50 % of familial cases when screened for known CRC cancer susceptibility genes. The genetics of undefined-familial CRC is complex and recent studies have implied additional clinically actionable mutations for CRC in susceptibility genes for other cancers. To clarify the contribution of non-CRC susceptibility genes to undefined-familial CRC we conducted a mutational screen of 114 cancer susceptibility genes in 847 patients with early-onset undefined-familial CRC and 1609 controls by analysing high-coverage exome sequencing data. We implemented American College of Medical Genetics and Genomics standards and guidelines for assigning pathogenicity to variants. Globally across all 114 cancer susceptibility genes no statistically significant enrichment of likely pathogenic variants was shown (6.7 % cases 57/847, 5.3 % controls 85/1609; P = 0.15). Moreover there was no significant enrichment of mutations in genes such as TP53 or BRCA2 which have been proposed for clinical testing in CRC. In conclusion, while we identified genes that may be considered interesting candidates as determinants of CRC risk warranting further research, there is currently scant evidence to support a role for genes other than those responsible for established CRC syndromes in the clinical management of familial CRC.
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK. sara.dobbins@icr.ac.uk.
authors.forename: Sara E
authors.initials: SE
authors.lastname: Dobbins
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Broderick
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Chubb
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
authors.forename: Ben
authors.initials: B
authors.lastname: Kinnersley
authors.affiliation: Division of Pathology, The Institute of Cancer Research, London, UK.
authors.forename: Amy L
authors.initials: AL
authors.lastname: Sherborne
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.|Division of Pathology, The Institute of Cancer Research, London, UK.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000209:etiology / Q000235:genetics*; D058685:Genetic Pleiotropy; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics; D053484:RecQ Helicases / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; C476078:FLCN protein, human; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; C097151:Bloom syndrome protein; D053484:RecQ Helicases
keywords: Cancer susceptibility; Colorectal; Exome sequencing; Familial colorectal cancer; Germline; Pleiotropism