title: Genetic diagnosis of high-penetrance susceptibility for colorectal cancer (CRC) is achievable for a high proportion of familial CRC by exome sequencing.
abstract: OBJECTIVE
  Knowledge of the contribution of high-penetrance susceptibility to familial colorectal cancer (CRC) is relevant to the counseling, treatment, and surveillance of CRC patients and families.
  
  
  METHODS
  To quantify the impact of germline mutation to familial CRC, we sequenced the mismatch repair genes (MMR) APC, MUTYH, and SMAD4/BMPR1A in 626 early-onset familial CRC cases ascertained through a population-based United Kingdom national registry. In addition, we evaluated the contribution of mutations in the exonuclease domain (exodom) of POLE and POLD1 genes that have recently been reported to confer CRC risk.
  
  
  RESULTS
  Overall mutations (pathogenic, likely pathogenic) in MMR genes make the highest contribution to familial CRC (10.9%). Mutations in the other established CRC genes account for 3.3% of cases. POLE/POLD1 exodom mutations were identified in three patients with family histories consistent with dominant transmission of CRC. Collectively, mutations in the known genes account for 14.2% of familial CRC (89 of 626 cases; 95% CI = 11.5, 17.2).
  
  
  CONCLUSIONS
  A genetic diagnosis is feasible in a high proportion of familial CRC. Mainstreaming such analysis in clinical practice should enable the medical management of patients and their families to be optimized. Findings suggest CRC screening of POLE and POLD1 mutation carriers should be comparable to that afforded to those at risk of HNPCC. Although the risk of CRC associated with unexplained familial CRC is in general moderate, in some families the risk is substantive and likely to be the consequence of unidentified genes, as exemplified by POLE and POLD1. Our findings have utility in the design of genetic analyses to identify such novel CRC risk genes.
authors.affiliation: All authors: Institute of Cancer Research, London, United Kingdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: Chubb
authors.affiliation: All authors: Institute of Cancer Research, London, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Broderick
authors.affiliation: All authors: Institute of Cancer Research, London, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Frampton
authors.affiliation: All authors: Institute of Cancer Research, London, United Kingdom.
authors.forename: Ben
authors.initials: B
authors.lastname: Kinnersley
authors.affiliation: All authors: Institute of Cancer Research, London, United Kingdom.
authors.forename: Amy
authors.initials: A
authors.lastname: Sherborne
authors.affiliation: All authors: Institute of Cancer Research, London, United Kingdom.
authors.forename: Steven
authors.initials: S
authors.lastname: Penegar
authors.affiliation: All authors: Institute of Cancer Research, London, United Kingdom.
authors.forename: Amy
authors.initials: A
authors.lastname: Lloyd
authors.affiliation: All authors: Institute of Cancer Research, London, United Kingdom.
authors.forename: Yussanne P
authors.initials: YP
authors.lastname: Ma
authors.affiliation: All authors: Institute of Cancer Research, London, United Kingdom.
authors.forename: Sara E
authors.initials: SE
authors.lastname: Dobbins
authors.affiliation: All authors: Institute of Cancer Research, London, United Kingdom. richard.houlston@icr.ac.uk.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000328:Adult; D000368:Aged; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis / Q000235:genetics; D045647:DNA Glycosylases / Q000235:genetics; D053843:DNA Mismatch Repair / Q000235:genetics; D004257:DNA Polymerase II / Q000235:genetics; D004258:DNA Polymerase III / Q000235:genetics; D059472:Exome; D005240:Feasibility Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D000075223:Poly-ADP-Ribose Binding Proteins; D011237:Predictive Value of Tests; D012042:Registries; D018570:Risk Assessment; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D051901:Smad4 Protein / Q000235:genetics; D006113:United Kingdom / Q000453:epidemiology
chemical_list: C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; D000075223:Poly-ADP-Ribose Binding Proteins; C497796:SMAD4 protein, human; D051901:Smad4 Protein; C498211:BMPR1A protein, human; D052005:Bone Morphogenetic Protein Receptors, Type I; C434055:POLD1 protein, human; D004257:DNA Polymerase II; D004258:DNA Polymerase III; C119525:POLE protein, human; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase