title: Exome resequencing identifies potential tumor-suppressor genes that predispose to colorectal cancer.
abstract: Inherited factors account for around one third of all colorectal cancers (CRCs) and include rare high penetrance mutations in APC, MSH2, MSH6, and POLE. Here, we sought novel tumor-suppressor genes that predispose to CRC by exome resequencing 50 sporadic patients with advanced CRC (18 diagnosed ≤35 years of age) at a mean coverage of 30×. To help identify potentially pathogenic alleles, we initially sought rare or novel germline truncating mutations in 1,138 genes that were likely to play a role in colorectal tumorigenesis. In total, 32 such mutations were identified and confirmed, and included an insertion in APC and a deletion in POLE, thereby validating our approach for identifying disease alleles. We sought somatic mutations in the corresponding genes in the CRCs of the patients harboring the germline lesions and found biallelic inactivation of FANCM, LAMB4, PTCHD3, LAMC3, and TREX2, potentially implicating these genes as tumor suppressors. We also identified a patient who carried a germline truncating mutation in NOTCH3, part of the Notch signaling cascade that maintains intestinal homeostasis. Our whole exome analyses provided further gene lists to facilitate the identification of potential predisposition alleles.
authors.affiliation: Institute of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, UK.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Smith
authors.forename: Marc
authors.initials: M
authors.lastname: Naven
authors.forename: Rebecca
authors.initials: R
authors.lastname: Harris
authors.forename: James
authors.initials: J
authors.lastname: Colley
authors.forename: Hannah
authors.initials: H
authors.lastname: West
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.forename: Richard
authors.initials: R
authors.lastname: Adams
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Maughan
authors.forename: Laura
authors.initials: L
authors.lastname: Nichols
authors.forename: Richard
authors.initials: R
authors.lastname: Kaplan
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Wagner
authors.forename: Howard L
authors.initials: HL
authors.lastname: McLeod
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Cheadle
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics*; D019295:Computational Biology / Q000379:methods; D004257:DNA Polymerase II / Q000235:genetics; D059472:Exome / Q000235:genetics*; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D018095:Germ-Line Mutation; D006801:Humans; D000075223:Poly-ADP-Ribose Binding Proteins; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods*
chemical_list: C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; C499374:NOTCH3 protein, human; D000075223:Poly-ADP-Ribose Binding Proteins; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D004257:DNA Polymerase II; C119525:POLE protein, human