title: Multiple rare nonsynonymous variants in the adenomatous polyposis coli gene predispose to colorectal adenomas.
abstract: It has been proposed that multiple rare variants in numerous genes collectively account for a substantial proportion of multifactorial inherited predisposition to a variety of diseases, including colorectal adenomas (CRA). We have studied this hypothesis by sequencing the adenomatous polyposis coli (APC) gene in 691 unrelated North American patients with CRAs and 969 matched healthy controls. Rare inherited nonsynonymous variants of APC were significantly overrepresented in patients who did not carry conventional pathogenic mutations in the APC or MutY homologue genes [non-familial adenomatous polyposis (FAP) non-MUTYH-associated polyposis (MAP) patients; 81 of 480, 16.9%] compared with patients with FAP or MAP (20 of 211, 9.5%, P = 0.0113), and this overrepresentation was highest in those non-FAP non-MAP patients with 11 to 99 CRAs (30 of 161, 18.6%, P = 0.0103). Furthermore, significantly more non-FAP non-MAP patients carried rare nonsynonymous variants in the functionally important beta-catenin down-regulating domain compared with healthy controls (32 of 480 versus 37 of 969, P = 0.0166). In silico analyses predicted that approximately 46% of the 61 different variants identified were likely to affect function, and upon testing, 7 of 16 nonsynonymous variants were shown to alter beta-catenin-regulated transcription in vitro. These data suggest that multiple rare nonsynonymous variants in APC play a significant role in predisposing to CRAs.
authors.affiliation: Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom.
authors.forename: Duncan
authors.initials: D
authors.lastname: Azzopardi
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Dallosso
authors.forename: Kristilyn
authors.initials: K
authors.lastname: Eliason
authors.forename: Brant C
authors.initials: BC
authors.lastname: Hendrickson
authors.forename: Natalie
authors.initials: N
authors.lastname: Jones
authors.forename: Edward
authors.initials: E
authors.lastname: Rawstorne
authors.forename: James
authors.initials: J
authors.lastname: Colley
authors.forename: Valentina
authors.initials: V
authors.lastname: Moskvina
authors.forename: Cynthia
authors.initials: C
authors.lastname: Frye
authors.forename: Julian R
authors.initials: JR
authors.lastname: Sampson
authors.forename: Richard
authors.initials: R
authors.lastname: Wenstrup
authors.forename: Thomas
authors.initials: T
authors.lastname: Scholl
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Cheadle
mesh_terms: D000236:Adenoma / Q000235:genetics*; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D000328:Adult; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics*; D004252:DNA Mutational Analysis; D015536:Down-Regulation; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D017434:Protein Structure, Tertiary; D051176:beta Catenin / Q000378:metabolism
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D051176:beta Catenin