Multiple rare nonsynonymous variants in the 'adenomatous polyposis coli' gene predispose to colorectal adenomas

Azzopardi, Duncan Lee, Dallosso, Anthony Richard, Eliason, Kristilyn, Hendrickson, Brant C., Jones, Natalie, Rawstorne, Edward Charles, Colley, James, Escott-Price, Valentina ORCID: https://orcid.org/0000-0003-1784-5483, Frye, Cynthia, Sampson, Julian Roy ORCID: https://orcid.org/0000-0002-2902-2348, Wenstrup, Richard, Scholl, Thomas and Cheadle, Jeremy Peter ORCID: https://orcid.org/0000-0001-9453-8458 2008. Multiple rare nonsynonymous variants in the 'adenomatous polyposis coli' gene predispose to colorectal adenomas. Cancer Research 68 (2) , pp. 358-363. 10.1158/0008-5472.CAN-07-5733

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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 β-catenin down-regulating domain compared with healthy controls (32 of 480 versus 37 of 969, P = 0.0166). In silico analyses predicted that ∼46% of the 61 different variants identified were likely to affect function, and upon testing, 7 of 16 nonsynonymous variants were shown to alter β-catenin–regulated transcription in vitro. These data suggest that multiple rare nonsynonymous variants in APC play a significant role in predisposing to CRAs.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Subjects:	Q Science > QH Natural history > QH426 Genetics R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Uncontrolled Keywords:	nonsynonymous variants; APC; colorectal adenomas; missense variants; colorectal cancer
Publisher:	American Association for Cancer Research
ISSN:	0008-5472
Last Modified:	07 Dec 2022 07:29
URI:	https://orca.cardiff.ac.uk/id/eprint/29852

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