The APC Variant p.Glu1317Gln predisposes to colorectal adenomas by a novel mechanism of relaxing the target for tumorigenic somatic APC mutations

Dallosso, Anthony Richard, Jones, Siân, Azzopardi, Duncan Lee, Escott-Price, Valentina ORCID: https://orcid.org/0000-0003-1784-5483, Al-Tassan, Nada A., Williams, Geraint Trefor ORCID: https://orcid.org/0000-0003-3768-9940, Idziaszczyk, Shelley Alexis, Davies, D. Rhodri, Milewski, Peter, Williams, Sally, Beynon, John, Sampson, Julian Roy ORCID: https://orcid.org/0000-0002-2902-2348 and Cheadle, Jeremy Peter ORCID: https://orcid.org/0000-0001-9453-8458 2009. The APC Variant p.Glu1317Gln predisposes to colorectal adenomas by a novel mechanism of relaxing the target for tumorigenic somatic APC mutations. Human Mutation 30 (10) , pp. 1412-1418. 10.1002/humu.21089

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Abstract

Multiple rare nonsynonymous variants in APC predispose to colorectal adenomas. The mechanisms through which such variants act have been unclear, but it has been proposed that a specific (“just-right”) level of β-catenin signaling is required for colorectal tumorigenesis. This appears to be mediated by selection for APC genotypes that retain one, or rarely two, 20 amino acid β-catenin downregulating repeats (20AARs). We investigated the mechanism through which the variant p.Glu1317Gln (c.3949G>C) contributes to colorectal tumorigenesis. We compared the patterns of somatic APC mutations in tumors from patients with attenuated familial adenomatous polyposis (AFAP) who did, or did not, coinherit p.Glu1317Gln with their AFAP-causing APC mutations. Only 8.2% (4/49) of tumors carrying p.Glu1317Gln had somatic mutations predicted to result in mutant polypeptides retaining a single 20AAR, compared to 62.1% (36/58) of those which did not carry this variant (P=5.64×10−9). Furthermore, tumors with p.Glu1317Gln often carried somatic mutations that were unusually early or late (downstream of the second 20AAR) in the APC open reading frame. These data support a novel mechanism in which p.Glu1317Gln in combination with other weak mutant APC alleles (generating polypepetides with zero, two, or three 20AARs) can provide the necessary growth advantage for colorectal tumorigenesis.

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 > R Medicine (General)
Uncontrolled Keywords:	APC; AFAP; nonsynonymous variants; colorectal tumorigenesis; FAP
Publisher:	Wiley-Blackwell
ISSN:	1059-7794
Last Modified:	05 Feb 2024 07:20
URI:	https://orca.cardiff.ac.uk/id/eprint/22708

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