Large intron 14 rearrangement in APC results in splice defect and attenuated FAP

Abstract

Familial Adenomatous Polyposis (FAP [OMIM 175100]) is an autosomal dominant colorectal cancer predisposition syndrome characterized by hundreds to thousands of colonic polyps and, if untreated by a combination of screening and/or surgical intervention, a ~99% lifetime risk of colorectal cancer. A subset of FAP patients develop an attenuated form of the condition characterized by lower numbers of colonic polyps (highly variable, but generally less than 100) and a lower lifetime risk of colorectal cancer, on the order of 70%. We report the diagnosis of three attenuated FAP families due to a 1.4-kb deletion within intron 14 of the APC, originally reported clinically as a variant of unknown significance (VUS). Sequence analysis suggests that this arose through an Alu-mediated recombination event with sequences from chromosome 6q22.1. This mutation tracks to members who presented with an attenuated FAP phenotype, with variable age of onset and severity. Sequence analysis of mRNA revealed an increase in the level of aberrant splicing of exon 14, resulting in the generation of an exon13-exon15 splice-form that is predicted to lead to a frameshift and protein truncation at codon 673. The relatively mild phenotypic presentation and the intra-familial variation are consistent with the leaky nature of exon 14 splicing in normal APC. The inferred founder of these three families may account for as-yet undetected affected branches of this kindred. This and similar types of intronic mutations may account for a significant proportion of FAP cases where APC clinical analysis fails because of the current limitations of testing options.

IFN/STAT signaling controls tumorigenesis and the drug response in colorectal cancer

“…A number of organoids established from the same patients offer us the opportunity to explore the role of the inter‐patient genetic variations in tumor formation (Figure A). Correlations between clinical manifestations and germline APC mutations have previously been suggested . However, in our cohort, these correlations were not observed.…”

“…Correlations between clinical manifestations and germline APC mutations have previously been suggested. [17][18][19][20] However, in our cohort, these correlations were not observed. For instance, large germline deletions in the promoter region of the APC gene were identified in typical CFAP Figure 1B).…”

Alternative Spliced Variants as Biomarkers of Colorectal Cancer

“…For instance, a truncated APC mutant resulted from a G>A substitution at -1 splice acceptor site in exon 8 creating a mutationadjacent cryptic splice acceptor site, leaded to familial polyposis [50]. Rather than the use of a cryptic splice site, mutations are preferred to result in exon skipping [50][51][52][53], although the identical general outcomes are in pose encountered premature termination codons ahead of time or generated a frameshift with the consequence of truncated APC proteins. In addition to exon skipping, introduction of an extra exon (1A) consisted with 77 nucleotides between exons 1 and 2 during colorectal cancer progression and colorectal cell differentiation [54] is still a way to destroy the canonical splicing.…”

On the sequence-directed nature of human gene mutation: The role of genomic architecture and the local DNA sequence environment in mediating gene mutations underlying human inherited disease

“…AMR between nonallelic sequences is also a frequent cause of human genetic disease as evidenced by the many recently described examples [e.g. Abo-Dalo et al, 2010; Champion et al, 2010; Cozar et al, 2011; Gentsch et al, 2010; Goldmann et al, 2010; Franke et al, 2009; Resta et al, 2010; Shlien et al, 2010; Tuohy et al, 2010; Yang et al, 2010; Zhang et al, 2010]. …”