Genotype-Phenotype Correlations in Attenuated Adenomatous Polyposis Coli

Abstract

Germ-line mutations of the tumor suppressor APC are implicated in attenuated adenomatous polyposis coli (AAPC), a variant of familial adenomatous polyposis (FAP). AAPC is recognized by the occurrence of <100 colonic adenomas and a later onset of colorectal cancer (age >40 years). The aim of this study was to assess genotype-phenotype correlations in AAPC families. By protein-truncation test (PTT) assay, the entire coding region of the APC gene was screened in affected individuals from 11 AAPC kindreds, and their phenotypic differences were examined. Five novel germ-line APC mutations were identified in seven kindreds. Mutations were located in three different regions of the APC gene: (1) at the 5' end spanning exons 4 and 5, (2) within exon 9, and (3) at the 3' distal end of the gene. Variability in the number of colorectal adenomas was most apparent in individuals with mutations in region 1, and upper-gastrointestinal manifestations were more severe in them. In individuals with mutations in either region 2 or region 3, the average number of adenomas tended to be lower than those in individuals with mutations in region 1, although age at diagnosis was similar. In all AAPC kindreds, a predominance of right-sided colorectal adenomas and rectal polyp sparing was observed. No desmoid tumors were found in these kindreds. Our data suggest that, in AAPC families, the location of the APC mutation may partially predict specific phenotypic expression. This should help in the design of tailored clinical-management protocols in this subset of FAP patients.

APC mutation and phenotypic spectrum of Singapore familial adenomatous polyposis patients

“…6 Mutation in the very 5' and 3' ends of the protein as well as the alternatively spliced sites in exon 9 have been associated with a more attenuated form of FAP. [7][8][9] Truncating mutations between codons 463 and 1387 are associated with congenital hypertrophy of the retinal pigment epithelium (CHRPE), 10 whilst truncating mutations between codons 1403 and 1578 are associated with Gardner's syndrome 11 such as increased desmoids and mandibular lesions but not CHRPE.…”

Mutation analysis of the MYH gene in an Australian series of colorectal polyposis patients with or without germline APC mutations

“…These families are known as attenuated FAP (AFAP) as they do not display a colonic phenotype consistent with symptoms typical of adenomatous polyposis. [2][3][4] The genetic basis of FAP was identified in 1991 and found to be associated with germline mutations in the APC gene. [5][6][7][8] Mutational analysis of the APC gene has revealed genotype/phenotype correlations that explain AFAP and a number of other features that commonly occur in FAP patients with disease.…”

A novel indel in exon 9 of APC upregulates a ‘skip exon 9’ isoform and causes very severe familial adenomatous polyposis

“…Nevertheless, there are exceptions where mutation carriers from the same family can present with profuse polyposis, possibly due to other modifiers. [7][8][9] We have previously identified another very lowly expressed isoform that skips exon 9 completely (unpublished data). In this study, we report a novel indel at the 5 0 end of exon 9 that upregulates this 'skip exon 9' isoform and concomitantly downregulates exon 9a, resulting in very severe polyposis and six synchronous advanced cancers in a 37-year-old female proband.…”