Phenotypic Expression of Disease in Families That Have Mutations in the 5′ Region of the Adenomatous Polyposis Coli Gene

Abstract

Families with adenomatous polyposis that have proximal 5' mutations of the adenomatous polyposis coli gene are more likely to have a heterogeneous phenotype with delayed development of colonic polyposis and colorectal cancer than are families with distal 5' mutations of the gene. Management should include genotyping of patients who are at risk, colonoscopic surveillance of genotypically positive persons, and prophylactic colectomy if several adenomas are found.

Variable phenotype of familial adenomatous polyposis in pedigrees with 3′ mutation in the APC gene

“…We found that mutation in the 3' end of the APC gene was associated with intrapedigree variability of both colonic and extracolonic 15 Analogous to the boundary for phenotypic manifestations of mutations at the 5' end of the APC gene, a boundary at the 3' end of the gene at codon 1596 separates families with variable intrapedigree phenotype from classic FAP phenotype.…”

“…29 This is consistent with the delayed development of colorectal cancer observed in AAPC families with proximal 5' mutations. 15 Nevertheless, the cumulative risk of colorectal cancer seems to reach 100% in attenuated adenomatous polyposis caused by 5' mutation of the APC gene, 15 and 3' families may follow a similar course. 19 Extracolonic manifestations characteristic of FAP also showed intrafamilial variation and did not correlate with phenotypic expression of colorectal polyposis.…”

“…Genotype-phenotype correlation studies have reported that mutations in the extreme 5' end of the APC gene are associated with a less severe phenotype of FAP, [7][8][9][10][11][12][13][14][15] termed attenuated adenomatous polyposis coli (AAPC) by Spirio et al in 1992. 11 The clinical characteristics of the attenuated variant include fewer than 100 colorectal adenomas (oligopolyposis) at presentation but notable phenotypic variation within pedigrees, and a delayed onset of colorectal cancer which occurs on average 12 years later than in classic FAP.…”

Genetic Susceptibility Factors in Aggressive Breast Cancer in African-American Women and the Effects of Carcinogens and Modifiers.

“…Patients who have frameshift mutations between codons 1250 and 1330 develop more than 5000 polyps, whereas mutations outside this region generally leads to less than 2000 polyps and milder disease (Nagase et al 1992b;Friedl et al 1996). Families with mutations located toward the 5' end of codon 158 are more likely to have heterogeneous features including delayed development of colonic polyposis ■ "*■ and colorectal cancer than families with more distal 5'mutations in the gene (Giardiello et al 1997). Other mutations such as a frameshift mutation and a termination at codons 1862 and 1987 have been associated with greater variability in the number of colorectal adenomas, and mutations at codon 1309 results in thousands of adenomas at a young age and earlier death (Caspari et al 1995;Gaytheretal.…”

A Complex Rearrangement in the APC Gene Uncovered by Multiplex Ligation-Dependent Probe Amplification

“…3 Traditional diagnostic methods can identify APC mutations in 50 to 90% of patients with typical FAP and in 20 to 30% of patients with AFAP, depending on the patients examined and the methods used (Solomon C, Burt RW: APC-Associated Polyposis Conditions. GeneReviews: http://www.geneclinics.org., accessed October 21,2005). 4 -7 Recently, large genomic deletions encompassing one to several exons or even the entire APC gene have been identified by use of multiplex ligation-dependent probe amplification (MLPA) in ϳ7 to 12% of all patients with typical FAP.…”