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

Abstract

Background-Germline mutation in the adenomatous polyposis coli (APC) gene on chromosome 5 causes familial adenomatous polyposis. "Attenuated" phenotype has been reported with mutation in the 5' end of the gene (5' to codon 158), but genotype-phenotype relations at the 3' end (3' to codon 1596) have not been described fully. Aims-To describe and compare colorectal and extracolonic phenotypes in a case series of families with mutation in the 3' end of the APC gene. Methods-Thirty one at risk or aVected members from four families with a mutation in the APC gene located at codon 1979 or 2644 were evaluated. Results-Variable intrapedigree colorectal phenotype was observed: some members at older age had oligopolyposis (fewer than one hundred colorectal adenomas) whereas other members had classic polyposis at young age. Colorectal cancer was diagnosed at older mean age (50 (7) years) in the four families than in classic FAP pedigrees (39 (14) years). Extracolonic lesions characteristic of FAP occurred with 3' APC mutations, but variability in intrapedigree and interpedigree extracolonic phenotype and dissociation of severity of extracolonic manifestations from number of colorectal polyps was noted. Conclusions-Families with 3' mutations of the APC gene exhibit variable intrapedigree phenotype similar to the heterogeneity noted in families with proximal 5' mutations. Genotyping of FAP and oligopolyposis pedigrees can guide appropriate surveillance of the upper and lower gastrointestinal tract in aVected members. (Gut 1998;43:548-552)

Notable intrafamilial phenotypic variability in a kindred with familial adenomatous polyposis and an APC mutation in exon 9

“…There have been correlations made between the different mutation types, their sites, and the phenotypic mani- festations 12 14 15 17 21-23 However, there can be notable variation in intrafamilial phenotype 9-1724.…”

Genetic and clinical characterisation of familial adenomatous polyposis: a population based study

“…20 Segment 1A (exons 1-9) was amplified with primers 1AF 5′ -CTG CAG CTT CAT ATG ATC -3′ and 1AR 5′-AGA GTC TTT GTC ATT GCA T -3′, and segment 1B (exons [8][9][10][11][12][13][14] with primers 1BF 5′-GCA ACT TCT GGT AAT GGT C-3′ and 1BR 5′-CAT AAT CAC CAT AGA GAC T-3′. Exon 15 was amplified from genomic DNA in four segments, as described by Powell and colleagues.…”

“…It has been ascribed to mutations in the 5′ part of the gene (before codon 157 in exon 4), in the alternatively spliced part of exon 9, or in the most 3′ part of the gene beyond codon 1595 in exon 15. [10][11][12] These seemingly straightforward correlations between genotype and phenotype are complicated by reports describing kindreds with similar mutations but different phenotypes. [13][14][15] Furthermore, the tissue specific role of given APC mutations in the development of rare associated malignancies such as hepatoblastomas, brain tumours (Turcot's syndrome), or thyroid cancers remains to be elucidated.…”

Hereditary Colorectal Cancer

“…38, 40,42 It is 10 to 20 percent for the I1307K APC polymorphism, which occurs predominantly in Ashkenazi Jews (Fig. 3).…”