Whole-gene APC deletions cause classical familial adenomatous polyposis, but not attenuated polyposis or “multiple” colorectal adenomas

Abstract

Familial adenomatous polyposis (FAP) is a dominantly inherited colorectal tumor predisposition that results from germ-line mutations in the APC gene (chromosome 5q21). FAP shows substantial phenotypic variability: classical polyposis patients develop more than 100 colorectal adenomas, whereas those with attenuated polyposis (AAPC) have fewer than 100 adenomas. A further group of individuals, so-called ''multiple'' adenoma patients, have a phenotype like AAPC, with 3-99 polyps throughout the colorectum, but mostly have no demonstrable germ-line APC mutation. Routine mutation detection techniques fail to detect a pathogenic APC germ-line mutation in approximately 30% of patients with classical polyposis and 90% of those with AAPC͞multiple adenomas. We have developed a real-time quantitative multiplex PCR assay to detect APC exon 14 deletions. When this technique was applied to a set of 60 classical polyposis and 143 AAPC͞multiple adenoma patients with no apparent APC germ-line mutation, deletions were found exclusively in individuals with classical polyposis (7 of 60, 12%). Fine-mapping of the region suggested that the majority (6 of 7) of these deletions encompassed the entire APC locus, confirming that haploinsufficiency can result in a classical polyposis phenotype. Screening for germ-line deletions in APC mutation-negative individuals with classical polyposis seems warranted.

APC Haploinsufficiency, but Not CTNNB1 or CDH1 Gene Mutations, Accounts for a Fraction of Familial Adenomatous Polyposis Patients Without APC Truncating Mutations

“…However, the precise nature of this APC defect may be difficult to define because Yan et al (2002) reported that in one FAP patient with a reduced expression of APC, the entire coding region, as well as the 3'-UTR and promoter, were completely normal. Sieber et al (2002) have recently developed an assay on genomic DNA to detect APC deletions. With this approach, 7 (12%) of 60 classic FAP and 0 of 143 AAPC patients without apparent APC mutations proved to carry a full gene deletion.…”

Colorectal cancer and genetic alterations in the Wnt pathway

“…Frameshift mutations outnumber nonsense changes by about twoto-one, and the most common nonsense changes are C>T mutations, probably resulting from spontaneous deamination of 5-methylcytosine (Laurent-Puig et al, 1998). In addition to protein-truncating mutations, deletions of the whole gene or exon(s) have been reported in about 5% of FAP cases (Sieber et al, 2002).…”

Mutation spectrum of the APC gene in 83 Korean FAP families

“…The majority of the APC germline mutations identified to date are frameshift or nonsense mutations in the 5' half of the gene, leading to production of a truncated protein (Nagase et al 1992). More than 800 APC germline mutations have been reported to date, very few of which are missense changes (Sieber et al, 2002). A number of screening methods have been applied to the APC gene in mutation studies worldwide, leading to identification of germline APC mutations in 52-81% of all FAP patients (Friedl et al 2001).…”