title: 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 AAPC/multiple 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 AAPC/multiple 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.
authors.affiliation: Molecular and Population Genetics Laboratory, Imperial Cancer Research Fund, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom.
authors.forename: O M
authors.initials: OM
authors.lastname: Sieber
authors.forename: H
authors.initials: H
authors.lastname: Lamlum
authors.forename: M D
authors.initials: MD
authors.lastname: Crabtree
authors.forename: A J
authors.initials: AJ
authors.lastname: Rowan
authors.forename: E
authors.initials: E
authors.lastname: Barclay
authors.forename: L
authors.initials: L
authors.lastname: Lipton
authors.forename: S
authors.initials: S
authors.lastname: Hodgson
authors.forename: H J W
authors.initials: HJ
authors.lastname: Thomas
authors.forename: K
authors.initials: K
authors.lastname: Neale
authors.forename: R K S
authors.initials: RK
authors.lastname: Phillips
authors.forename: S M
authors.initials: SM
authors.lastname: Farrington
authors.forename: M G
authors.initials: MG
authors.lastname: Dunlop
authors.forename: H J
authors.initials: HJ
authors.lastname: Mueller
authors.forename: M L
authors.initials: ML
authors.lastname: Bisgaard
authors.forename: S
authors.initials: S
authors.lastname: Bulow
authors.forename: P
authors.initials: P
authors.lastname: Fidalgo
authors.forename: C
authors.initials: C
authors.lastname: Albuquerque
authors.forename: M I
authors.initials: MI
authors.lastname: Scarano
authors.forename: W
authors.initials: W
authors.lastname: Bodmer
authors.forename: I P M
authors.initials: IP
authors.lastname: Tomlinson
authors.forename: K
authors.initials: K
authors.lastname: Heinimann
mesh_terms: D000236:Adenoma / Q000235:genetics; D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics; D017931:DNA Primers; D005091:Exons; D017353:Gene Deletion; D017491:Genes, APC / Q000502:physiology*; D005820:Genetic Testing / Q000379:methods; D006801:Humans; D016133:Polymerase Chain Reaction / Q000379:methods
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D017931:DNA Primers