Whole-gene APC deletions cause classical familial adenomatous polyposis, but not attenuated polyposis or "multiple" colorectal adenomas.
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.
Sieber
O M
OM
Molecular and Population Genetics Laboratory, Imperial Cancer Research Fund, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom.
Lamlum
H
H
Crabtree
M D
MD
Rowan
A J
AJ
Barclay
E
E
Lipton
L
L
Hodgson
S
S
Thomas
H J W
HJ
Neale
K
K
Phillips
R K S
RK
Farrington
S M
SM
Dunlop
M G
MG
Mueller
H J
HJ
Bisgaard
M L
ML
Bulow
S
S
Fidalgo
P
P
Albuquerque
C
C
Scarano
M I
MI
Bodmer
W
W
Tomlinson
I P M
IP
Heinimann
K
K
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
D025601:Adenomatous Polyposis Coli Protein; D017931:DNA Primers