title: Different combinations of biallelic APC mutation confer different growth advantages in colorectal tumours.
abstract: New facets to Knudson's [corrected] "two-hit" hypothesis have been proposed recently in relation to adenomatous polyposis coli (APC): protein inactivation may be selected weakly, and the two hits may be interdependent. We reviewed published data on 165 sporadic and 102 familial adenomatous polyposis-associated colorectal tumors with two characterized mutations. Using a Poisson model, we redefined the mutation cluster region (MCR) to residues 1281-1556 and confirmed that the locations of pairs of APC mutations are interdependent (P < 0.0001). A mathematical model, based on the data for sporadic tumors, implied different growth advantages for different combinations of APC mutations: genotype I/I (I: mutation inside MCR) was 3.9 times more likely to be selected than IO or IL (O: mutation outside MCR, L: allelic loss), which were 27.8 times more likely to be selected than OO or OL.
authors.affiliation: Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom.
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Cheadle
authors.forename: Michael
authors.initials: M
authors.lastname: Krawczak
authors.forename: Meinir W
authors.initials: MW
authors.lastname: Thomas
authors.forename: Angela K
authors.initials: AK
authors.lastname: Hodges
authors.forename: Nada
authors.initials: N
authors.lastname: Al-Tassan
authors.forename: Nick
authors.initials: N
authors.lastname: Fleming
authors.forename: Julian R
authors.initials: JR
authors.lastname: Sampson
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics; D000483:Alleles; D002455:Cell Division / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D017491:Genes, APC; D005838:Genotype; D006801:Humans; D008957:Models, Genetic; D009154:Mutation; D016012:Poisson Distribution