Different combinations of biallelic APC mutation confer different growth advantages in colorectal tumours.
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.
Cheadle
Jeremy P
JP
Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom.
Krawczak
Michael
M
Thomas
Meinir W
MW
Hodges
Angela K
AK
Al-Tassan
Nada
N
Fleming
Nick
N
Sampson
Julian R
JR
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