Mutations associated with microsatellite unstable colorectal carcinomas exhibit widespread intratumoral heterogeneity.
Although microsatellite instability (MSI) has been shown to be present in 15% of sporadic colorectal carcinomas, the genetic events underlying the development of these tumors have not been well described. By investigating intratumoral heterogeneity, this study attempts to elucidate whether MSI-positive colorectal carcinomas develop as the result of a random accumulation of mutations or as an ordered, stepwise sequence of genetic alterations. Eighty-six regions from 16 MSI-positive sporadic colorectal carcinomas were examined for mutations in repeat nucleotide sequences of the tumour suppressor genes transforming growth factor beta type II receptor (TGFBRII), insulin-like growth factor II receptor (IGFIIR), and BAX, and the mismatch repair genes MSH3 and MSH6. At least 2 and up to 5 of these genes were mutated in each tumour, and widespread intratumoral heterogeneity was observed for each gene. Regions of tumour with TGFBRII mutations were correlated with a poorly differentiated histology. Unlike the situation in microsatellite stable colorectal carcinomas, the findings of the present study did not suggest that a particular sequence of tumour suppressor and mismatch repair genes are mutated during colorectal tumorigenesis. It seems likely that a random accumulation of mutations, as a result of a defect in the mismatch repair pathway, drives tumour progression in this type of colorectal carcinoma.
Barnetson
R
R
Department of Cancer Genetics, Kolling Institute, Royal North Shore Hospital, St. Leonard's, University of Sydney, Australia.
Jass
J
J
Tse
R
R
Eckstein
R
R
Robinson
B
B
Schnitzler
M
M
D015179:Colorectal Neoplasms / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods; D018740:Genetic Heterogeneity; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics