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Mutations associated with microsatellite unstable colorectal carcinomas exhibit widespread intratumoral heterogeneity.

Abstract
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.
AuthorsR Barnetson, J Jass, R Tse, R Eckstein, B Robinson, M Schnitzler
JournalGenes, chromosomes & cancer (Genes Chromosomes Cancer) Vol. 29 Issue 2 Pg. 130-6 (Oct 2000) ISSN: 1045-2257 [Print] United States
PMID10959092 (Publication Type: Journal Article)
CopyrightCopyright 2000 Wiley-Liss, Inc.
Topics
  • Colorectal Neoplasms (genetics)
  • DNA Mutational Analysis (methods)
  • Genetic Heterogeneity
  • Humans
  • Microsatellite Repeats (genetics)
  • Mutation (genetics)
  • Trinucleotide Repeat Expansion (genetics)

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