Characterisation of a subtype of colorectal cancer combining features of the suppressor and mild mutator pathways

Jeremy R. Jass, Kelli G. Biden, Margaret C. Cummings, Lisa A. Simms, Michael Walsh, Estelle Schoch, Stephen J. Meltzer, Caroline Wright, Jeffrey Searle, Joanne Young, Barbara A. Leggett

Research output: Contribution to journalArticlepeer-review

Abstract

Background - 10% of sporadic colorectal cancers are characterised by a low level of microsatellite instability (MSI-L). These are not thought to differ substantially from microsatellite-stable (MSS) cancers, but MSI-L and MSS cancers are distinguished clinicopathologically and in their spectrum of genetic alterations from cancers showing high level microsatellite instability (MSI-H). Aims - To study the distribution of molecular alterations in a series of colorectal cancers stratified by DNA microsatellite instability. Methods - A subset of an unselected series of colorectal cancers was grouped by the finding of DNA MSI at 0 loci (MSS) (n = 51), 1-2 loci (MSI-L) (n = 38) and 3-6 loci (MSI-H) (n = 25). The frequency of K-ras mutation, loss of heterozygosity (LOH) at 5q, 17p and 18q, and patterns of p53 and β catenin immunohistochemistry was determined in the three groups. Results - MSI-H cancers had a low frequency of K-ras mutation (7%), LOH on chromosomes 5q (0%), 17p (0%) and 18q (12.5%), and a normal pattern of immunostaining for p53 and β catenin. MSI-L cancers differed from MSS cancers in terms of a higher frequency of K-ras mutation (54% v 27%) (p = 0.01) and lower frequency of 5q LOH (23% v 48%) (p = 0.047). Whereas aberrant β catenin expression and 5q LOH were concordant (both present or both absent) in 57% of MSS cancers, concordance was observed in only 20% of MSI-L cancers (p = 0.01). Conclusions - MSI-L colorectal cancers are distinct from both MSI-H and MSS cancers. This subset combines features of the suppressor and mutator pathways, may be more dependent on K-ras than on the APC gene in the early stages of neoplastic evolution, and a proportion may be related histogenetically to the serrated (hyperplastic) polyp.

Original languageEnglish (US)
Pages (from-to)455-460
Number of pages6
JournalJournal of clinical pathology
Volume52
Issue number6
DOIs
StatePublished - 1999

Keywords

  • Colorectal adenocarcinoma
  • Loss of heterozygosity
  • Microsatellite instability
  • Ras mutation
  • Serrated polyp

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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