Aberrant methylation status of known methylation-sensitive CpG islands in gastrointestinal stromal tumors without any correlation to the state of c-kit and PDGFRA gene mutations and their malignancy

Cancer Sci. 2008 Feb;99(2):253-9. doi: 10.1111/j.1349-7006.2007.00682.x.


To identify additional alterations to c-kit or platelet-derived growth factor receptor alpha (PDGFRA) genes in gastrointestinal stromal tumors (GIST), we investigated the methylation status of nine known methylation-sensitive CpG islands (p15, p16, p73, 0-6-methylguanine-DNA methyltransferase, E-cadherin, mutL homolog 1, colon cancer nonpolyposis type 2 (escherichia), methylated in tumors [MINT]1, MINT2, and MINT31), and compared the results with the malignant potential and gain-of-function mutation types of GIST. Thirty-five GIST (c-kit mutations in 25 cases, PDGFRA mutations in seven cases, and lacking either mutation in three cases) were subjected to methylation-specific polymerase chain reaction to detect the methylation status of the nine methylation-sensitive CpG islands. Aberrant DNA methylation of these loci was found in 94% of all GIST. The rates of DNA methylation at each locus were as follows: hMLH1, 60%; MINT2, 51%; MGMT, 49%; p73, 49%; p16, 20%; E-cadherin, 14%; MINT1, 9%; p15, 6%; and MINT31, 0%. CpG islands methylator phenotype, which was defined as methylation involving more than three gene promoters, was found in 57% of GIST with c-kit or PDGFRA gene mutations. According to the risk categories, CpG islands methylator phenotype was present in 55% of low-risk GIST, and in 58% of high-risk GIST. Our results suggested that in addition to c-kit or PDGFRA mutations, the aberrant methylation of CpG islands, especially of mismatch-repair genes, may have a role in the tumorigenesis of GIST.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • CpG Islands*
  • DNA Methylation
  • Female
  • Gastrointestinal Stromal Tumors / genetics*
  • Gastrointestinal Stromal Tumors / metabolism
  • Humans
  • Male
  • Middle Aged
  • Mutation*
  • Proto-Oncogene Proteins c-kit / genetics*
  • Receptor, Platelet-Derived Growth Factor alpha / genetics*


  • Proto-Oncogene Proteins c-kit
  • Receptor, Platelet-Derived Growth Factor alpha