9p21 locus analysis in high-risk gastrointestinal stromal tumors characterized for c-kit and platelet-derived growth factor receptor alpha gene alterations

Cancer. 2005 Jul 1;104(1):159-69. doi: 10.1002/cncr.21113.


Background: Gastrointestinal stromal tumors (GISTs) are noncomplex sarcomas that often are due to c-kit-activating and platelet-derived growth factor receptor alpha gene (PDGFRalpha)-activating mutations and perturbations of their related signaling pathways. Molecular and cytogenetic findings have indicated correlations between tumor progression and high-risk GISTs with c-kit mutations, the overexpression of genes such as ezrin, and losses at 9p. In particular, it was reported recently that malignant GISTs showed alterations in the p16INK4a gene located at the 9p21 locus.

Methods: To assess the involvement of p14ARF and p15INK4b in addition to p16INK4a in GISTs, the authors undertook a molecular and cytogenetic study of the 9p21 locus. A series of 22 pre-Gleevec era, cryopreserved, high-risk GISTs that were characterized well in terms of KIT and PDGFRalpha receptors were investigated for mRNA expression, homozygous deletions, mutations, and promoter methylation of locus 9p21, in some instances complemented by fluorescent in situ hybridization studies.

Results: The results indicated the loss of p16INK4a mRNA expression in 41% of the GISTs, mainly due to the homozygous deletion of both the p16INK4a gene and the p14ARF gene (24%). No mutations were found, and promoter methylation (detected by means of methylation-specific polymerase chain reaction analysis in 27% of tumors) was restricted mainly to the p15INK4b gene (20%). It is noteworthy that, in all of the methylated GISTs, the epigenetic promoter alteration was coupled with mRNA expression.

Conclusions: Alterations in the 9p21 locus were found cumulatively in 54% of the tumors in the current series and were represented mainly by the loss of tumor suppressor gene expression. The p16INK4a deletion, which always was coupled with p14ARF gene loss, seemed to be the most common 9p21 inactivation mechanism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Cell Cycle Proteins / genetics
  • Chromosome Deletion
  • Chromosomes, Human, Pair 9*
  • Cyclin-Dependent Kinase Inhibitor p15
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • DNA Methylation
  • Female
  • Gastrointestinal Stromal Tumors / genetics*
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • Phosphorylation
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-kit / genetics*
  • Receptor, Platelet-Derived Growth Factor alpha / genetics*
  • Tumor Suppressor Protein p14ARF / genetics
  • Tumor Suppressor Proteins / genetics


  • CDKN2B protein, human
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p15
  • Cyclin-Dependent Kinase Inhibitor p16
  • Tumor Suppressor Protein p14ARF
  • Tumor Suppressor Proteins
  • Proto-Oncogene Proteins c-kit
  • Receptor, Platelet-Derived Growth Factor alpha