9p21 locus analysis in high-risk gastrointestinal stromal tumors characterized for c-kit and platelet-derived growth factor receptor α gene alterations
✍ Scribed by Federica Perrone; Elena Tamborini; Gian Paolo Dagrada; Federica Colombo; Lorena Bonadiman; Veronica Albertini; Maria Stefania Lagonigro; Elisa Gabanti; Stefano Caramuta; Angela Greco; Gabriella Della Torre; Alessandro Gronchi; Marco Alessandro Pierotti; Silvana Pilotti
- Publisher
- John Wiley and Sons
- Year
- 2005
- Tongue
- English
- Weight
- 248 KB
- Volume
- 104
- Category
- Article
- ISSN
- 0008-543X
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✦ Synopsis
Abstract
BACKGROUND
Gastrointestinal stromal tumors (GISTs) are noncomplex sarcomas that often are due to c‐kit‐activating and platelet‐derived growth factor receptor α gene (PDGFRα)‐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 p16^INK4a^ gene located at the 9p21 locus.
METHODS
To assess the involvement of p14^ARF^ and p15^INK4b^ in addition to p16^INK4a^ 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 PDGFRα 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 p16^INK4a^ mRNA expression in 41% of the GISTs, mainly due to the homozygous deletion of both the p16^INK4a^ gene and the p14^ARF^ 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 p15^INK4b^ 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 p16^INK4a^ deletion, which always was coupled with p14^ARF^ gene loss, seemed to be the most common 9p21 inactivation mechanism. Cancer 2005. © 2005 American Cancer Society.