Abstract
Abstract Aims Gastrointestinal stromal tumors (GISTs) have distinct gene expression patterns according to anatomical localisation and genotype, with potential impact on biological aggressiveness. DNA methylation of CpG dinucleotides in the promoter region of genes is an important mechanism for regulation of gene expression. We performed a large-scale analysis of DNA methylation in GISTs to identify methylation patterns associated with clinico-pathological parameters and prognosis. Methods Seventy-five GISTs with either KIT or PDGFRA mutations were analysed for DNA methylation of 1.505 CpG sites in the promoter regions of 807 cancer-related genes using a large-scale approach (Cancer Methylation Panel I, Illumina). Epigenetic regulation of Secreted Phosphoprotein 1 (SPP1) expression was analysed at mRNA and protein levels in GIST882 and GIST48b cells after treatment with a demethylating agent. Impacts on tumorigenesis-related signalling pathways were analysed by Western Blot after stimulation of GIST cell lines with SPP1. Prognostic impact of SPP1 at methylation and protein levels were investigated in 75 and 121 GIST tumor samples, respectively, and compared to classical prognostic parameters tumor size, mitotic counts and tumor localisation. Results Principal component analysis revealed distinct DNA methylation patterns according to anatomical localisation, genotype and mitotic counts. Hypomethylation of a CpG dinucleotide 647 base pairs upstream of the transcription start site of SPP1 was significantly correlated to SPP1 mRNA and protein level, and also to tumor progression (p=0.003). In vitro analyses confirmed epigenetic regulation of SPP1 expression, and demonstrated potential impact on proliferation and invasion. High protein level of SPP1 was significantly correlated to shorter disease-free survival in univariate (p=2x10−7) and multivariate (p<1x10−6) analyses. Conclusion The expression of SPP1 is regulated epigenetically in GISTs, and high expression of SPP1 is a novel and independent prognostic parameter in GISTs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5005. doi:1538-7445.AM2012-5005
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