title: Combined DNA methylation and gene expression profiling in gastrointestinal stromal tumors reveals hypomethylation of SPP1 as an independent prognostic factor.
abstract: Gastrointestinal stromal tumors (GISTs) have distinct gene expression patterns according to localization, genotype and aggressiveness. DNA methylation at CpG dinucleotides is an important mechanism for regulation of gene expression. We performed targeted DNA methylation analysis of 1.505 CpG loci in 807 cancer-related genes in a cohort of 76 GISTs, combined with genome-wide mRNA expression analysis in 22 GISTs, to identify signatures associated with clinicopathological parameters and prognosis. Principal component analysis revealed distinct DNA methylation patterns associated with anatomical localization, genotype, mitotic counts and clinical follow-up. Methylation of a single CpG dinucleotide in the non-CpG island promoter of SPP1 was significantly correlated with shorter disease-free survival. Hypomethylation of this CpG was an independent prognostic parameter in a multivariate analysis compared to anatomical localization, genotype, tumor size and mitotic counts in a cohort of 141 GISTs with clinical follow-up. The epigenetic regulation of SPP1 was confirmed in vitro, and the functional impact of SPP1 protein on tumorigenesis-related signaling pathways was demonstrated. In summary, SPP1 promoter methylation is a novel and independent prognostic parameter in GISTs, and might be helpful in estimating the aggressiveness of GISTs from the intermediate-risk category.
authors.affiliation: Institute of Pathology, Friedrich Alexander University, Erlangen-Nuremberg, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Haller
authors.forename: Jitao David
authors.initials: JD
authors.lastname: Zhang
authors.forename: Evgeny A
authors.initials: EA
authors.lastname: Moskalev
authors.forename: Alexander
authors.initials: A
authors.lastname: Braun
authors.forename: Claudia
authors.initials: C
authors.lastname: Otto
authors.forename: Helene
authors.initials: H
authors.lastname: Geddert
authors.forename: Yasser
authors.initials: Y
authors.lastname: Riazalhosseini
authors.forename: Aoife
authors.initials: A
authors.lastname: Ward
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Balwierz
authors.forename: Inga-Marie
authors.initials: IM
authors.lastname: Schaefer
authors.forename: Silke
authors.initials: S
authors.lastname: Cameron
authors.forename: B Michael
authors.initials: BM
authors.lastname: Ghadimi
authors.forename: Abbas
authors.initials: A
authors.lastname: Agaimy
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Fletcher
authors.forename: Jörg
authors.initials: J
authors.lastname: Hoheisel
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
authors.forename: Martin
authors.initials: M
authors.lastname: Werner
authors.forename: Stefan
authors.initials: S
authors.lastname: Wiemann
authors.forename: Ozgür
authors.initials: O
authors.lastname: Sahin
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005500:Follow-Up Studies; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics* / Q000401:mortality; D020869:Gene Expression Profiling; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D053495:Osteopontin / Q000235:genetics*; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; C506895:SPP1 protein, human; D053495:Osteopontin
keywords: GIST; SPP1; methylation