title: Aberrant DNA methylation associated with aggressiveness of gastrointestinal stromal tumour.
abstract: OBJECTIVE
  The majority of gastrointestinal stromal tumors (GISTs) have KIT mutations; however, epigenetic abnormalities that could conceivably potentiate the aggressiveness of GISTs are largely unidentified. Our aim was to establish epigenetic profiles associated with the malignant transformation of GISTs.
  
  
  METHODS
  Methylation of four tumor suppressor genes, RASSF1A, p16, CDH1, and MGMT was analyzed in GISTs. Additionally, genome-wide DNA methylation profiles were compared between small, malignant-prone, and malignant GISTs using methylated GpG island amplification microarrays (MCAM) in a training set (n=40). Relationships between the methylation status of genes identified by MCAM and clinical features of the disease were tested in a validation set (n=75).
  
  
  RESULTS
  Methylation of RASSF1A progressively increased from small to malignant GISTs. p16 was specifically methylated in malignant-prone and malignant GISTs. MCAM analysis showed that more genes were methylated in advanced than in small GISTs (average of 473 genes vs 360 genes, respectively, P=0.012). Interestingly, the methylation profile of malignant GISTs was prominently affected by their location. Two genes, REC8 and PAX3, which were newly-identified via MCAM analysis, were differentially methylated in small and malignant GISTs in the training and validation sets. Patients with methylation of at least REC8, PAX3, or p16 had a significantly poorer prognosis (P=0.034).
  
  
  CONCLUSIONS
  Our results suggest that GIST is not, in epigenetic terms, a uniform disease and that DNA methylation in a set of genes is associated with aggressive clinical behavior and unfavorable prognosis. The genes identified may potentially serve as biomarkers for predicting aggressive GISTs with poor survivability.
authors.affiliation: Division of Molecular Oncology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Akira
authors.initials: A
authors.lastname: Sawaki
authors.forename: Seiji
authors.initials: S
authors.lastname: Ito
authors.forename: Toshirou
authors.initials: T
authors.lastname: Nishida
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Takahashi
authors.forename: Minoru
authors.initials: M
authors.lastname: Toyota
authors.forename: Hiromu
authors.initials: H
authors.lastname: Suzuki
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Shinomura
authors.forename: Ichiro
authors.initials: I
authors.lastname: Takeuchi
authors.forename: Keiko
authors.initials: K
authors.lastname: Shinjo
authors.forename: Byonggu
authors.initials: B
authors.lastname: An
authors.forename: Hidemi
authors.initials: H
authors.lastname: Ito
authors.forename: Kenji
authors.initials: K
authors.lastname: Yamao
authors.forename: Makiko
authors.initials: M
authors.lastname: Fujii
authors.forename: Hideki
authors.initials: H
authors.lastname: Murakami
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Osada
authors.forename: Hiromi
authors.initials: H
authors.lastname: Kataoka
authors.forename: Takashi
authors.initials: T
authors.lastname: Joh
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Sekido
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kondo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics*; D018450:Disease Progression; D044127:Epigenesis, Genetic; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D046152:Gastrointestinal Stromal Tumors / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D016147:Genes, Tumor Suppressor; D019942:Genes, p16; D055106:Genome-Wide Association Study; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics; D011379:Prognosis; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors; C507675:REC8 protein, human; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha