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Updated: May 7, 2026
Methyl-binding DNA capture Sequencing for Patient Tissues
Published on: October 31, 2016
Aberrant DNA methylation associated with aggressiveness of gastrointestinal stromal tumour
Yasuyuki Okamoto1, Akira Sawaki, Seiji Ito
1Division of Molecular Oncology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan.
Background And Aims:
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).
Conclusion:
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.
Insights
Epigenetic changes, specifically DNA methylation, are linked to gastrointestinal stromal tumor (GIST) aggressiveness. New gene markers like REC8 and PAX3 may predict poor prognosis in GIST patients.
Area of Science:
- Oncology
- Epigenetics
- Genomics
Background:
- Gastrointestinal stromal tumors (GISTs) often harbor KIT mutations.
- Epigenetic alterations potentially driving GIST aggressiveness remain largely unexplored.
- This study aimed to identify epigenetic profiles associated with GIST malignant transformation.
Purpose of the Study:
- To establish epigenetic profiles linked to the malignant transformation of GISTs.
- To identify potential biomarkers for predicting aggressive GIST behavior.
Main Methods:
- Analyzed methylation of tumor suppressor genes (RASSF1A, p16, CDH1, MGMT) in GISTs.
- Compared genome-wide DNA methylation using methylated GpG island amplification microarrays (MCAM) in training (n=40) and validation (n=75) sets.
- Correlated methylation status with clinical features.
Main Results:
- Progressive RASSF1A methylation observed from small to malignant GISTs.
- p16 methylation was specific to malignant-prone and malignant GISTs.
- MCAM identified differentially methylated genes (REC8, PAX3) and showed increased methylation in advanced GISTs; methylation of REC8, PAX3, or p16 correlated with poorer prognosis.
Conclusions:
- GIST exhibits epigenetic heterogeneity, not uniformity.
- DNA methylation patterns in specific genes are associated with aggressive clinical behavior and poor prognosis.
- Identified genes may serve as predictive biomarkers for aggressive GISTs.
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