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P1.14 - Thymoma/Other Thoracic Malignancies (Not CME Accredited Session) (ID 946)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Presentations: 1
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
P1.14-20 - The Expression of DNA Methylation of GAD1 Gene is an Indicator of Malignant Behavior in Thymic Epithelial Tumor. (ID 13354)
16:45 - 18:00 | Author(s): Nuliamina Wusiman
Genome-wide screening for aberrantly methylated CpG islands was performed in 7 thymic carcinoma (TC) samples and 8 type-B3 thymoma samples using HumanMethylation450 K BeadChip (Illumina, Santa Clara, CA, USA) analysis. We identified 22 genes as commonly hypermethylated in TC comparing with B3 thymoma. GAD1（glutamic acid decarboxylase 1）was one of the most significant hypermethylated genes in TC. GAD1 is the enzyme that synthesizes GABA. Recent some reports showed that it is significantly increased in neoplastic tissues. However, the mechanism underlying this increase remains elusive. In this study, we examine mRNA and protein expressions and DNA methylation of GAD1 in thymic epithelial tumors (TETs).a9ded1e5ce5d75814730bb4caaf49419 Method
In total, 49 thymic tumour samples (A; 5, AB; 2, B1; 4, B2; 11, B3; 9, carcinoma; 18) and 20 paired normal tissues were obtained from patients with histologically proven TET, who underwent surgery at the Tokushima University Hospital (Tokushima, Japan) between 1990 and 2016. The methylation status of thymic epithelial tumor samples was validated by pyrosequencing in a larger cohort. The expression status was analysed by quantitative polymerase chain reaction (PCR) and immunohistochemistry (IHC).4c3880bb027f159e801041b1021e88e8 Result
The previous study (Oncogene 2015, 1–14) showed that the key locus responsible for GAD1 reactivation was mapped to a DNA methylation-sensitive CTCF-binding site (CTCF-BS3) within the third intron of GAD1. We targeted this region for pyrosequencing. Pyrosequencing confirmed that DNA methylation of GAD1 gene of TC was significantly higher than that of thymoma (36.5% versus 7.3%, p<0.001), and that DNA methylation of GAD1 gene of thymoma was similar to that of normal thymus (7.3% vs 8.6%). Quantitative PCR and IHC staining revealed that GAD1 mRNA and protein expression levels of TC were higher than those of thymoma (RT-PCR; 8.84 vs 0.72). There were not differences of DNA methylation and expression of GAD1 among subtype of thymoma according to WHO histologic classification. There was a tendency of hypermethylated GAD1 gene in Stage IV comparing with other Stage (Masaoka’s clinical staging).
TC frequently had DNA methylation of CTCF-binding site 3 in GAD1 gene, and high levels of mRNA and protein of GAD1. GAD1 may represent an epigenetic therapeutic target in TC.6f8b794f3246b0c1e1780bb4d4d5dc53
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