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  MA20 - Thymic Tumors: From Molecular to Clinical Results and New Challenges in Other Rare Thoracic Tumors (ID 149)

  • Event: WCLC 2019
  • Type: Mini Oral Session
  • Track: Thymoma/Other Thoracic Malignancies
  • Presentations: 1
  • Now Available
  • Moderators:Kazuya Kondo, Edith Michelle Marom
  • Coordinates: 9/10/2019, 11:30 - 13:00, San Francisco (2009)

  • 30281

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    MA20.02 - GAD1 Expression and Its Methylation Become Indicators of Malignant Behavior in Thymic Epithelial Tumor (Now Available) (ID 2370)

    11:30 - 13:00  |  Author(s): Nuliamina Wusiman
    • Abstract
    • Presentation
    • Slides

    Background
    

    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 93 genes as commonly hypermethylated in TC comparing to type-B3 thymoma. GAD1 （glutamic acid decarboxylase 1） was one of the most significant hypermethylated genes in TC. GAD1 catalyzes the production ofγ-aminobutyric acid (GABA). Some recent reports showed that GAD1 expression is significantly increased in neoplastic tissues. However, the underlying mechanism of elevated GAD1 remains elusive. In this study, we examine mRNA and protein expressions and DNA methylation of GAD1 in thymic epithelial tumors (TETs).

    Method
    

    In total, 95 thymic tumor samples (A; 9, AB; 11, B1; 19, B2; 21, B3; 14, carcinoma; 21) and 22 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. The expression status was analyzed by quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC).

    Result
    

    The previous study (Oncogene 2015, 1–14) showed that the key locus responsible for GAD1 reactivation was mapped to DNA methylation-sensitive CTCF-binding site (CTCF-BS3) within the third intron of GAD1. We targeted this region for pyrosequencing, which confirmed that DNA methylation of GAD1 in TC was significantly higher than in thymoma (32.8% versus 4.0%, P<0.001). It revealed a high degree of both sensitivity and specificity for discriminating TCs and thymomas (AUC=0.936). There was no significant difference in the methylation rate between thymoma and normal thymus (P = 0.917); however, the DNA methylation rate in TC was higher than in normal thymus (P=0.015). qPCR revealed that GAD1 mRNA expression levels in TC were higher than in thymoma (qPCR; 2.03 vs 0.38, P < 0.001). IHC showed statically different GAD1 expression between TC and thymoma (93.75% vs 28.98%, P < 0.001). There was a slight positive correlation between the mRNA expression levels and methylation levels (Spearman’s rank correlation coefficient, ρ = 0.427); however, no differences of DNA methylation and expression of GAD1 was observed among subtype of thymoma according to WHO histologic classification.

    Conclusion
    

    TC had frequent DNA methylation of CTCF-binding site 3 in GAD1, and high levels of mRNA and protein of GAD1. GAD1 may resent an epigenetic therapeutic target in TC.

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