Correlation between BRAF mutation and promoter methylation of TIMP3, RARβ2 and RASSF1A in thyroid cancer

Mariana Brait, Myriam Loyo, Eli Rosenbaum, Kimberly L. Ostrow, Alina Markova, Silvana Papagerakis, Marianna Zahurak, Steven N. Goodman, Martha Zeiger, David Sidransky, Christopher B. Umbricht, Mohammad O. Hoque

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

Our aim was to comprehensively analyze promoter hypermethylation of a panel of novel and known methylation markers for thyroid neoplasms and to establish their relationship with BRAF mutation and clinicopathologic parameters of thyroid cancer. A cohort of thyroid tumors, consisting of 44 cancers and 44 benign thyroid lesions, as well as 15 samples of adjacent normal thyroid tissue, was evaluated for BRAF mutation and promoter hypermethylation. Genes for quantitative methylation specific PC R (QMSP) were selected by a candidate gene approach. Twenty-two genes were tested: TSHR, RASSF1A, RARβ2, DAPK, hMLH1, ATM, S100, p16, CTNNB1, GSTP1, CALCA, TIMP3, TGFβR2, THBS1, MINT1, CTNNB1, MT1G, PAK3, NISCH, DCC, AIM1 and KIF1A. The PC R-based "mutector assay" was used to detect BRAF mutation. All p values reported are two sided. Considerable overlap was seen in the methylation markers among the different tissue groups. Significantly higher methylation frequency and level were observed for KIF1A and RARβ2 in cancer samples compared with benign tumors. A negative correlation between BRAF mutation and RASSF1A methylation, and a positive correlation with RARβ2 methylation were observed in accordance with previous results. In addition, positive correlation with TIMP3 and a marginal correlation with DCC methylation were observed. The present study constitutes a comprehensive promoter methylation profile of thyroid neoplasia and shows that results must be analyzed in a tissue-specific manner to identify clinically useful methylation markers. Integration of genetic and epigenetic changes in thyroid cancer will help identify relevant biologic pathways that drive its development.

Original languageEnglish (US)
Pages (from-to)710-719
Number of pages10
JournalEpigenetics
Volume7
Issue number7
DOIs
StatePublished - 2012

Keywords

  • BRAF
  • Biomarkers
  • Hypermethylation
  • RARβ2
  • RASSF1A
  • TIMP3
  • Thyroid cancer
  • Thyroid tissue

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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  • Cite this

    Brait, M., Loyo, M., Rosenbaum, E., Ostrow, K. L., Markova, A., Papagerakis, S., Zahurak, M., Goodman, S. N., Zeiger, M., Sidransky, D., Umbricht, C. B., & Hoque, M. O. (2012). Correlation between BRAF mutation and promoter methylation of TIMP3, RARβ2 and RASSF1A in thyroid cancer. Epigenetics, 7(7), 710-719. https://doi.org/10.4161/epi.20524