Association of aberrant methylation of tumor suppressor genes with tumor aggressiveness and BRAF mutation in papillary thyroid cancer

Shuiying Hu, Dingxie Liu, Ralph P. Tufano, Kathryn A. Carson, Eli Rosenbaum, Yoram Cohen, Elizabeth H. Holt, Katja Kiseljak-Vassiliades, Kerry J. Rhoden, Sara Tolaney, Stephen Condouris, Giovanni Tallini, William H. Westra, Christopher B. Umbricht, Martha A. Zeiger, Joseph A. Califano, Vasily Vasko, Mingzhao Xing

Research output: Contribution to journalArticlepeer-review

146 Scopus citations


The role of aberrant tumor suppressor gene methylation in the aggressiveness of papillary thyroid cancer (PTC) has not been documented. By showing promoter methylation-induced gene silencing in PTC-derived cell lines, we first demonstrated the functional consequence of methylation of several recently identified tumor suppressor genes, including those for tissue inhibitor of metalloproteinase-3 (TIMP3), SLC5A8, death-associated protein kinase (DAPK) and retinoic acid receptor β2 (RARβ2). We then investigated the role of methylation of these genes in the aggressiveness of PTC by examining the relationship of their aberrant methylation to clinicopathological characteristics and BRAF mutation in 231 primary PTC tumors. Methylation of TIMP3, SLC5A8 and DAPK was significantly associated with several aggressive features of PTC, including extrathyroidal invasion, lymph node metastasis, multifocality and advanced tumor stages. Methylation of these genes was also significantly associated with BRAF mutation in PTC, either individually or collectively in various combinations. Methylation of these genes, either individually or collectively, occurred more frequently in more aggressive classical and tall-cell PTC subtypes than in less aggressive follicular-variant PTC, with the latter known to infrequently harbor BRAF mutation. Several other tumor suppressor genes investigated were not methylated. These results suggest that aberrant methylation and hence silencing of TIMP3, SLC5A8, DAPK and RARβ, in association with BRAF mutation, may be an important step in PTC tumorigenesis and progression.

Original languageEnglish (US)
Pages (from-to)2322-2329
Number of pages8
JournalInternational Journal of Cancer
Issue number10
StatePublished - Nov 15 2006


  • BRAF mutation
  • DAP kinase
  • Methylation
  • RARβ2
  • SLC5A8
  • TIMP3
  • Thyroid cancer
  • Tumor suppressor gene

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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