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

✍ Scribed by 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

• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: French
• Weight: 208 KB
• Volume: 119
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.22110

✦ Synopsis

Abstract

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 TIMP____3, SLC____5A____8 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 TIMP____3, SLC____5A____8, DAPK and RAR__β__2, in association with BRAF mutation, may be an important step in PTC tumorigenesis and progression. © 2006 Wiley‐Liss, Inc.