Association of aberrant methylation of tumor suppressor genes with tumor aggressiveness and BRAF mutation in papillary thyroid cancer.
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 beta2 (RARbeta2). 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 RARbeta2, in association with BRAF mutation, may be an important step in PTC tumorigenesis and progression.
Hu
Shuiying
S
Department of Medicine, Division of Endocrinology and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Liu
Dingxie
D
Tufano
Ralph P
RP
Carson
Kathryn A
KA
Rosenbaum
Eli
E
Cohen
Yoram
Y
Holt
Elizabeth H
EH
Kiseljak-Vassiliades
Katja
K
Rhoden
Kerry J
KJ
Tolaney
Sara
S
Condouris
Stephen
S
Tallini
Giovanni
G
Westra
William H
WH
Umbricht
Christopher B
CB
Zeiger
Martha A
MA
Califano
Joseph A
JA
Vasko
Vasily
V
Xing
Mingzhao
M
D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000473:pathology; D027682:Cation Transport Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000378:metabolism*; D064550:Death-Associated Protein Kinases; D018450:Disease Progression; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D027501:Monocarboxylic Acid Transporters; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D018168:Receptors, Retinoic Acid / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics
D051017:Apoptosis Regulatory Proteins; D027682:Cation Transport Proteins; D004273:DNA, Neoplasm; D027501:Monocarboxylic Acid Transporters; D018168:Receptors, Retinoic Acid; C476760:SLC5A8 protein, human; C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; C082925:retinoic acid receptor beta; C482119:BRAF protein, human; D064550:Death-Associated Protein Kinases; D048493:Proto-Oncogene Proteins B-raf; D017871:Calcium-Calmodulin-Dependent Protein Kinases