TY - JOUR
T1 - Correlation between BRAF mutation and promoter methylation of TIMP3, RARβ2 and RASSF1A in thyroid cancer
AU - Brait, Mariana
AU - Loyo, Myriam
AU - Rosenbaum, Eli
AU - Ostrow, Kimberly L.
AU - Markova, Alina
AU - Papagerakis, Silvana
AU - Zahurak, Marianna
AU - Goodman, Steven N.
AU - Zeiger, Martha
AU - Sidransky, David
AU - Umbricht, Christopher B.
AU - Hoque, Mohammad O.
N1 - Funding Information:
were separated on an agarose gel and visualized by ethidium This work was supported by (National Cancer Institute Grant bromide staining. Analysis of the products was performed using U01-CA84986, P50 DE019032 and R01 CA107247-04) and a the colorimetric Mutector assay according to the manufacturer’s grant from the American Cancer Society (RSG-08-0031-CCE). instructions (TrimGen). A detection primer was designed that The funding agencies had no role in the design of the study, data does not permit primer extension when the target base is wild-collection, analysis, interpretation of the results, preparation of type. When the target base is mutated, primer extension con-the manuscript, or the decision to submit the manuscript for pub-tinues and a color reaction is observed. The assay was preformed lication. Under a licensing agreement between Oncomethylome according to the manufacturer’s instructions. The melanoma cell Sciences, SA and the Johns Hopkins University, D.S. is entitled to
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
KW - BRAF
KW - Biomarkers
KW - Hypermethylation
KW - RARβ2
KW - RASSF1A
KW - TIMP3
KW - Thyroid cancer
KW - Thyroid tissue
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UR - http://www.scopus.com/inward/citedby.url?scp=84863803871&partnerID=8YFLogxK
U2 - 10.4161/epi.20524
DO - 10.4161/epi.20524
M3 - Article
C2 - 22694820
AN - SCOPUS:84863803871
SN - 1559-2294
VL - 7
SP - 710
EP - 719
JO - Epigenetics
JF - Epigenetics
IS - 7
ER -