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Thyroid Physiology

Thyroid Disease

Cancer

Thyroid Cancer

• Abraham

• Carrasco

• Chow

• Feldt-Rasmussen

• Filetti, Arturi

• Franceschi

• Gartner

• Jeong, Kim

• Kogai

• Kristensen

• Maier, Krohn, Paschke

• Mastorakos

• Mutaku, Many

• Neumann, Paschke

• Park

• Ringel

• Schlumberger

• Skubis-Zegadlo

• Smit

• Son

• Spitzweg

• Venkataraman

• Verkooijen

• West

• Xing, Sidransky

• Zaichick

Xing, Sidransky

Early occurrence of RASSF1A hypermethylation and its mutual exclusion with BRAF mutation in thyroid tumorigenesis.

Xing M, Cohen Y, Mambo E, Tallini G, Udelsman R, Ladenson PW, Sidransky D.

Cancer Res. 2004 Mar 1;64(5):1664-8.
 

"Follicular epithelial cell-derived thyroid tumors are common neoplasms comprised mainly of benign thyroid adenomas, follicular thyroid cancers, and papillary thyroid cancers (PTCs). Hypermethylation of the tumor suppressor gene RASSF1A and activating mutation of BRAF gene have been reported recently in thyroid cancers. To additionally investigate the roles of these two epigenetic/genetic alterations in thyroid tumor progression, we examined their occurrences and relationship in both benign and malignant thyroid neoplasms. With real-time quantitative methylation-specific PCR, we found that 4 of 9 (44%) benign adenomas, 9 of 12 (75%) follicular thyroid cancers tumors, and 6 of 30 (20%) of PTC tumors harbored promoter methylation in > or = 25% of RASSF1A alleles. Additional quantitative analysis revealed RASSF1A methylation only in BRAF mutation-negative PTCs. A similar inverse correlation of RASSF1A methylation with BRAF mutation was seen in thyroid tumor cell lines. Our results, therefore, suggest that epigenetic inactivation of RASSF1A through aberrant methylation is an early step in thyroid tumorigenesis. Like the previously reported mutually exclusive relationship between BRAF mutation and other Ras pathway components such as RET/PTC rearrangement, a mutually exclusive relationship also exists between BRAF mutation and RASSF1A methylation in thyroid tumorigenesis."

Hypermethylation of the Pendred syndrome gene SLC26A4 is an early event in thyroid tumorigenesis.

Xing M, Tokumaru Y, Wu G, Westra WB, Ladenson PW, Sidransky D.

Cancer Res. 2003 May 1;63(9):2312-5.

"Expression of the recently cloned Pendred syndrome gene SLC26A4 or PDS has been found to be decreased or even absent in various thyroid tumors. To explore the underlying mechanism, we conducted DNA sequencing and methylation-specific PCR studies in 64 primary thyroid tumors and 6 thyroid cell lines. We found aberrant hypermethylation of the SLC26A4 gene in 44% of histologically benign adenomas, 46% of follicular thyroid cancers, 71% of papillary thyroid cancers, 71% of anaplastic thyroid cancers, and 100% of cell lines. A reciprocal relationship between methylation and expression of the gene was confirmed in cell lines and thyroid tissues. We have thus demonstrated epigenetic changes as a new mechanism in altering the SLC26A4 gene function, in addition to genetic mutation in Pendred syndrome. SLC26A4 gene methylation in benign adenomas and the relatively well-differentiated WRO cell line suggest that this alteration is an early event in thyroid tumorigenesis."

Methylation of the thyroid-stimulating hormone receptor gene in epithelial thyroid tumors: a marker of malignancy and a cause of gene silencing.

Xing M, Usadel H, Cohen Y, Tokumaru Y, Guo Z, Westra WB, Tong BC, Tallini G, Udelsman R, Califano JA, Ladenson PW, Sidransky D.

Cancer Res. 2003 May 1;63(9):2316-21.

"Thyroid-stimulating hormone receptor (TSHR) expression is frequently silenced in epithelial thyroid cancers associated with decreased or absent TSH-promoted iodine uptake. To study the underlying molecular mechanism of decreased TSHR expression, we examined the methylation status of the TSHR gene promoter by sequencing bisulfite-treated DNA from thyroid tumors. After identification of methylated sites by sequencing bisulfite-treated DNA, we used methylation-specific polymerase chain reaction and found frequent CpG methylation in papillary thyroid cancer (23 of 39 patients; 59%) and follicular thyroid cancers (7 of 15 patients; 47%). In contrast, we saw no methylation in normal thyroid tissues and benign adenomas (0 of 8 patients; 0%). In human thyroid tumor cell lines, we observed that TSHR was normally expressed at the protein and mRNA level in cells where the TSHR gene was unmethylated, whereas it was silenced in cell lines where the TSHR promoter was hypermethylated. Treatment of the latter cells with a demethylating agent partially restored TSHR expression. We thus demonstrate aberrant methylation of human TSHR as a likely molecular pathway responsible for the silencing of this gene in thyroid cancers. We propose that methylation of TSHR may provide a novel diagnostic marker of malignancy and a basis for potential use of demethylating agents in conjunction with TSH-promoted radioiodine therapy for epithelial thyroid cancers."

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