This Article Full Text Full Text (PDF) All Versions of this Article: 90/2/1149    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Weber, F. Articles by Eng, C. Search for Related Content PubMed PubMed Citation Articles by Weber, F. Articles by Eng, C. Related Collections Thyroid Endocrine Oncology

Silencing of the Maternally Imprinted Tumor Suppressor ARHI Contributes to Follicular Thyroid Carcinogenesis

Clinical Cancer Genetics Program (F.W., K.A.W., C.E.), Human Cancer Genetics Program (F.W., C.P., K.A.W., C.E.), Comprehensive Cancer Center (C.E.), and Division of Human Genetics (C.E.), Department of Internal Medicine, Division of Human Cancer Genetics, Department of Molecular Virology, Immunology, and Medical Genetics (F.W., K.A.W., C.P., C.E.), Department of Pathology (C.D.M.), The Ohio State University, Columbus, Ohio 43210; Department of General Surgery and Transplantation (F.W., A.F., C.E.B.), University of Essen, D-45122 Essen, Germany; Division of Medical Genetics (M.A.A.), University of Leicester, Leicester LE1 7RH, United Kingdom; and Cancer Research U.K. Human Cancer Genetics Research Group (C.E.), University of Cambridge, Cambridge CB2 1XZ, United Kingdom

Address all correspondence and requests for reprints to: Charis Eng, M.D., Ph.D., Human Cancer Genetics Program, The Ohio State University, 420 West 12th Avenue, Suite 690 TMRF, Columbus, Ohio 43210. E-mail: eng.25{at}osu.edu.

The two most common subtypes of thyroid cancer, follicular thyroid carcinoma (FTC) and papillary thyroid carcinoma, have been extensively studied, but our fundamental understanding of the molecular events in thyroid epithelial oncogenesis is still limited. Unreported data from our previous published global gene expression analysis revealed that the tumor suppressor gene aplysia ras homolog I (ARHI) is frequently underexpressed in FTCs. In this study, we elucidated the frequency and mechanism of ARHI silencing in benign and malignant thyroid neoplasia. We demonstrated that underexpression of ARHI occurs principally in FTCs (P = 0.0018), including its oncocytic variant (11 of 13), even at minimally invasive stage but not classic papillary thyroid carcinoma (two of seven) or follicular adenoma (FA) (three of 14). FTCs show strong allelic imbalance with reduction in copy number/loss of heterozygosity (LOH) in 69%, compared with less than 10% for FAs. In combination with our LOH data, bisulfite sequencing in a subset of samples revealed that FA displays a symmetric methylation pattern, likely representing one unmethylated allele and one presumptively imprinted allele, whereas FTC shows a virtually complete methylation pattern, representing LOH of the nonimprinted allele with only the hypermethylated allele remaining. Furthermore, we showed that pharmacologic inhibition of histone deacetylation but not demethylation could reactivate ARHI expression in the FTC133 FTC cell line. Therefore, our data suggest that silencing of the putative maternally imprinted tumor suppressor gene ARHI, primarily by large genomic deletion in conjunction with hypermethylation of the genomically imprinted allele, serves as a key early event in follicular thyroid carcinogenesis.

This article has been cited by other articles:

				J J L Wong, N J Hawkins, and R L Ward Colorectal cancer: a model for epigenetic tumorigenesis Gut, January 1, 2007; 56(1): 140 - 148. [Full Text] [PDF]

				F. Weber, R. E. Teresi, C. E. Broelsch, A. Frilling, and C. Eng A Limited Set of Human MicroRNA Is Deregulated in Follicular Thyroid Carcinoma J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3584 - 3591. [Abstract] [Full Text] [PDF]

				M. S. Sarquis, F. Weber, L. Shen, C. E. Broelsch, S. M. Jhiang, J. Zedenius, A. Frilling, and C. Eng High Frequency of Loss of Heterozygosity in Imprinted, Compared with Nonimprinted, Genomic Regions in Follicular Thyroid Carcinomas and Atypical Adenomas J. Clin. Endocrinol. Metab., January 1, 2006; 91(1): 262 - 269. [Abstract] [Full Text] [PDF]

				F. Weber, L. Shen, M. A. Aldred, C. D. Morrison, A. Frilling, M. Saji, F. Schuppert, C. E. Broelsch, M. D. Ringel, and C. Eng Genetic Classification of Benign and Malignant Thyroid Follicular Neoplasia Based on a Three-Gene Combination J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2512 - 2521. [Abstract] [Full Text] [PDF]