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High Frequency of Loss of Heterozygosity in Imprinted, Compared with Nonimprinted, Genomic Regions in Follicular Thyroid Carcinomas and Atypical Adenomas

Genomic Medicine Institute (F.W., C.E.), Cleveland Clinic Lerner Research Institute, Cleveland, Ohio 44195; Department of Genetics (C.E.), Case Western Reserve University School of Medicine, Cleveland, Ohio 44106; Human Cancer Genetics Program (M.S.S., F.W., C.E.), Comprehensive Cancer Center (C.E.), Department of Molecular Virology, Immunology, and Medical Genetics (M.S.S., F.W., C.E.), Division of Epidemiology and Biometrics (L.S.), and Department of Physiology and Cell Biology (S.M.J.), The Ohio State University, Columbus, Ohio 43210; Faculdade de Medicina (M.S.S.), Universidade Federal de Minas Gerais, 30130 Belo Horizonte, Brazil; Bolsista do CNPq (M.S.S.), 30130 Belo Horizonte, Brazil; Department of General Surgery and Transplantation (F.W., A.F., C.E.B.), University of Essen, 45122 Essen, Germany; Department of Surgery (J.Z.), Karolinska University Hospital, SE-171 76 Stockholm, Sweden; and Cancer Research U.K. Human Cancer Genetics Research Group (C.E.), University of Cambridge, CB2 1XZ Cambridge, United Kingdom

Address all correspondence and requests for reprints to: Charis Eng, M.D., Ph.D., Genomic Medicine Institute, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, NE-30 (Room NE3-307), Cleveland, Ohio 44195. E-mail: engc{at}ccf.org.

Context: Many mammalian genes that are imprinted regulate cell growth, differentiation, and apoptosis. Because imprinting silences one of the two alleles, resulting in functional haploinsufficiency, we hypothesized that loss of heterozygosity (LOH) at an imprinted locus may result in the deletion of the only functional copy of an imprinted tumor suppressor gene.

Objective: The goal of this study was to specifically address this hypothesis that in thyroid neoplasias loss of imprinted loci becomes enriched during oncogenesis.

Design: In total, thyroid tissue was obtained from 72 patients with thyroid neoplasias comprising 34 follicular thyroid carcinomas (FTCs) and 38 follicular adenomas. We performed PCR-based LOH analysis of DNA from paired normal-tumor samples using 18 markers mapped to imprinted regions (IR) and 13 markers in nonimprinted regions (NIR).

Results: Overall LOH frequencies for the IR markers were 26% for the adenomas and 38% for the carcinomas. In the NIR, the overall LOH frequency was 23 and 26% for adenomas and FTCs, respectively. The difference in LOH frequencies between IR and NIR was statistically significant only for the carcinomas (P = 0.001), although there was a similar trend for the atypical adenomas (ATY, P = 0.06).

Conclusions: Our observations suggest that IRs are more prone to genomic instability in FTCs. The fact that the ATY trended toward differential IR/NIR LOH, similar to FTC, may suggest that loss of IR might be instrumental in the adenoma-carcinoma sequence in thyroid carcinogenesis and that ATY could be an important intermediate in this pathway.

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