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Submitted on August 19, 2005
Accepted on October 17, 2005
Genomic Medicine Institute (FW, CE), Cleveland Clinic Lerner Research Institute, Cleveland, OH; Department of Genetics (CE), Case Western Reserve University School of Medicine, Cleveland, OH; Human Cancer Genetics Program (MMS, FW, CE), Comprehensive Cancer Center (CE), Department of Molecular Virology, Immunology and Medical Genetics (MSS, FW, CE), Division of Epidemiology and Biometrics (LS), Department of Physiology and Cell Biology (SMJ), The Ohio State University, Columbus, OH, USA; Faculdade de Medicina da Universidade Federal de Minas Gerais Belo Horizonte, Brazil (MMS); Bolsista do CNPq (MMS); Department of General Surgery and Transplantation, University of Essen, Essen, Germany (FW, AF, CEB); Department of Surgery, Karolinska University Hospital, Sweden (J. Z); Cancer Research UK Human Cancer Genetics Research Group, University of Cambridge, Cambridge, UK (CE)
* To whom correspondence should be addressed. 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 (TSG).
Objective: The goal of this study is 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 non-imprinted 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 statically significant only for the carcinomas (P = 0.001) although there was a similar trend for the atypical adenomas (ATY, P = 0.06).
Conclusion: Our observations suggest that IR are more prone to genomic instability in FTC. 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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