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Genome-Wide Copy Number Imbalances Identified in Familial and Sporadic Medullary Thyroid Carcinoma

Cancer Genetics (D.J.M., G.T., A.-L.R., B.G.R.), Kolling Institute of Medical Research, and Pacific Laboratory Medicine Services, Departments of Anatomical Pathology (J.P.) and Surgery (L.D.), Royal North Shore Hospital, St. Leonards, New South Wales 2065, Australia; Departments of Molecular Medicine (D.J.M., G.T., A.-L.R., B.G.R.), Pathology (J.P.), and Medicine (B.G.R.), University of Sydney, New South Wales 2006, Australia; and Department of General and Trauma Surgery (K.M.-S., H.-D.R.), Heinrich-Heine University, 40225 Düsseldorf, Germany

Address all correspondence and requests for reprints to: Dr. Deborah J. Marsh, Cancer Genetics, Kolling Institute of Medical Research, Royal North Shore Hospital, St. Leonards, Sydney, New South Wales 2065, Australia. E-mail: debbie_marsh{at}med.usyd.edu.au.

Medullary thyroid carcinoma (MTC) is a malignant tumor of the calcitonin-secreting parafollicular C cells of the thyroid occurring sporadically and as a component of the multiple endocrine neoplasia type 2/familial medullary thyroid carcinoma syndrome. The primary genetic cause of multiple endocrine neoplasia type 2 is germline mutation of the RET protooncogene. Somatic point mutations in RET also occur in sporadic MTC. Although RET mutation is likely sufficient to cause C-cell hyperplasia, the precursor lesion to MTC, tumor progression is thought to be due to clonal expansion caused by the accumulation of somatic events. Using the genome-scanning technique comparative genomic hybridization, we identified chromosomal imbalances that occur in MTC including deletions of chromosomes 1p, 3q26.3-q27, 4, 9q13-q22, 13q, and 22q and amplifications of chromosome 19. These regions house known tumor suppressor genes as well as genes encoding subunits of the multicomponent complex of glycosylphosphatidylinositol-linked proteins (glial cell line-derived neurotrophic factor family receptors -2–4) and their ligands glial cell line-derived neurotrophic factor, neurturin, persephin, and artemin that facilitate RET dimerization and downstream signaling. Chromosomal imbalances in the MTC cell line TT were largely identical to those identified in primary MTC tumors, consolidating its use as a model for studying MTC.

This work was supported by Cure Cancer Australia (formerly the Leo and Jenny Leukemia and Cancer Foundation), the Ramaciotti Foundation, and the National Health and Medical Research Council (NHMRC), Australia. D.J.M. is an R. D. Wright Fellow (NHMRC, Australia).

Abbreviations: CCH, C-cell hyperplasia; CGH, comparative genomic hybridization; FMTC, familial medullary thyroid carcinoma; LOH, loss of heterozygosity; MEN 2, multiple endocrine neoplasia type 2; MTC, medullary thyroid carcinoma; VHL, von Hippel Lindau syndrome.

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