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James A. Fagin, Perspective: Lessons Learned from Molecular Genetic Studies of Thyroid Cancer—Insights into Pathogenesis and Tumor-Specific Therapeutic Targets, Endocrinology, Volume 143, Issue 6, 1 June 2002, Pages 2025–2028, https://doi.org/10.1210/endo.143.6.8832
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Thyroid cancer derived from follicular cells is the most common endocrine malignancy. The past decade has seen progress in our understanding of the pathogenesis of the various forms of this condition, and translation of these discoveries to clinical practice now seems within reach. In this review, I will discuss some recent salient observations on the molecular genetics of these tumors, and how they impact on our understanding of their pathogenesis.
Rearrangements of the RET tyrosine kinase receptor gene in papillary thyroid carcinomas
RET encodes the membrane tyrosine kinase receptor for a family of ligands, the prototype of which is glial cell-derived neurotropic growth factor (1). The RET protooncogene is involved in the regulation of growth, survival, differentiation, and migration of cells of neural crest origin. Germline mutations of RET confer predisposition to multiple endocrine neoplasia type 2, familial medullary thyroid carcinoma and Hirschprung’s disease. The RET gene is not normally expressed in thyroid follicular cells. Aberrant expression of various chimeric forms of RET in papillary thyroid cancers result from chromosomal rearrangements in which the promoter/s of unrelated gene/s are linked to the C-terminal fragment of RET. There are several types of RET rearrangements found in human thyroid papillary carcinomas, formed by the fusion of the intracellular tyrosine kinase domain of the gene with different 5′ gene fragments. RET/PTC1 is formed by a paracentric inversion of the long arm of chromosome 10 leading to fusion with a gene named H4/D10S170 (2). RET/PTC2 is formed by a reciprocal translocation between chromosomes 10 and 17, resulting in the juxtaposition of the TK domain of c-RET with a portion of the RIα regulatory subunit of cAMP-dependent PKA (3). RET/PTC3 is also a result of an intrachromosomal rearrangement and is formed by fusion with the RFG/ELE1 gene (4, 5). Although RET/PTC1 and RET/PTC3 are the most common recombined forms of RET, recently several new variants of RET/PTC have been identified in which the oncoprotein is rearranged with other upstream partners in papillary carcinomas from children exposed to radiation after Chernobyl (6–8). In all cases examined so far, the truncated fragment of RET lacks the extracellular and transmembrane domains, and the aberrant protein is located within the cytosol. The respective promoters of the 5′ partners in the RET/PTC rearrangements drive expression of the chimeric gene products. Signaling is dependent on dimerization, and the domain conferring this property is derived from the N-terminal fragment donated by the respective upstream gene. Indeed, all N termini contain coiled-coil or leucine zipper motifs that cause unregulated oligomerization and RET kinase activation.
