ONCOGENIC ACTIVATION OF THE RET PROTOONCOGENE IN THYROID-CANCER

Recent studies have established that the ret protooncogene is involved in the development of thyroid tumors, including medullary and papilla ry thyroid carcinomas. Germ line mutations of the ret protooncogene we re identified in multiple endocrine neoplasia (MEN) types 2A and 2B th at share the clinical feature of medullary thyroid carcinoma and pheoc hromocytoma. MEN 2A mutations involved cysteine residues in the extrac ellular domain and induced disulfide-linked homodimerization of the Re t protein on the cell surface, leading to activation of its intrinsic tyrosine kinase. On the other hand, a single point mutation in the tyr osine kinase domain was found in MEN 2B, as well as in 30 to 40% of sp oradic medullary carcinoma. This mutation also resulted in activation of Ret tyrosine kinase without the formation of its covalent homodimer ization. Differences in the mechanisms of ret activation might account for the different phenotypes observed in MEN 2A and MEN 2B. In additi on, somatic rearrangement of the ret protooncogene was frequently dete cted in papillary thyroid carcinoma, particularly from adult Europeans . A recent report demonstrated that the same rearrangement was observe d in approximately 60% of papillary carcinomas of children from areas contaminated by the Chernobyl accident, suggesting that ret rearrangem ent was induced as a direct consequence of radiation exposure. In this review, I focus on the ret mutations detected in thyroid cancer and d iscuss the mechanisms of its oncogenic activation.