THE RET PROTOONCOGENE IN MEDULLARY AND PAPILLARY THYROID-CARCINOMA - MOLECULAR-FEATURES, PATHOPHYSIOLOGY AND CLINICAL IMPLICATIONS

The evolution of cancer is a multistep phenomenon, and multiple cellul ar genetic lesions are involved in the emergence of the malignant neop lasm. Several early events have been implicated in the neoplastic tran sformation of thyrocytes, and recent reports have described the involv ement of specific genetic alterations in different types of thyroid ne oplasms: ras point mutations are frequently observed in rumours with f ollicular histology, gsp - the mutated form of the alpha subunit of th e Gs-protein - is encountered in up to 73% of papillary or follicular thyroid carcinomas, and a high prevalence of p53 point mutations has b een found in anaplastic thyroid carcinomas but not in differentiated f ollicular tumours. More recent studies revealed that the RET proto-onc ogene is involved in the oncogenesis of medullary thyroid carcinoma (M TC) and papillary thyroid carcinoma (PTC) by activation of its tyrosin e kinase either by point mutation or rearrangement. In this review the most important recently published data on alterations of the RET prot o-oncogene in heritable and sporadic MTCs and in PTCs will be summariz ed. Emphasis will be directed to the pathophysiological mechanisms of tumour initiation, the indications and limitations of DNA testing, and the clinical implications of identified RET defects in thyroid lesion s.