The RET proto-oncogene in medullary and papillary thyroid carcinoma. Molecular features, pathophysiology and clinical implications.

The evolution of cancer is a multistep phenomenon, and multiple cellular genetic lesions are involved in the emergence of the malignant neoplasm. Several early events have been implicated in the neoplastic transformation of thyrocytes, and recent reports have described the involvement of specific genetic alterations in different types of thyroid neoplasms: ras point mutations are frequently observed in tumours with follicular histology, gsp-the mutated form of the alpha subunit of the Gs-protein-is encountered in up to 73% of papillary or follicular thyroid carcinomas, and a high prevalence of p53 point mutations has been found in anaplastic thyroid carcinomas but not in differentiated follicular tumours. More recent studies revealed that the RET proto-oncogene is involved in the oncogenesis of medullary thyroid carcinoma (MTC) and papillary thyroid carcinoma (PTC) by activation of its tyrosine kinase either by point mutation or rearrangement. In this review the most important recently published data on alterations of the RET proto-oncogene in heritable and sporadic MTCs and in PTCs will be summarized. 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 lesions.