Cellular and Molecular Biology



Molecular mechanisms of medullary thyroid carcinoma: current approaches in diagnosis and treatment

S.A. Boikos and C.A. Stratakis

Section on Endocrinology and Genetics, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, Bethesda, Maryland, USA.

Offprint requests to: Constantine A. Stratakis, MD, DMSc, Director, Pediatric Endocrinology, Head, Developmental Endocrinology & Genetics Program, NICHD, NIH, Building 10, CRC, Room I-3330, 10 Center Dr., MSC1103, Bethesda, Maryland 20892, USA. e-mail: stratakc@mail.nih.gov

Summary. Medullary thyroid carcinoma is the most common cause of death among patients with multiple endocrine neoplasia (MEN) 2. Dominant-activating mutations in the RET proto-oncogene have been shown to have a central role in the development of MEN 2 and sporadic medullary thyroid cancer (MTC): about half of sporadic MTCs are caused by somatic genetic changes of the RET oncogene. Inactivating mutations of the same gene lead to Hirschprung disease and other developmental defects. Thus, RET genetic changes lead to phenotypes that largely depend on their location in the gene and the function and timing of developmental expression of the RET protein. The reproducibility of the phenotype caused by each RET genotype led to MEN 2/MTC being among the first conditions in Medicine where a drastic measure is applied to prevent cancer, following genetic testing: thyroidectomy is currently routinely done in young children that are carriers of MTC-predisposing RET mutations. RET inhibitors have been also developed recently and are used in various types of thyroid and other cancers. This report reviews the RET involvement in the etiology of MEN 2 and MTC and updates the therapeutic approach in preclinical and clinical studies. Histol Histopathol 23, 109-116 (2007)

Key words: Multiple endocrine neoplasia type 22, Medullary thyroid cancer, RET oncogene, Tyrosine kinase inhibitors