GERMLINE AND SOMATIC MUTATIONS IN AN ONCOGENE - RET MUTATIONS IN INHERITED MEDULLARY-THYROID CARCINOMA

Inherited cancer syndromes predispose an individual to the development of specific tumors. Somatic and germline mutations in the same tumor suppressor gene, as described in Knudson's two-mutation model, are wel l recognized. Inherited mutations in the RET proto-oncogene, which enc odes a receptor tyrosine kinase, predispose individuals to the multipl e endocrine neoplasia type 2 (MEN 2) cancer syndromes. The major compo nent tumor of these syndromes is medullary thyroid carcinoma (MTC). To date, somatic mutations in RET have not been identified in tumors fro m individuals with MEN 2, although they have been well documented in s poradic MEN 2-related tumors. We have identified, among 16 MEN 2 cases with well-defined RET germline mutations, a somatic missense mutation at codon 918 of RET in 3 of 15 MTCs and in a sample with hyperplastic C-cells (the presumed precursor to hereditary MTC). We suggest that t he presence of a somatic mutation, in addition to the preexisting germ line mutation in hereditary MTCs, may contribute to tumorigenesis in v ivo.