NOVEL GERMLINE RET PROTOONCOGENE MUTATIONS ASSOCIATED WITH MEDULLARY-THYROID CARCINOMA (MTC) - MUTATION ANALYSIS IN JAPANESE PATIENTS WITH MTC

Germ-like and somatic mutations in the RET protooncogene are associate d with inherited and sporadic medullary thyroid carcinoma (MTC). The m ajority of patients with multiple endocrine neoplasia type 2A (MEN2A) and familial medullary thyroid carcinoma (FMTC) carry germ-line point mutations that result in the substitution of one of five cysteine resi dues. We investigated exons 10, 11, 13, 14 and 16 of the RET proto-onc ogene in 33 unrelated Japanese patients with MTC. Eleven of the 33 cas es (33%) were found to have germ-line mutations. Three previously unre ported mutations in exon 10 and 11 were identified: one in codon 620, (TGC-->GGC), resulting in a cysteine to glycine substitution, and two in codon 630, (TGC-->TCC) and (TGC-->TAC), resulting in cysteine to se rine and cysteine to tyrosine changes, respectively. The new mutations were present in the germ-line DNA of four unrelated patients for whom a family history of MTC had not been documented. Because the new RET alleles described here involve cysteine residues in a region of protei n previously associated with FMTC and MEN2A, it is very likely that th ey represent mutations that predispose to the development of MTC.