Somatic and MEN 2A de novo mutations identified in the RET proto-oncogene by screening of sporadic MTC: s

Since germllne mutations in the RET proto-oncogene (RET) predisposingto tumor development In Familial Medullary Thyroid Carcinoma(FMTC), Multiple endocrine neoplasia type 2A (MEN 2A), and Multipleendocrine neoplasia type 2B (MEN 2B) were reported, It has becomepossible to identify gene carriers with a very high degree ofaccuracy. Mutations in FMTC and MEN 2A exclusively affect cystelneresidues in exon 10 and 11 of RET, whereas in MEN 2B codon 918in exon 16 is involved. This latter mutation has also been describedin a subset of apparently sporadic medullary thyroid carcinomas(MTC). Mutations in MEN 2B often occur as de novo germline mutations,whereas de novo mutations have not yet been described In FMTCor MEN 2A. We analyzed ten MTC: s and ten pheochromocytomas,all clinically judged to be sporadically occurring, by directDNA sequencing of exons 10, 11, and 16 of RET. This analysisrevealed a de novo germline mutation of codon 634 in exon 11In a patient with MTC. In addition, somatic mutations of codon918 in exon 16 in six of the remaining MTC: s were found, Interestingly,the presence of this somatic mutation was associated with asignificantly less favorable clinical outcome.