Endocrine Abstracts

Medullary Thyroid Carcinoma (MTC) can be associated with Hirschsprung’s disease (HSCR). Mutations in exon 10 of the RET proto-oncogene were found in patients with co-occurrence of HSCR and MTC. The aim of the study was to screen the MTC risk exons in patients with HSCR. The genetic analysis comprised 73 HSCR patients (53 males, 20 females) who were operated on and followed-up during 2001-2006. The cohort consisted of 48 patients with classical HSCR, 11 with long colonic aganglionosis and 14 with total colonic aganglionosis (TCA). DNAs were isolated from blood after signing informed consent approved by ethical committee. HSCR patients and 10 available family members were tested for RET mutations in exons 10,11,13,14,15 and 16. Direct sequencing revealed RET mutations in 7 (9.6%) HSCR patients. Three groups of mutations were detected. Typical MTC risk mutations were found in 2 HSCR patients with TCA: Cys609Tyr and Cys620Arg (both exon 10). Atypical mutation Tyr791Phe (exon 13) was detected in 2 classical HSCR patients. This mutation is causative for MTC only and has not been associated with HSCR till now. Novel mutations with unknown function for HSCR and MTC were found in 3 patients – del603(A) (exon 10), Gly798Ser (exon 13) and Ser649Leu (exon 11). Two of these patients had TCA and the third one had classical HSCR. MTC developed in 2 patients and 2 family members with typical mutations for HSCR-MTC. These mutation carriers underwent total thyroidectomy (TTE), the other RET positive patients are screened for calcitonin level and they are without TTE till now. Results showed the benefit of systematic RET mutation screening in HSCR families in order to identify the risk of MTC. We recommend to investigate not only exon 10 but also other MTC risk exons in all HSCR patients. This work was supported by grant GACR 301/06/P425.