RET MUTATION ANALYSIS - CLINICAL-APPLICAT IONS IN HEREDITARY AND SPORATID FORMS OF MEDULLARY-THYROID CARCINOINA (MTC)

MTC occurs sporadically or as part of multiple endocrine neoplasia typ e 2 (MEN 2) syndromes or as familial MTC (FMTC). 97% of the patients a ffected with MEN 2B Show a germline mutation in codon 918 (exon 16) wi thin the tyrosine kinase domain of the RET protooncogene. In 97% of ME N 2A patients, the germline mutation affects one of five cysteine codo ns within exons 10 and 11 in the extracellular domain. Only 65% of FMT C patients are found to have a germline mutation of RET. These mutatio ns affect either the cysteine rich domain (as MEN 2A mutations) or cod ons 768 (exon 13) or 804 (exon 14) within the tyrosine kinase domain. In families affected with hereditary form of MTC, mutation analysis is now commonly used to determine generic status. Individuals without th e mutation would be considered unaffected and would not require furthe r biochemical screening. Individuals who inherit the MEN 2 mutation wo uld undergo biochemical screening tests and have thyroidectomy as soon as these tests are abnormal. Risk of phaeochromocytoma in affected pa tients depends on she position of RET mutation. This risk is high if t he patient has a codon 634 mutation and low if he has a mutation withi n exon 10, 13 or 14. Frequency of adrenal follow-up could so be adapte d with regards to the localisation of RET germline mutation. When a ne w MTC case is diagnosed the distinction between a true sporadic and a de novo hereditary case is important for future clinical management of both the patient and his family. The absence of RET exerts 10, 11, 13 , and 14 germline mutations appears to rule out MEN 2A to a high proba bility. However the presence of a familial form of MTC cannot be exclu ded conclusively. Since codon 918 somatic mutations ale found in 25% o f MTC fromtruly sporadic cases, mutation analysis of RET in tumour DNA may help in distinguishing the sporadic cases from those that are in fact heritable.