[Analysis of the RET gene and medullary cancer of the thyroid. Contribution to the diagnosis and treatment]. / Analyse du gène RET et cancer médullaire de la thyroïde. Apport au diagnostic et au traitement.

MTC occurs sporadically or as part of multiple endocrine neoplasia type 2 (MEN 2) syndromes or as familial MTC (FMTC). 97% of the patients affected with MEN 2B show a germline mutation in codon 918 (exon 16) within the tyrosine kinase domain of the RET protooncogene. In 97% of MEN 2A patients, the germline mutation affects one of five cysteine codons within exons 10 and 11 in the extracellular domain. Only 65% of FMTC patients are found to have a germline mutation of RET. These mutations affect either the cysteine rich domain (as MEN 2A mutations) or codons 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 genetic status. Individuals without the mutation would be considered unaffected and would not require further biochemical screening. Individuals who inherit the MEN 2 mutation would undergo biochemical screening tests and have thyroidectomy as soon as these tests are abnormal. Risk of phaeochromocytoma in affected patients depends on the position of RET mutation. This risk is high if the patient has a codon 634 mutation and low if he has a mutation within exon 10, 13 or 14. Frequency of adrenal follow-up could so be adapted with regards to the localisation of RET germline mutation. When a new 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 exons 10, 11, 13, and 14 germline mutations appears to rule out MEN 2A to a high probability. However the presence of a familial form of MTC cannot be excluded conclusively. Since codon 918 somatic mutations are found in 25% of MTC from truly sporadic cases, mutation analysis of RET in tumour DNA may help in distinguishing the sporadic cases from those that are in fact heritable.

RET proto-oncogene mutations in French MEN 2A and FMTC families.

Constitutional mutations of the RET proto-oncogene have been identified in multiple endocrine neoplasia type 2A (MEN 2A), type 2B (MEN 2B) and familial medullary thyroid carcinoma (FMTC) families. We sequenced RET exons 10 and 11 in 86 unrelated patients with an inherited predisposition to MTC (excluding MEN 2B). Germ-line mutations were identified in 93% of the MEN 2A families and 67% of the FMTC families tested. All were missense mutations affecting one of three cysteines in the extracellular domain of the RET tyrosine kinase receptor. The prevalence of phaeochromocytoma and hyperparathyroidism was significantly higher in families with a mutation of cysteine 634. These data confirm the preferential localisation of MEN 2A and FMTC associated mutations and the strong correlation between clinical manifestations and the position of RET mutation. Although direct sequencing of RET exons 10 and 11 allows the identification of a constitutional mutation in a large proportion of MEN 2A and FMTC families, our data sustain the existence of other MTC predisposing mutations elsewhere in RET coding or regulating region.