Molecular genetic diagnostic program of multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma syndromes in Hungary

Abstract

Medullary thyroid carcinoma (MTC) occurs usually in sporadic form, but about a quarter of the cases are hereditary and appear as part of one of the multiple endocrine neoplasia type 2 (MEN2) syndromes. Mutations in the RET protooncogene are known to be the cause of the MEN2A and familial medullary thyroid carcinoma (FMTC) syndromes in the majority of the families. Direct DNA testing allows prophylactic thyroidectomy to be offered to individuals carrying a mutation in the above codons, and in mutation-negative cases it reduces the yearly screening-related burden on family members at risk of the disease. By DNA sequencing and PCR-restriction fragment length polymorphisms, 65 MTC probands were examined for mutations in residues 609, 611, 618, 620 of exon 10, and in residues 634, 768, 804 of exons 11, 13, and 14 respectively of the RET protooncogene. In our study, mutations in the above codons were detected in all of the 14 clinically MEN2A and FMTC families. One of these mutations, TGC609 TCC has not been reported previously. Of the 14 probands with the mutation, 25 relatives also had the identified mutation and 18 relatives proved to be non-carriers. Among the 51 probands with clinically sporadic MTC, none was found to carry a mutation in the above positions even if indirect signs of MTC, pheochromocytoma or hyperparathyroidism could be detected in some families. The frequency of the TGC634AGC mutation is unexpectedly high in our samples, which can probably be attributed to a founder effect. We conclude that screening for mutations in these codons is effective in families fulfilling the strict clinical criteria of MEN2A or FMTC.

Screening of six risk exons of the RET proto-oncogene in families with medullary thyroid carcinoma in the Czech Republic

“…Germ-line mutations were found in 22% of these probands of all MTC families. This result is in agreement with the data stating that up to 25% of MTC cases are inherited (Egawa et al 1998, Klein et al 2001. Genetic testing of our 106 MTC families revealed germ-line mutations in the RET proto-oncogene in 23 index patients and in 24 relatives and excluded the germ-line mutation in 53 family members.…”

Neoplasia Endócrina Múltipla Tipo 2: Manejo Diagnóstico e Terapêutico

“…Em 9 (13,8%) casos foram detectadas mutações em códon 634 do proto-oncongene RET. Concluíram que o estudo genético de pacientes com risco de CMT e/ou MEN-2A é fator importante no diagnóstico precoce, prognóstico e tratamento da doença (5). Em casos avançados, como no caso descrito, tal análise não interfere no prognóstico da doença (5).…”

“…Cerca de 10 a 30% dos casos de CMT estão associados a MEN-2A (5). O feocromocitoma está presente em 40-50% dos casos.…”

Reply to, “RET Germline Mutations in Codon 609 and MEN2A Phenotype: Are They All Created Equal?” by Machens and Dralle (ASO-2009-06-0652)

“…It does appear plausible that three of the five reports of C609S mutations could have overlap, as they all originate from Semmelweis University in Budapest. [1][2][3] Although there are discrepancies between these three reports, such as the age of one affected person with pheochromocytoma, and whether there are two or three family members with medullary thyroid cancer (MTC), it seems reasonable to suspect that these studies are discussing the same family. Combining this C609S family with that described by Kinlaw et al and the recent report by Mian et al, 6/29 (21%) affected family members had pheochromocytoma, and the youngest case of MTC was found at an age of 17 years.…”