LATS Young Investigator Awards


Marcia Puñales

Winner 2003


CLINICAL PRESENTATION AND NATURAL COURSE OF MULTIPLE ENDOCRINE NEOPLASIA (MEN) 2A OF HETEROZYGOTES IN RET CODON 634 MUTATION

Puñales MK, Graf H1, Gross JL and Maia AL.
Endocrine Division, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, and Serviço de Endocrinologia e Metabologia do Paraná (SEMPR), Universidade Federal do Paraná, Curitiba, PR1, Brazil

SUMMARY

Genetic testing for germline mutations in the RET proto-oncogene has become available and today forms the basis for MTC screening procedures. Early prophylactic thyroidectomy must be considered to ensure definitive cure. However, no universal consensus exists as to the optimal timing and extent of prophylatic surgery in these patients. A recent study has proposed a division of hereditary MTC into three risk groups, based on age at disease onset and genotype: high risk group, codon 634 and 618 mutations; intermediate risk group, codon 790, 620 and 611 mutations; and low risk group, codon 768 and 804 mutations. Our group established a protocol for molecular analysis of hereditary medullary thyroid carcinoma (MTC) in southern Brazil, in 1997. Seventeen independent families with RET germline mutation have been identified. Because neither molecular diagnosis nor the pentagastrin test were available before the establishment of this protocol, we had the opportunity to observe a large number of patients in whom the disease has evolved naturally without medical intervention, namely prophylactic thyroidectomy. We observed a wide spectrum in terms of clinical presentation and natural course of the disease even among genetically-related individuals. Sixty-nine individuals from 12 different families presented a codon 634 mutation, the most prevailing missense mutation in our series. The specific mutations identified were C634Y (n=49), C634R (n=13), and C634W (n=7). Individuals with the C634R mutation presented significantly more distant metastases at diagnosis than subjects with the C634Y or C634W mutations (54.5% vs. 19.4% vs. 14.3%, respectively, P=0.03). Further analysis of the estimated cumulative frequency of lymph node and/or distant metastases by Kaplan-Meier curves showed that the appearance of lymph nodes and metastases occurred later in patients with C634Y than in those with C634R (P=0.001). These results suggest that specific nucleotide and amino acid exchanges at codon 634 might have a direct impact on tumor aggressiveness in MEN 2A syndrome and it should be take into account when considering timely prophylactic thyroidectomy to gene carriers.