Mutation analysis of the RET protooncogene

Background. Evidence that germline mutations in the RET proto-oncogene are the underlying cause of the familial form of medullary thyroid carcinoma (MTC) made it possible to identify gene carriers with a very high degree of accuracy. Aiming to define the mutational profile observed in our patients and to assess gene carriers’ compliance with an early surgery, we reviewed results of molecular analysis of RET performed at our institution since 1994.
Methods. One hundred fifty-eight individuals were screened for germline mutations of the RET protooncogene.
Seventy-seven patients had apparently sporadic MTC; 8 patients had both MTC and
pheochromocytoma or MTC and clinical features of multiple endocrine neoplasia type 2B despite a negative family history; 8 patients were known to belong to affected kindreds; and 65 individuals were at-risk individuals to develop MTC.
Results. A germline mutation in RET was identified in 4% of apparently sporadic MTC patients, in 100% of patients with MTC and pheochromocytoma or MTC and clinical features of multiple
endocrine neoplasia type 2B, and in 100% of probands of clinically established kindreds. The most affected codon was 634 (58%) followed by codon 804 (16%). Among at-risk individuals, 49% were
identified as gene carriers. Seven individuals were submitted to prophylactic thyroidectomy (mean age, 17.7
12.5 years; range: 3-42 years), and all but 1 had MTC.
Conclusions.

RET mutational spectrum observed in the present population disclosed a higher frequency
of codon 804 mutations than expected. Compliance with an early prophylactic surgery seemed to be influenced not only by medical advice and cultural factors but also by the aggressiveness of disease in gene carriers’ families. (Surgery 2007;141:90-5.)
From the Department of Endocrinology,a the Molecular Pathobiology Research Center (CIPM),b the Department of Head and Neck Surgery,c and the Department of Pathology,d Portuguese Cancer Center, Lisboa
Medullary thyroid carcinoma (MTC), which arises from the calcitonin-producing “C” cells of the thyroid, occurs in both sporadic and familial forms. The familial form is inherited as an autosomal
dominant trait and accounts for 25% to 30% of all cases.1-3 In this setting, it may be isolated (FMTC) or part of the syndrome of multiple endocrine neoplasias type 2 (MEN 2). The subtype MEN 2A is characterized by the occurrence of MTC in association with pheochromocytoma and less commonly with hyperparathyroidism. The subtype MEN 2B is characterized by MTC, pheochromocytoma, and developmental abnormalities such as ganglioneuromas and marfanoid habitus. Until 1993, distinction between a sporadic or inherited form was based on individual and family history, histology multiplicity, and biochemical screening of family members at risk for disease. In 1993, different germline point mutations of the REarranged during Transfection (RET) protooncogene were found to predispose to the familial forms of MTC.4-8 Since then, DNA-based strategies have evolved, allowing a correct identification of asymptomatic carriers and avoiding unpleasant stimulation tests. Identification of a germline mutation in a patient with MTC enables classification of the tumour as being of the inherited type, regardless of the absence of family history or associated endocrinopathies.
Accepted for publication March 28, 2006.
Reprint requests: Maria João Martins Bugalho, Serviço de Endocrinologia e Centro de Investigação de Patobiologia Molecular (CIPM), Instituto Português de Oncologia Francisco Gentil, Centro Regional de Oncologia de Lisboa, S.A., R. Professor Lima Basto, 1099-023, Lisboa, Portugal. E-mail: mjbugalho@ipolisboa.minsaude.pt.
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© 2007 Mosby, Inc. All rights reserved. doi:10.1016/j.surg.2006.03.025 90 SURGERY