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Minerva Endocrinol. 2009 Mar;34(1):11-28.

Genetic mutations in thyroid carcinoma.

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Department of Endocrinology Polytechnic University of the Marche Region Ancona, Italy.


Thyroid carcinoma is the most common endocrine neoplasm and the seventh most frequent human malignancy. It can be distinguished into differentiated and undifferentiated. Differentiated tumors include those arising from thyrocytes, i.e. papillary and follicular carcinoma, while medullary carcinoma originates from parafollicular or C cells. Anaplastic carcinoma comprises undifferentiated tumors. The factors inducing thyroid carcinoma development are not fully understood despite some well-established associations, such as the one between ionizing radiation and papillary carcinoma and that between iodine deficiency and follicular carcinoma. Genetic investigations of differentiated thyroid tumors have documented mutation of genes involved in the regulation of MAP kinase pathway activation in papillary carcinoma, and of genes involved in the regulation of the PI3 kinase pathway in follicular carcinoma. Analysis of their clinical course and of positivity for mutations has demonstrated that prognosis is greatly affected by the type of mutated gene. Genetic investigations therefore have the potential to direct diagnosis, but especially to tailor therapy and follow-up to the individual patient and even the individual gene. Anaplastic carcinoma, a highly aggressive, undifferentiated form, can arise as such or else be the de-differentiated progression of a papillary or a follicular carcinoma. It displays a mutated tumor suppressor gene (p53), which is crucial in the regulation of cell apoptosis, in addition to the mutations found in papillary and follicular forms. Medullary carcinoma is a malignant neoplasm with an intermediate clinical course between differentiated and undifferentiated forms. It manifests more frequently as a sporadic neoplasm or as a familial MEN. The latter is a high-penetrance, autosomal dominant hereditary disorder. Identification of the gene responsible for medullary carcinoma has radically changed the diagnostic approach to the familial forms, enabling early neonatal diagnosis of mutation carriers and of the disease, and early surgical approach by prophylactic thyroidectomy. Genetic studies have significantly affected the endocrinologist's diagnostic approach, as in the case of medullary carcinoma; over the next few years they are expected to provide further information to tackle papillary and follicular thyroid carcinoma. This review addresses the main genetic mutations responsible for neoplastic transformation in thyroid disorders.

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