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A Novel Point Mutation of the RET Protooncogene Involving the Second Intracellular Tyrosine Kinase Domain in a Family with Medullary Thyroid Carcinoma

Department of Endocrine Neoplasia and Hormonal Disorders (C.J., G.T.D., P.N.S, E.A.B., R.V.-S., R.F.G., G.J.C, A.O.H.), Division of Internal Medicine, Department of Surgical Oncology (S.S., D.B.E.), and Department of Pathology (A.E.-N.), The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Address all correspondence and requests for reprints to: Ana O. Hoff, The University of Texas M. D. Anderson Cancer Center, Department of Endocrine Neoplasia and Hormonal Disorders, 1515 Holcombe Boulevard, Unit 435, Houston, Texas 77030. E-mail: aohoff{at}mdanderson.org.

Hereditary medullary thyroid carcinoma, a tumor that arises from the parafollicular cells of the thyroid gland, occurs in isolation (as in familial medullary thyroid carcinoma), in association with hyperparathyroidism and pheochromocytoma (as in multiple endocrine neoplasia type 2A), or in association with pheochromocytoma, marfanoid habitus, and mucosal neuromas (as in multiple endocrine neoplasia type 2B). These genetic syndromes are associated with germline-activating mutations of the RET protooncogene, a cell surface tyrosine kinase receptor, which is believed to modulate specific intracellular signaling pathways involved in the regulation of C cell proliferation and apoptosis. RET-activating mutations involve two important functional areas of the receptor: the cysteine-rich extracellular domain and the intracellular tyrosine kinase domain. Multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma are more commonly associated with mutations in the cysteine-rich extracellular domain, whereas multiple endocrine neoplasia type 2B is exclusively associated with mutations involving the second intracellular tyrosine kinase domain. Here, we describe a novel missense mutation of the RET protooncogene that substitutes arginine for proline at codon 912 of the intracellular tyrosine kinase domain in a family with medullary thyroid carcinoma.

C.J. holds joint Endocrinology, Diabetes, and Metabolism Fellowship at The University of Texas M.D. Anderson Cancer Center and Baylor College of Medicine (Houston, TX).

Abbreviations: MTC, Medullary thyroid carcinoma; FMTC, familial MTC; MEN, multiple endocrine neoplasia; TK, tyrosine kinase.

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