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Molecular Mechanisms of Disease: The RET Proto-oncogene

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Medullary Thyroid Cancer

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Abstract

Multiple endocrine neoplasia type 2 (MEN2 ) is a rare disorder with distinct clinical features that were key to the elucidation of its underlying molecular cause. Oncogenic transformation of the thyroid C-cell in MEN2 is highly penetrant and progresses through a hyperplastic process prior to malignancy. Tumor burden is assessed by the measurement of serum calcitonin levels, and thyroidectomy is the primary treatment. Clearly defined kindreds with MEN2 were used to map the causative gene to chromosome 10 and to identify mutations in the RET proto-oncogene. The discovery that MEN2 is caused by activating mutations of the RET gene has served to guide an evolving strategy of prophylactic thyroidectomy for the treatment of hereditary MTC and therapeutic strategies for sporadic MTC, where RET activation in the most commonly observed genetic defect. Thyroid C cells are known to express RET at high levels relative to most other cell types; therefore, aberrant activation of the receptor is thought to preferentially sensitize these cells to transformation. A role of RET in medullary thyroid carcinoma has also served to highlight the importance of the MAPK and PI3K signaling pathways in its initiation and progression. Newly published studies demonstrate equally important functions of RET to prevent apoptosis, perhaps allowing the survival of tumor-initiating cell populations. A growing understanding of how RET interacts with growth and death pathways in normal C-cell function, during oncogenic transformation, and finally in tumor progression has helped drive the development of molecular-targeted therapies for the treatment of metastatic medullary thyroid carcinoma.

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Acknowledgments

G.J. Cote, M.C. Hofmann, and R. Bagheri-Yarmand are supported by NIH/NCI grant P50 CA168505. M.C. Hofmann additionally supported by NIH/NICHD R01 HD081244.

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  1. Department of Endocrine Neoplasia and Hormonal Disorders, MD Anderson Cancer Center, The University of Texas, 1515 Holcombe Blvd., Unit 1461, Houston, TX, 77030, USA

    Gilbert J. Cote, Rozita Bagheri-Yarmand, Marie-Claude Hofmann & Robert F. Gagel

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Cote, G.J., Bagheri-Yarmand, R., Hofmann, MC., Gagel, R.F. (2016). Molecular Mechanisms of Disease: The RET Proto-oncogene. In: Wang, T., Evans, D. (eds) Medullary Thyroid Cancer. Springer, Cham. https://doi.org/10.1007/978-3-319-39412-1_5

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