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Evaluation of potential mechanisms underlying genotype–phenotype correlations in multiple endocrine neoplasia type 2

Oncogene volume 25, pages 6637–6647 (2006)Cite this article

Abstract

Distinct dominant activating mutations in the RET proto-oncogene are responsible for the development of multiple endocrine neoplasia type 2 (MEN 2). Concise examination of the mutated codons led to the detection of a striking genotype–phenotype correlation between the mutated codon and the MEN 2 phenotype in terms of onset and aggressiveness of the disease, suggesting that manifestation and clinical progression is conditioned by the type of mutation. To gain insight into the molecular basis for this genotype–phenotype correlation, we analysed the impact of common and rare mutations identified in MEN 2A (C609Y, C634R), MEN 2B (A883F, M918T) and familial medullary thyroid carcinoma (Y791F) patients on several aspects of cell transformation, including proliferation, apoptosis, anchorage-independent growth and signaling. We found that tumor cells arising from distinct extracellular or intracellular MEN 2 mutations clearly differ in their proliferation properties owing to the activation of different molecular pathways, but importantly, also in resistance to apoptosis. Whereas MEN 2A mutants resulted in accelerated cell proliferation, MEN 2B-RET mutants significantly enhanced suppression of apoptosis, which may account, at least partially, for some of the clinical differences in MEN 2 patients.

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Acknowledgements

We thank Heike Bergmann for preparation of immunohistological sections. This work was supported by DFG Grant PU 188/3-3 (BMP).

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Author notes

  1. M Drosten

    Present address: Centro Nacional de Investigaciones Oncológicas, Molecular Oncology Programme, Melchor Fernández Almagro 3, 28029, Madrid, Spain

Authors and Affiliations

  1. Department of Vectorology and Experimental Gene Therapy, University of Rostock, Rostock, Germany

    N Miše, M Drosten, T Racek & B M Pützer

  2. Department of Pathology, University of Leipzig, Medical School, Leipzig, Germany

    A Tannapfel

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  1. N Miše
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  2. M Drosten
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  3. T Racek
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Correspondence to B M Pützer.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Miše, N., Drosten, M., Racek, T. et al. Evaluation of potential mechanisms underlying genotype–phenotype correlations in multiple endocrine neoplasia type 2. Oncogene 25, 6637–6647 (2006). https://doi.org/10.1038/sj.onc.1209669

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