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RET-mediated gene expression pattern is affected by isoform but not oncogenic mutation

Authors

  • Jessica G. Hickey,

    1. Division of Cancer Biology and Genetics, Cancer Research Institute Queen's University, Kingston, ON, Canada, K7L 3N6
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  • Shirley M. Myers,

    1. Division of Cancer Biology and Genetics, Cancer Research Institute Queen's University, Kingston, ON, Canada, K7L 3N6
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  • Xuefei Tian,

    1. Division of Cancer Biology and Genetics, Cancer Research Institute Queen's University, Kingston, ON, Canada, K7L 3N6
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  • Shu Jun Zhu,

    1. Division of Cancer Biology and Genetics, Cancer Research Institute Queen's University, Kingston, ON, Canada, K7L 3N6
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  • Julie L. V. Shaw,

    1. Division of Cancer Biology and Genetics, Cancer Research Institute Queen's University, Kingston, ON, Canada, K7L 3N6
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  • Scott D. Andrew,

    1. Division of Cancer Biology and Genetics, Cancer Research Institute Queen's University, Kingston, ON, Canada, K7L 3N6
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  • Douglas S. Richardson,

    1. Division of Cancer Biology and Genetics, Cancer Research Institute Queen's University, Kingston, ON, Canada, K7L 3N6
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  • Julia Brettschneider,

    1. Division of Cancer Care and Epidemiology, Cancer Research Institute, Queen's University, Kingston, ON, Canada, K7L 3N6
    2. Department of Community Health and Epidemiology, Queen's University, Kingston, ON, Canada, K7L 3N6
    3. Department of Statistics, University of Warwick, Coventry CV4 7AL, UK
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  • Lois M. Mulligan

    Corresponding author
    1. Division of Cancer Biology and Genetics, Cancer Research Institute Queen's University, Kingston, ON, Canada, K7L 3N6
    • Division of Cancer Biology and Genetics, Cancer Research Institute at Queen's University, Botterell Hall Rm A315C, Queen's University, Kingston, ON, Canada K7L 3N6
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Abstract

The inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN 2) is caused by mutations of the RET receptor tyrosine kinase and is characterized by medullary thyroid carcinoma. MEN 2 subtypes have distinct mutational spectrums and vary in severity. The most severe disease subtype, MEN 2B, is associated with a specific RET mutation (M918T) that has been predicted to alter downstream signaling and target gene expression patterns. We used gene expression microarray analysis to identify target genes modulated by RET. We compared two oncogenic RET mutants, associated with MEN 2A (2ARET) or MEN 2B (2BRET) disease subtypes, that are predicted to have distinct downstream target genes. We showed that overall, 2ARET and 2BRET modulated genes with similar functional ontologies. Further, when we validated our microarray data by quantitative real time PCR, we did not detect major differences in gene expression associated with these mutants when differences in receptor activity levels were considered. We did, however, detect differences in gene expression induced by two RET COOH-terminal isoforms, RET9 and RET51, irrespective of the RET form present (wildtype, 2ARET, or 2BRET). Our data suggest that similar transcriptional programs contribute to all forms of MEN 2 but that differences in target gene expression may contribute to developmental pattern differences observed between RET isoforms. © 2009 Wiley-Liss, Inc.

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