Data from Synergistic Effect of Oncogenic <i>RET</i> and Loss of <i>p18</i> on Medullary Thyroid Carcinoma Development

Abstract

<div>Abstract<p>Activating mutations in the <i>RET</i> proto-oncogene are associated with both familial and sporadic medullary thyroid carcinoma (MTC) development; however, the genetic mechanisms underlying MTC tumorigenesis remain largely unknown. Recently, we have identified somatic inactivating mutations in the cell cycle inhibitor gene <i>P18</i> in human MTC, which coincided with activating <i>RET</i> mutations, suggesting a role for loss of <i>P18</i> in combination with oncogenic <i>RET</i> in the multistep process of MTC development. Therefore, we crossed transgenic mice expressing oncogenic <i>RET</i> (<i>RET2B</i>) with mice lacking <i>p18</i> (and <i>p27</i>, another cell cycle inhibitor) and monitored MTC development. <i>RET2B;p18<sup>+/−</sup></i> mice and <i>RET2B;p18<sup>−/−</sup></i> mice developed MTC with a highly increased incidence compared with their corresponding single mutant littermates. In addition, expression of oncogenic <i>RET</i> causes an earlier age of onset and larger MTCs in <i>p18<sup>−/−</sup>;p27<sup>+/−</sup></i> mice. In a subset of MTCs of <i>RET2B;p18<sup>+/−</sup>(;p27<sup>+/−</sup>)</i> mice, p18<sup>Ink4c</sup> expression was completely lost. This loss of p18<sup>Ink4c</sup> expression correlated with higher proliferation rates as well as with larger MTCs, indicating that loss of <i>p18</i> in combination with oncogenic <i>RET</i> not only increases the risk for MTC development but also enhances MTC progression. Our data strongly indicate that oncogenic <i>RET</i> and loss of <i>p18</i> cooperate in the multistep tumorigenesis of MTC. [Cancer Res 2008;68(5):1329–37]</p></div>