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Synergistic Effect of Oncogenic RET and Loss of p18 on Medullary Thyroid Carcinoma Development

¹ Department of Metabolic and Endocrine Diseases, Division of Biomedical Genetics, and ² Department of Clinical Endocrinology, Division of Internal Medicine and Dermatology, University Medical Center Utrecht, Utrecht, the Netherlands; and ³ Department of Biological Sciences and Purdue Cancer Center, Purdue University, West Lafayette, Indiana

Requests for reprints: Jo W.M. Höppener, P.O. Box 85090, 3508 AB, Utrecht, the Netherlands. Phone: 31-88-755-4987; Fax: 31-88-755-4295; E-mail: j.w.m.hoeppener{at}umcutrecht.nl.

Key Words: p18^Ink4c • medullary thyroid carcinoma • multistep tumorigenesis • RET • mouse model • p27^Kip1

Activating mutations in the RET 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 P18 in human MTC, which coincided with activating RET mutations, suggesting a role for loss of P18 in combination with oncogenic RET in the multistep process of MTC development. Therefore, we crossed transgenic mice expressing oncogenic RET (RET2B) with mice lacking p18 (and p27, another cell cycle inhibitor) and monitored MTC development. RET2B;p18^+/– mice and RET2B;p18^–/– mice developed MTC with a highly increased incidence compared with their corresponding single mutant littermates. In addition, expression of oncogenic RET causes an earlier age of onset and larger MTCs in p18^–/–;p27^+/– mice. In a subset of MTCs of RET2B;p18^+/–(;p27^+/–) mice, p18^Ink4c expression was completely lost. This loss of p18^Ink4c expression correlated with higher proliferation rates as well as with larger MTCs, indicating that loss of p18 in combination with oncogenic RET not only increases the risk for MTC development but also enhances MTC progression. Our data strongly indicate that oncogenic RET and loss of p18 cooperate in the multistep tumorigenesis of MTC. [Cancer Res 2008;68(5):1329–37]