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

Abstract

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 +/À mice and RET2B;p18 À/À 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 +/À mice. In a subset of MTCs of RET2B;p18Ink4c 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]

Exome sequencing reveals mutant genes with low penetrance involved in MEN2A-associated tumorigenesis

“…The efforts to find non-RET driver genes in MTC started decades ago. Loss of p18 showed a synergistic effect with oncogenic RET in development of MTC (Van Veelen et al 2008). Overexpression of EGFR, and VEGFR2 was associated with metastatic phenotype of MTC (Ciampi et al 2013).…”

“…Other MTC-associated loci that have been reported include P18, Sprouty1, NRAS, and others (Takahashi et al 2006, Van Veelen et al 2008, Macià et al 2012. However, there have been no conclusive findings defining non-RET genetic events in MEN2A-associated tumors.…”

2813 Comprehensive genomic profiling of clinically advanced medullary thyroid carcinoma

“…Future clinical studies need to address whether CCND1 or CDK4 amplification may associate with sensitivity to CDK4/6 inhibitors, as preliminary clinical data suggest for other tumor types [34,35]. CDKN2C has previously been observed to be inactivated in MTC and CDKN2C loss cooperated with oncogenic RET to promote MTC development in mice [36,37]. Alterations in cell cycle genes co-existent with RET mutations may therefore contribute to resistance to RET targeting.…”

Animal models of medullary thyroid cancer: state of the art and view to the future

“…Several studies evidenced the spontaneous development of C-cell hyperplasia in mice lacking CDKN2C (Franklin et al 2000, van Veelen et al 2008 or CDKN1B (Franklin et al 2000).…”

“…Some experiments have taken advantage of these transgenic models to perform a screen for genes that dominantly suppress or enhance dRet MEN2 phenotypes. In this context, sin3a, which negatively regulates the transcription of a wide array of genes (van Oevelen et al 2008), emerged as a new important mediator of dRet MEN2 (Read et al 2005). The dRet transgenic models have also been used to quickly and effectively identify compounds of potential therapeutic value for MTC.…”