Abstract 2199: A murine insertional mutagenesis screen to identify oncogenes and tumor suppressor genes involved in Schwann cell tumorigenesis

Abstract

Abstract Introduction: Schwann cell tumors can occur sporadically, or in association with inherited tumor pre-disposition syndromes, such as Neurofibromatosis type 1 and type 2. A common feature of Schwann cell neoplasia is overexpression of the epidermal growth factor receptor (EGFR) and loss of p53 pathway function. To gain more insight into the genetic basis of neoplastic Schwann cell diseases we are using the conditional Sleeping Beauty (SB) transposon-based somatic mutagenesis system. Methods: To create mutations in Schwann cells and their precursors, five transgenes were introduced into mice. The first transgene conditionally expresses the Sleeping Beauty (SB11) transposase enzyme when Cre recombinase is also expressed1,2. The second transgene is an oligodendritic and Schwann cell specific Cre-recombinase controlled by the CNP (3’-cyclic nucleotide 3’-phosphodiesterase) promoter. The third transgene is a concatomer of oncogenic transposons (T2/Onc) capable of activating and/or disrupting endogenous gene expression. Since loss of p53 function and/or overexpression of epidermal growth factor receptor (EGFR) are associated with Malignant Peripheral Nerve Sheath Tumors (MPNSTs), CNP-EGFR and conditional dominant negative p53R270H alleles are also included3,4. Mice possessing all five transgenes experience transposition and insertional mutations in Schwann cell lineage cells. Results: SB is expressed and active in the Schwann cell lineage with variegated expression in other tissue types. Mice that harbor both a conditional dominant negative p53 allele and CNP-EGFR transgene develop nervous tissue tumors at 70% penetrance. These tumors are primarily neurofibromas, but in addition, there are Schwannomas, oculomotor nerve tumors, and dermal MPNSTs. Preliminary data indicate that MPNSTs develop more frequently in mice that are also undergoing SB transposon mutagenesis. Initial analysis of transposon insertion sites showed over 10 common sites of transposon insertion (CIS), implicating new genes in the pathogenesis of Schwann cell tumors. Among the CIS were the Neurofibromatosis type 1 and type 2 genes (Nf1 and Nf2), validating the screen. The Pten gene was also often targeted, consistent with the hypothesis that loss of Pten activity could play a major role in Schwann cell tumor progression. These and other CIS-associated genes will be discussed. Conclusions: Expression of EGFR at high levels cooperates with loss of function mutations in the p53 gene to induce Schwann cell tumors. SB insertional mutagenesis can contribute to Schwann cell tumorigenesis and identify new candidates in tumor progression. 1. Keng, V.W., et al. (2009). Nat Biotechnol. 3:264-74 2. Starr, T.K., et al. (2009). Science. 323:1747-50 3. Rasheed, B.K., et al. (1994). Cancer Res. 54:1324-1330 4. Perry, A., et al. (2002). Jour. Neuropathol. Exp. Neurol. 61:702-709 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2199.