Abstract 4349: The chromosome 17q oncogene LASP1 promotes metastatic dissemination of medulloblastoma

Abstract

Abstract Medulloblastoma is the most common malignant brain tumor and one of the leading causes of cancer-related mortality in children. Treatment failure mainly occurs in children harboring tumors with microscopic or macroscopic metastases at the time of diagnosis, which typically show gain of 17q (often based on an isochromosome 17q), a common cytogenetic hallmark of intermediate and high-risk medulloblastoma. To pinpoint the oncogene(s) targeted by 17q gain, mRNA expression profiling was carried out in primary tumors with and without this indicative aberration and identified LIM and SH3 protein 1 (LASP1) as one of the most up-regulated genes on chromosome 17q in tumors with 17q gain. LASP1 (earlier named MLN50) was initially identified from a cDNA library of nodal breast cancer metastases and is highly expressed in more than 50% of metastatic human breast cancer, ovarian cancer, and hepatocellular carcinoma. In our study in medulloblastoma, a strong association of LASP1 mRNA abundance with 17q gain and metastatic disease at diagnosis was confirmed by quantitative real-time PCR in an independent cohort of 101 primary tumor samples. Protein expression was analyzed by immunohistochemistry in a large cohort of patients (n=207). High LASP1 protein expression was found to be strongly correlated with 17q gain, metastatic dissemination, and inferior overall and progression-free survival confirming our results on transcript level. Furthermore, multivariate analyses revealed LASP1 protein expression as an independent novel prognostic marker for overall survival and tumor progression in medulloblastoma. In vitro experiments in three established medulloblastoma cell lines demonstrate a strong reduction of cell migration and decreased proliferation upon LASP1 knockdown via siRNA, further indicating a functional role for LASP1 in the progression and metastatic dissemination of medulloblastoma. In conclusion, we have identified LASP1 as an important player in the metastatic dissemination of medulloblastoma which additionally has a high potential to serve as a molecular biomarker for outcome prediction in future prospective studies. Furthermore, LASP1 comprises a promising novel candidate molecule for future targeted therapy approaches in high-risk medulloblastoma. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. 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 4349.