Abstract 3824: Integrated analysis of array-CGH and gene expression profiling identifies HSPA5 as a prognostic marker in SHH pathway-actived Medulloblastoma

• Published in: Cancer research (Chicago, Ill.) Ill.), 2013-04, Vol.73 (8_Supplement), p.3824-3824
• Main Authors: Lo, Angela Kwok-Fung, Wang, Jian, Shen, Jianhe, Yu, Alexander, Chow, Wing-Yuk, Su, Jack, Adesina, Adekunle, Dauser, Robert, Whitehead, William, Chintagumpala, Murali, Guerra, Rudy, Man, Tsz-Kwong, Lau, Ching C.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2013-3824

Medulloblastoma (MB) is the most malignant brain tumor in children and is characterized by marked biological and clinical heterogeneity. It includes four distinct molecular subtypes [wingless (WNT), sonic hedgehog (SHH), Group 3 and Group 4]. Previous attempts to identify prognostic markers applicable to all MBs were unsuccessful and we therefore hypothesize that each molecular subtype of MB may be associated with its unique prognostic markers. The aim of this study is to identify prognostic markers specific for SHH-active MB tumors. We analyzed SNP-array CGH data and gene expression profiling for 60 pediatric MBs and compared the molecular results with clinical outcome data. Using unsupervised hierarchical clustering, we identified 18 MBs that have activated SHH signaling. This subtype of SHH-active tumors also have frequent chromosome 9q loss which are associated with more favorable outcome. In an attempt to identify candidate genes on chromosome 9q with survival impact, we found that low expression of Heat Shock 70kDa Protein 5 (HSPA5) was significantly associated with better event free survival (EFS) in SHH MB patients independent of other clinical variables. This finding had been validated in two other independent MB cohorts. By immuohistochemistry and western blotting, we confirmed the negative correlation between patient survival and HSPA5 protein expression in SHH tumors. Furthermore, in vitro study indicated that knockdown of HSPA5 by siRNA caused dramatic growth suppression in SHH active MB cells. These findings suggest that HSPA5 is a potential prognostic marker in predicting survival of SHH active MB patients and this protein may also be exploited as therapeutic target for SHH MBs that do not harbor chromosome 9q loss. Citation Format: Angela Kwok-Fung Lo, Jian Wang, Jianhe Shen, Alexander Yu, Wing-Yuk Chow, Jack Su, Adekunle Adesina, Robert Dauser, William Whitehead, Murali Chintagumpala, Rudy Guerra, Tsz-Kwong Man, Ching C. Lau. Integrated analysis of array-CGH and gene expression profiling identifies HSPA5 as a prognostic marker in SHH pathway-actived Medulloblastoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3824. doi:10.1158/1538-7445.AM2013-3824