Integrated Analysis of Acgh, Gene Expression and Mirna Profiling Identifies Mir-189 As A Negative Prognostic Marker in Medulloblastomas with Activated Shh Signaling

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO Medulloblastoma (MB) is the most common malignant brain tumor in children. In order to identify molecular markers that can predict clinical outcome, we generated expression profiling and microRNA profiling data of 71 MBs. For 55 of these MBs, we also generated the SNP array comparative genomic hybridization (aCGH) data . Failure of clinical variables and most prognostic markers reported by others in outcome prediction is consistent with the hypothesis that MB is a highly heterogeneous disease possibly originating from various cell lineages with different mechanisms of pathogenesis, marked by activation of certain signaling pathways. To date the best characterized pathway in MB is the Sonic Hedgehog (SHH) pathway. Constitutive activation of SHH signaling, leading to failure of proper migration and differentiation of granule neuron progenitor cells, accounts for nearly 30% of sporadic MBs. Through unsupervised hierarchical clustering based on our expression profiling data, we identified a subset of 21 MBs with activated SHH signaling, marked by elevated expression level of target genes of this pathway, including GLI3, SFRP1, and CXCR4. A frequent genomic aberration in this subset of MBs is the loss of chromosome 9q, which harbors PTCH1, a key regulator of the SHH pathway. Nine out of 10 patients with 9q abnormality had activated SHH signaling. Among those 17 patients with activated SHH signaling for which we have aCGH data, 7/9 patients bearing 9q loss or LOH survived (median follow-up 95 months) while 7/8 patients without 9q abnormalities died. This strongly suggested that 9q loss or LOH is associated with a favorable outcome in MB patients with activated SHH signaling (P = 0.015). To further elucidate molecular markers on 9q that may be associated with clinical outcome, we identified differentially expressed genes and miRNAs on 9q that were associated with copy number loss and then assessed their correlation with patient\#8217;s survival. This analysis revealed that the expression of miR-189 is a negative prognostic marker of OS or EFS, independent of clinical variables (residual tumor size, metastasis status, and treatment, P = 0.008 for OS and 0.005 for EFS, cox proportional hazard model). MiR-189 is expressed from the same precursor hairpin as miR-24, which can inhibit the expression of tumor suppressor genes p16 and ACVR1B. In summary, we identified miR-189 as a novel negative prognostic marker in a subgroup of MBs with activated SHH signaling. This result may facilitate the stratification of MB patients and provide insights into the development of novel therapeutic targets. These data also highlight the utility of genomic profiling for molecular classification of MBs and potential stratification of patients to personalized treatment based on outcome prediction. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-300.