A five-gene hedgehog signature developed as a patient preselection tool for hedgehog inhibitor therapy in medulloblastoma

Purpose: Distinct molecular subgroups of medulloblastoma (MB), including hedgehog (Hh) pathway-activated disease, have been reported. We identified and clinically validated a five-gene Hh signature assay that can be used to preselect patients with Hh pathway-activated MB. Experimental Design: Genes characteristic of the Hh MB subgroup were identified through published bioinformatic analyses. Thirty-two genes shown to be differentially expressed in fresh frozen and formalin-fixed paraffin-embedded tumor samples and reproducibly analyzed by RT-PCR were measured in matched samples. These data formed the basis for building a multi-gene logistic regression model derived through elastic net methods from which the five-gene Hh signature emerged after multiple iterations. Based on signature gene expression levels, the model computed a propensity score to determine Hh activation using a threshold set a priori. The association between Hh activation status and tumor response to the Hh pathway inhibitor sonidegib (LDE225) was analyzed. Results: Five differentially expressed genes in MB (GLI1, SPHK1, SHROOM2, PDLIM3, and OTX2) were found to associate with Hh pathway activation status. In an independent validation study, Hh activation status of 25 MB samples showed 100% concordance between the five-gene signature and Affymetrix profiling. Further, in MB samples from 50 patients treated with sonidegib, all six patients who responded were found to have Hh-activated tumors. Three patients with Hh-activated tumors had stable or progressive disease. No patients with Hh-nonactivated tumors responded. Conclusions: This five-gene Hh signature can robustly identify Hh-activated MB and may be used to preselect patients who might benefit from sonidegib treatment.