PURPOSE: Distinct molecular subgroups of medulloblastoma, 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 medulloblastoma.
EXPERIMENTAL DESIGN: Gene characteristics of the Hh medulloblastoma 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. On the basis 
of 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 medulloblastoma (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 
medulloblastoma samples showed 100% concordance between the five-gene signature 
and Affymetrix profiling. Further, in medulloblastoma samples from 50 patients 
treated with sonidegib, all 6 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 
medulloblastoma and may be used to preselect patients who might benefit from 
sonidegib treatment.