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Focal high-level amplifications of
MYC
(
or MYCC
) define a subset of high-risk medulloblastoma patients. However, the prognostic role of
MYCN
oncogene amplification remains unresolved. We aimed to evaluate the prognostic value of this alteration alone and in combination with biological modifiers in 67 pediatric medulloblastomas with
MYCN
amplification (
MYCN
-MB). Twenty-one
MYCN
-MB were examined using gene expression profiling and array-CGH, whereas for 46 tumors immunohistochemical analysis and FISH were performed. All 67 tumors were further subjected to mutational analyses. We compared molecular, clinical, and prognostic characteristics both within biological
MYCN
-MB groups and with non-amplified tumors. Transcriptomic analysis revealed SHH-driven tumorigenesis in a subset of
MYCN
-MBs indicating a biological dichotomy of
MYCN
-MB. Activation of SHH was accompanied by variant-specific cytogenetic aberrations including deletion of 9q in SHH tumors. Non-SHH MB were associated with gain of 7q and isochromosome 17q/17q gain. Among clinically relevant variables, SHH subtype and 10q loss for non-SHH tumors comprised the most powerful markers of favorable prognosis in
MYCN
-MB. In conclusion, we demonstrate considerable heterogeneity within
MYCN
-MB in terms of genetics, tumor biology, and clinical outcome. Thus, assessment of disease group and 10q copy-number status may improve risk stratification of this group and may delineate
MYCN
-MB with the same dismal prognosis as
MYC
amplified tumors. Furthermore, based on the enrichment of
MYCN
and
GLI2
amplifications in SHH-driven medulloblastoma, amplification of these downstream signaling intermediates should be taken into account before a patient is enrolled into a clinical trial using a smoothened inhibitor.