Abstract

<div>Abstract<p><b>Purpose:</b> Microarray studies indicate medulloblastoma comprises distinct molecular disease subgroups, which offer potential for improved clinical management.</p><p><b>Experimental Design:</b> Minimal mRNA expression signatures diagnostic for the Wnt/Wingless (WNT) and Sonic Hedgehog (SHH) subgroups were developed, validated, and used to assign subgroup affiliation in 173 tumors from four independent cohorts, alongside a systematic investigation of subgroup clinical and molecular characteristics.</p><p><b>Results:</b> WNT tumors [12% (21/173)] were diagnosed >5 years of age (peak, 10 years), displayed classic histology, <i>CTNNB1</i> mutation (19/20), and associated chromosome 6 loss, and have previously been associated with favorable prognosis. SHH cases [24% (42/173)] predominated in infants (<3 years) and showed an age-dependent relationship to desmoplastic/nodular pathology; all infant desmoplastic/nodular cases (previously associated with a good outcome) were SHH-positive, but these relationships broke down in noninfants. <i>PTCH1</i> mutations were common [34% (11/32)], but <i>PTCH1</i> exon1c hypermethylation, chromosome 9q and <i>REN</i> (<i>KCTD11</i>) genetic loss were not SHH associated, and <i>SMO</i> or <i>SUFU</i> mutation, <i>PTCH1</i> exon1a or <i>SUFU</i> hypermethylation did not play a role, indicating novel activating mechanisms in the majority of SHH cases. SHH tumors were associated with an absence of <i>COL1A2</i> methylation. WNT/SHH-independent medulloblastomas [64% (110/173)] showed all histologies, peaked at 3 and 6 years, and were exclusively associated with chromosome 17p loss.</p><p><b>Conclusions:</b> Medulloblastoma subgroups are characterized by distinct genomic, epigenomic and clinicopathologic features, and clinical outcomes. Validated array-independent gene expression assays for the rapid assessment of subgroup affiliation in small biopsies provide a basis for their routine clinical application, in strategies including molecular disease-risk stratification and delivery of targeted therapeutics. <i>Clin Cancer Res; 17(7); 1883–94. ©2011 AACR</i>.</p></div>

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