Rapid Diagnosis of Medulloblastoma Molecular Subgroups

Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
Clinical Cancer Research (Impact Factor: 8.72). 02/2011; 17(7):1883-94. DOI: 10.1158/1078-0432.CCR-10-2210
Source: PubMed


Microarray studies indicate medulloblastoma comprises distinct molecular disease subgroups, which offer potential for improved clinical management.
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.
WNT tumors [12% (21/173)] were diagnosed >5 years of age (peak, 10 years), displayed classic histology, CTNNB1 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. PTCH1 mutations were common [34% (11/32)], but PTCH1 exon1c hypermethylation, chromosome 9q and REN (KCTD11) genetic loss were not SHH associated, and SMO or SUFU mutation, PTCH1 exon1a or SUFU hypermethylation did not play a role, indicating novel activating mechanisms in the majority of SHH cases. SHH tumors were associated with an absence of COL1A2 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.
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.

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Available from: Ed C Schwalbe
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    • "Genetic analyses have shown the enrichment of genes of WNT signaling pathway (adenomatous polyposis coli – APC, CTNN1, AXIN1, MYC, JUN, FRA, AXIN2, SMARCA4, CREBBP, MED13, CCND1 genes), CTNNB1 mutation, DDX3X mutations and loss of chromosome 6 (Kool et al. 2012; Northcott et al. 2012; Pugh et al. 2012; Robinson et al. 2012; Min et al. 2013). Loss of chromosome 6 is associated with 88% of WNT tumors (Schwalbe et al. 2011). Subgroup 3 and 4 display mostly classical histology, occur mostly in children and have poor (group 3) and intermediate (group 4) prognosis (Northcott et al. 2011; Li et al. 2013). "
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