Wnt/Wingless Pathway Activation and Chromosome 6 Loss Characterise a Distinct Molecular Sub-Group of Medulloblastomas Associated with a Favourable Prognosis

 Abstract

The accurate assessment of disease risk remains a major goal in children with medulloblastoma. Activation of the canonical Wnt/Wingless (Wnt/Wg) signalling pathway occurs in up to 25% of cases and is associated with a favourable disease outcome. To explore the molecular pathogenesis of Wnt/Wg-active medulloblastomas, and to investigate any genetic basis for their observed clinical behaviour, we assessed a series of primary medulloblastomas for evidence of Wnt/Wg pathway activation, alongside a genome-wide analysis of associated copy-number aberrations. Cases displaying evidence of Wnt/Wg activation (CTNNB1 mutation and/or β-catenin nuclear stabilisation) were exclusively associated with a distinct genomic signature involving loss of an entire copy of chromosome 6 but few other aberrations (p<0.001). In contrast, Wnt/Wg-negative tumours co-clustered into an unrelated sub-group characterised by multiple established genomic defects common in medulloblastoma (losses of chromosomes 17p, 8, 10 and 16; gains of chromosomes 7 and 17q). Further investigation of specific genetic defects in a larger independent cohort demonstrated that loss of chromosome 6 was exclusively observed in Wnt/Wg-active tumours, but not in Wnt/Wg-negative cases (8/13 vs. 0/19; p=0.0001), while pathway activation was independent of chromosome 17 aberrations, the most common chromosomal alterations detected in medulloblastoma (p=0.005). Wnt/Wg-active tumours could not be distinguished on the basis of clinical or pathological disease features. Our data indicate that Wnt/Wg-active tumours represent an independent molecular sub-group of medulloblastomas characterised by a distinct pattern of genomic aberrations. These findings provide a strong biological basis to support (i) the idiosyncratic clinical behaviour of Wnt/Wg-active medulloblastomas, and (ii) the development of β-catenin status as an independent marker for therapeutic stratification in this disease.

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Pages
2666 - 2670
doi
10.4161/cc.5.22.3446
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Report
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Wnt/Wingless Pathway Activation and Chromosome 6 Loss Characterise a Distinct Molecular Sub-Group of Medulloblastomas Associated with a Favourable Prognosis