Wnt/Wingless pathway activation and chromosome 6 loss characterize a distinct molecular sub-group of medulloblastomas associated with a favorable prognosis.
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 favorable disease outcome. To explore the molecular pathogenesis of Wnt/Wg-active medulloblastomas, and to investigate any genetic basis for their observed clinical behavior, 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 beta-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 tumors coclustered 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 tumors, 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 tumors could not be distinguished on the basis of clinical or pathological disease features. Our data indicate that Wnt/Wg-active tumors 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 (1) the idiosyncratic clinical behavior of Wnt/Wg-active medulloblastomas, and (2) the development of beta-catenin status as an independent marker for therapeutic stratification in this disease.
Clifford
Steven C
SC
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK. s.c.clifford@ncl.ac.uk
Lusher
Meryl E
ME
Lindsey
Janet C
JC
Langdon
Jacqueline A
JA
Gilbertson
Richard J
RJ
Straughton
Debbie
D
Ellison
David W
DW
D000293:Adolescent; D002528:Cerebellar Neoplasms / Q000145:classification* / Q000175:diagnosis* / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D002896:Chromosomes, Human, Pair 6; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008527:Medulloblastoma / Q000145:classification* / Q000175:diagnosis* / Q000235:genetics; D011379:Prognosis; D015398:Signal Transduction; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
D051153:Wnt Proteins; D051176:beta Catenin