ePrints

Wnt/Wingless pathway activation and chromosome 6 loss characterize a distinct molecular sub-group of medulloblastomas associated with a favorable prognosis

Lookup NU author(s): Professor Steven CliffordORCiD, Dr Meryl Lusher, Dr Janet Lindsey, Dr Jackie Langdon, Dr Richard Gilbertson, Debbie Straughton, Professor David Ellison

Downloads

• Published version [.pdf]

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 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.

Publication metadata

Author(s): Clifford SC, Lusher ME, Lindsey JC, Langdon JA, Gilbertson RJ, Straughton D, Ellison DW

Publication type: Article

Publication status: Published

Journal: Cell Cycle

Year: 2006

Volume: 5

Issue: 22

Pages: 2666-2670

Date deposited: 24/11/2010

ISSN (print): 1538-4101

ISSN (electronic): 1551-4005

Publisher: Landes Bioscience

URL: http://www.landesbioscience.com/journals/cc/article/3446/

PubMed id: 17172831

Funding

Share