Article

Rapid Diagnosis of Medulloblastoma Molecular Subgroups

Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
Clinical Cancer Research (Impact Factor: 8.19). 02/2011; 17(7):1883-94. DOI: 10.1158/1078-0432.CCR-10-2210
Source: PubMed

ABSTRACT 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.

1 Bookmark
 · 
180 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Over-expression of PDGF receptors (PDGFRs) has been previously implicated in high-risk medulloblastoma (MB) pathogenesis. However, the exact biological functions of PDGFRα and PDGFRβ signaling in MB biology remain poorly understood. Here, we report the subgroup specific expression of PDGFRα and PDGFRβ and their associated biological pathways in MB tumors. c-MYC, a downstream target of PDGFRβ but not PDGFRα, is involved in PDGFRβ signaling associated with cell proliferation, cell death, and invasion. Concurrent inhibition of PDGFRβ and c-MYC blocks MB cell proliferation and migration synergistically. Integrated analysis of miRNA and miRNA targets regulated by both PDGFRβ and c-MYC reveals that increased expression of JAG2, a target of miR-1280, is associated with high metastatic dissemination at diagnosis and a poor outcome in MB patients. Our study may resolve the controversy on the role of PDGFRs in MB and unveils JAG2 as a key downstream effector of a PDGFRβ-driven signaling cascade and a potential therapeutic target.
    Oncotarget 12/2014; · 6.63 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Endoscopic biopsy of brain tumors is an important part of the armamentarium of management of intra- and periventricular tumors that is generally considered an acceptable and, in some situations, a preferred method for tissue sampling. The diagnostic yield of the procedure has been variably reported. Technical aspects of the procedure should undoubtedly reflect on its success rate and accuracy. Such impact on diagnostic yield of endoscopic brain biopsy is infrequently discussed in the literature. A search of the medical literature was conducted for publications on endoscopic brain biopsy. These reports were analyzed regarding the various technical aspects. In the 43 publications analyzed, lenscopes were exclusively used in 22 reports and a tissue diagnosis was possible in 362 out of 387 endoscopic biopsies with a diagnostic yield of 93.54%. Only fiberscopes were used in 8 reports and a tissue diagnosis was possible in 100 out of 132 endoscopic biopsies with a diagnostic yield of 75.76%. The diagnostic yield in the mixed and unspecified groups was 88.95 and 88.04%, respectively. Very few details on the histopathological methods and tumor molecular genetics could be found. Endoscopic biopsy of brain tumors has a higher diagnostic yield when lenscopes are used. Neuronavigation seems to add to the diagnostic accuracy of the procedure. Studies detailing molecular genetic features of biopsied tumors are necessary in the future.
    Surgical Neurology International 01/2014; 5:159. DOI:10.4103/2152-7806.144597 · 1.18 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: As advances in the molecular and genetic profiling of pediatric medulloblastoma evolve, associations with prognosis and treatment are found (prognostic and predictive biomarkers) and research is directed at molecular therapies. Medulloblastoma typically affects young patients, where the implications of any treatment on the developing brain must be carefully considered. The aim of this article is to provide a clear comprehensible update on the role molecular profiling and subgroups in pediatric medulloblastoma as it is likely to contribute significantly toward prognostication. Knowledge of this classification is of particular interest because there are new molecular therapies targeting the Shh subgroup of medulloblastomas.
    Frontiers in Oncology 07/2014; 4:176. DOI:10.3389/fonc.2014.00176
    This article is viewable in ResearchGate's enriched format

Full-text

Download
86 Downloads
Available from
May 15, 2014