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

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.

Download full-text


Available from: Ed C Schwalbe, Sep 27, 2015
23 Reads
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Tumors of brain tissue and meninges create a heterogeneous group with various biological behavior, therapy management and differing prognosis. Some of these do not require treatment, some can be cured by surgery and some are rapidly fatal despite treatment. Despite huge progress in tumor research, innovations in diagnostic tools and therapy, prognosis remains, in case of malignant tumor types, very serious. There has been an increased understanding of molecular abnormalities occurring in primary brain tumors. Genome-wide analyses of tumors have improved the knowledge in tumor biology. The aim of the research is to explain the oncogenesis features thus leading to the use of new therapeutic modalities in order to prolong survival rate of patients and at the same time providing satisfactory life quality. This article offers a short review of the basic genetic alterations present with some histological types of brain tumors.
    General Physiology and Biophysics 06/2014; 33(3). DOI:10.4149/gpb_2014007 · 1.17 Impact Factor
  • Source
    • "On the other hand, neuropathologists have already gone through these long and controversial discussions and disagreements 20 years ago with regard to the classification of malignant gliomas or medulloblastomas. As a result, the neuropathology community has now attained major achievements in specifying useful molecular diagnostic approaches and targeted therapies in these brain tumors [33, 34, 38, 81, 83, 87]. It seems that we are 20 years behind, when it comes to LEATs and associated epilepsies, and urgently need to shift our attention toward developing and implementing a new, clinically applicable consensus terminology for the neuropathological diagnosis of LEAT. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Every fourth patient submitted to epilepsy surgery suffers from a brain tumor. Microscopically, these neoplasms present with a wide-ranging spectrum of glial or glio-neuronal tumor subtypes. Gangliogliomas (GG) and dysembryoplastic neuroepithelial tumors (DNTs) are the most frequently recognized entities accounting for 65 % of 1,551 tumors collected at the European Epilepsy Brain Bank (n = 5,842 epilepsy surgery samples). These tumors often present with early seizure onset at a mean age of 16.5 years, with 77 % of neoplasms affecting the temporal lobe. Relapse and malignant progression are rare events in this particular group of brain tumors. Surgical resection should be regarded, therefore, also as important treatment strategy to prevent epilepsy progression as well as seizure- and medication-related comorbidities. The characteristic clinical presentation and broad histopathological spectrum of these highly epileptogenic brain tumors will herein be classified as "long-term epilepsy associated tumors-LEATs". LEATs differ from most other brain tumors by early onset of spontaneous seizures, and conceptually are regarded as developmental tumors to explain their pleomorphic microscopic appearance and frequent association with Focal Cortical Dysplasia Type IIIb. However, the broad neuropathologic spectrum and lack of reliable histopathological signatures make these tumors difficult to classify using the WHO system of brain tumors. As another consequence from poor agreement in published LEAT series, molecular diagnostic data remain ambiguous. Availability of surgical tissue specimens from patients which have been well characterized during their presurgical evaluation should open the possibility to systematically address the origin and epileptogenicity of LEATs, and will be further discussed herein. As a conclusion, the authors propose a novel A-B-C terminology of epileptogenic brain tumors ("epileptomas") which hopefully promote the discussion between neuropathologists, neurooncologists and epileptologists. It must be our future mission to achieve international consensus for the clinico-pathological classification of LEATs that would also involve World Health Organization (WHO) and the International League against Epilepsy (ILAE).
    Acta Neuropathologica 05/2014; 128(1). DOI:10.1007/s00401-014-1288-9 · 10.76 Impact Factor
  • Source
    • "RNA was extracted and retro-transcribed from fresh primary tumour and subcutaneous metastases (neck and scalp). cDNA was analysed on a custom microfluid card with a panel of genes specific for MBL molecular subgroups [17,18]. Over-expression of c-MYC, NRP3, NRL, GABRA5, IMPG2, MAB21L2 and OTX2 was suggestive of a molecular Group 3 for all samples analysed (Figure 2A). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Extraneural metastases (ENM) rarely occur in medulloblastoma (MBL) patients and only few cases of subcutaneous localizations have been described. ENM indicate an aggressive disease associated with a worse prognosis. The characterization of metastatic tumours might be useful to understand their pathogenesis and to identify the most appropriate therapeutic strategies. We present the case of a child with Large Cell Anaplastic (LC/A) MBL, who developed multiple subcutaneous metastases in the scalp area after a ventriculo-peritoneal shunting procedure. The disease rapidly progressed and the child died despite chemotherapy and primary tumour surgical debulking.We molecularly classified the tumour as a group 3 MBL; in addition, we derived stem-like cells (SLC) from a metastatic lesion. Primary tumour, metastases and SLC were further analysed, particularly focusing on features linked to the cutaneous dissemination. Indeed, molecules involved in angiogenesis, cell invasion and epidermal growth factor signalling resulted highly expressed. The present report describes a very rare case of subcutaneous metastatic MBL. The tumour, metastases and SLC have been clinically, pathologically and molecularly characterized. Our case is an example of multidisciplinary approach aiming to characterize MBL aggressive behaviour.
    BMC Cancer 04/2014; 14(1):262. DOI:10.1186/1471-2407-14-262 · 3.36 Impact Factor
Show more