Definition of Disease-Risk Stratification Groups in Childhood Medulloblastoma Using Combined Clinical, Pathologic, and Molecular Variables

Abstract

Purpose Medulloblastomas are heterogeneous and include relatively good-prognosis tumors characterized by Wnt pathway activation, as well as those that cannot be successfully treated with conventional therapy. Developing a practical therapeutic stratification that allows accurate identification of disease risk offers the potential to individualize adjuvant therapy and to minimize long-term adverse effects in a subgroup of survivors. Methods Using formalin-fixed paraffin-embedded (FFPE) tissue for immunohistochemistry, fluorescent in situ hybridization, and direct sequencing to identify tumors with a Wnt pathway signature and those harboring copy number abnormalities (CNAs) of potential prognostic significance (MYC/MYCN amplification, CNAs of chromosome 6 and 17), we evaluated clinical, pathologic, and molecular outcome indicators and stratification models in a cohort (n = 207) of patients with medulloblastoma 3 to 16 years of age from the International Society of Pediatric Oncology CNS9102 (PNET3) trial. Results Metastatic disease and large-cell/anaplastic (LC/A) phenotype were the clinicopathologic variables associated with poor progression-free survival (PFS). Nuclear immunoreactivity for β-catenin, CTNNB1 mutation, and monosomy 6 all identified a group of good-prognosis patients. MYC amplification was associated with poor outcome, but other CNAs were not. Low-risk medulloblastomas were defined as β-catenin nucleopositive tumors without metastasis at presentation, LC/A phenotype, or MYC amplification. High-risk medulloblastomas were defined as tumors with metastatic disease, LC/A phenotype, or MYC amplification. Low-risk, standard-risk, and high-risk categories of medulloblastoma had significantly (P < .0001) different outcomes. Conclusion Integrating assays of molecular biomarkers undertaken on routinely collected diagnostic FFPE tissue into stratification schemes for medulloblastoma alongside clinical and pathologic outcome indicators can refine current definition of disease risk and guide adjuvant therapy.

Targeting the Inhibitor of Apoptosis Proteins as a Novel Therapeutic Strategy in Medulloblastoma

“…The demonstration that a small-molecule SHH inhibitor was able to eradicate widespread metastatic disease in a multiply relapsed patient has generated a high level of enthusiasm for this approach (27). However, the potential efficacy of these compounds is mitigated by the fact that tumors with SHH and WNT pathway activation represent only a minority of cases, and these patients already have favorable prognoses with standard therapy (3)(4)(5). The approach we have shown of targeting the apoptotic pathway offers an alternative targeted strategy that may be applicable more broadly to more resistant medulloblastoma subsets, including those with poorer prognoses.…”

“…The approach we have shown of targeting the apoptotic pathway offers an alternative targeted strategy that may be applicable more broadly to more resistant medulloblastoma subsets, including those with poorer prognoses. A variety of techniques have been used to divide medulloblastoma into different genetic subgroups, and thus help with clinical stratification (3)(4)(5). While IAP expression has not specifically been reported in these analyses, all subgroups have been shown to have activation of antiapoptotic mechanisms (4).…”

Role of MYC in Medulloblastoma

“…Most frequent in children between the ages 0 and 9, this aggressive tumor can occur at any age (Louis et al 2007). Histopathological variants also exist and are associated with different outcomes (Rutkowski et al 2005;Ellison et al 2011b). Most recently, transcriptional profiling identified four major MB subgroups: two associated with pathogenic abnormalities in the Wingless (WNT) and Sonic Hedgehog (SHH) developmental signaling pathways (the WNT and SHH subgroups), and two that are less well molecularly characterized and referred to as group 3 and group 4 tumors.…”

Natural history of a medulloblastoma: 30 months of wait and see in a child with a cerebellar incidentaloma

“…The present tumour can be classified histologically as WNT pathway-activated MB. This MB subtype is associated with a favourable prognosis [5,15]. One could speculate that the tumour acquired a stepwise accumulation of genetic aberrations over time, which -after a relatively stable phase -resulted in accelerated growth.…”