title: Histopathological and molecular prognostic markers in medulloblastoma: c-myc, N-myc, TrkC, and anaplasia.
abstract: Several molecular and histopathological prognostic markers have been proposed for the therapeutic stratification of medulloblastoma patients. Amplification of the c-myc oncogene, elevated levels of c-myc mRNA, or tumor anaplasia have been associated with worse clinical outcomes. In contrast, high TrkC mRNA expression generally presages longer survival. The goal of this study was to evaluate the prognostic value of c-myc, N-myc and TrkC expression in medulloblastomas and compare them to histopathological classification. We used in situ hybridization to measure expression of these molecular markers. c-myc mRNA was detected in 18 of 59 (31%) cases, and was significantly associated with shorter patient survival times on both univariate and multivariate analyses (p = 0.04). The presence of c-myc mRNA was also significantly associated with tumor anaplasia. While survival rates were higher for patients with low N-myc or high TrkC expression, these differences were not statistically significant. The group of patients with either moderate or severely anaplastic tumors showed only a trend towards shorter survival (p = 0.11). However, severe anaplasia alone was significantly prognostic (p = 0.002). Given the prognostic import of c-myc, we investigated 2 potential mechanisms by which its expression might be regulated: Wnt signaling and Mxi-1 mutation. Nuclear translocation of beta-catenin, a marker of Wnt pathway activation, was more common in medulloblastomas with high c-myc than in tumors overall, but the difference was not statistically significant. No Mxi-1 mutations were detected in the 22 cases examined. The association we describe between c-myc expression, tumor anaplasia, and worse clinical outcomes provides further evidence for the importance of this oncogene in medulloblastoma pathobiology.
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. ceberha@jhmi.edu
authors.forename: Charles G
authors.initials: CG
authors.lastname: Eberhart
authors.forename: John
authors.initials: J
authors.lastname: Kratz
authors.forename: Yunyue
authors.initials: Y
authors.lastname: Wang
authors.forename: Krista
authors.initials: K
authors.lastname: Summers
authors.forename: Duncan
authors.initials: D
authors.lastname: Stearns
authors.forename: Kenneth
authors.initials: K
authors.lastname: Cohen
authors.forename: Chi V
authors.initials: CV
authors.lastname: Dang
authors.forename: Peter C
authors.initials: PC
authors.lastname: Burger
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000708:Anaplasia / Q000235:genetics / Q000473:pathology*; D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor / Q000235:genetics*; D002528:Cerebellar Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D007223:Infant; D008297:Male; D008527:Medulloblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011237:Predictive Value of Tests; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D020812:Receptor, trkC / Q000235:genetics*; D015996:Survival Rate; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins; D015854:Up-Regulation / Q000235:genetics; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D020812:Receptor, trkC; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; C495270:CTNNB1 protein, human; C079440:MXI1 protein, human; C489427:MYC protein, human