Article

Clinical utility of fluorescence in situ hybridization (FISH) in nonbrainstem glioblastomas of childhood

Department of Neuropathology, NN Burdenko Neurosurgical Institute, Moscow, Russia.
Modern Pathology (Impact Factor: 6.36). 10/2005; 18(9):1258-63. DOI: 10.1038/modpathol.3800415
Source: PubMed

ABSTRACT Astrocytic gliomas are the most common pediatric brain tumors; however, nonbrainstem glioblastomas are extremely rare compared with their adult counterparts. Little information is available on the clinical significance of various molecular markers in pediatric grade IV astrocytomas. The current study was focused on the molecular analysis and clinico-pathological correlations in a set of 44 tumor samples obtained from pediatric patients with nonbrainstem glioblastomas. Fluorescence in situ hybridization (FISH) with a set of 10 commercial chromosome probes (1p36, 1q25, centromere (CEP)7, EGFR, CEP9, 9p21/p16, CEP10, 10q23/PTEN, 19p13, and 19q13) was performed. Disclosed molecular abnormalities, in descending order of frequency, included polysomy 7 (72%), loss of 10q23 (61%), loss of 9p21 (52%), loss of 1p36 (41%), gain of 1q25 (25%), polysomy 9 (16%), EGFR amplification (9%), loss of 19q13 (5%), polysomy 19 (5%), and codeletion 1p36/19q13 (2%). The overall survival time was markedly shorter only for those patients whose lesions harbored deletion of 10q23/PTEN locus (log-rank test; P=0.00007). By multivariate analysis, only loss of 10q23 locus reached an independent level of prognostic value (hazard ratio=2.88; P=0.01). There were no significant differences in patient survival for other molecular abnormalities. In conclusion, a FISH analysis of 10q23 dosage should be recommended as an ancillary laboratory method that allows further clinical subdivision of pediatric glioblastomas.

Full-text

Available from: Andrey Korshunov, Mar 25, 2014
0 Followers
 · 
95 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Overexpressions of EGFR and HER2 are thought to be prognostic factors of cholangiocarcinoma (CCA). The SOX4 transcription factor is involved in the development and cell fate decision. Although up-regulation of SOX4 has been described in multiple human malignancies, the prognostic value of SOX4 and its relationship to EGFR/HER2 in CCA remain unclear. In the current study, we showed that SOX4 and EGFR were overexpressed in 17 (29.3%), and 13 (22.8%) of the 58 intrahepatic cholangiocarcinomas (IHCCs), as well as 28 (30.1%), and 33 (35.1%) of the 93 extrahepatic cholangiocarcinomas (EHCCs), respectively. Overexpression of HER2 was exclusively identified in EHCCs, with the rate being 4.4% (4/90). In all, amplification of EGFR was identified in 1.8% (1/52) of IHCC cases, and in 2% (3/82) of EHCC cases. By contrast, HER2 amplification was present only in 3.5% (3/94) of the EHCC cases. Notably, Kaplan-Meier survival analysis suggested that SOX4 expression is a significant prognostic factor for poor prognosis in IHCC patients. Importantly, our findings suggested significant association of SOX4 and EGFR expression both in IHCC (P=0.035) and EHCC (P=0.012). SOX4 may modulate expression of EGFR, and SOX4+ /EGFR+ defines a subset of CCA patients with poor prognosis. Finally, in vitro data indicated that SOX4 inhibits cellular migratory capacity and promotes epithelial-mesenchymal transition (EMT) process of CCA cells. Collectively, our results define an important role for SOX4 in CCA by orchestrating EMT and modulation on EGFR expression. SOX4 expression may serve as a prognostic marker for patients with IHCC.
    Biochemical and Biophysical Research Communications 09/2014; 452(3). DOI:10.1016/j.bbrc.2014.08.124 · 2.28 Impact Factor
  • Source
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pediatric glioblastoma (pedGBM) is amongst the most common malignant brain tumors of childhood and carries a dismal prognosis. In contrast to adult GBM, few molecular prognostic markers for the pediatric counterpart have been established. We, therefore, investigated the prognostic significance of genomic and epigenetic alterations through molecular analysis of 202 pedGBM (1-18 years) with comprehensive clinical annotation. Routinely prepared formalin-fixed paraffin-embedded tumor samples were assessed for genome-wide DNA methylation profiles, with known candidate genes screened for alterations via direct sequencing or FISH. Unexpectedly, a subset of histologically diagnosed GBM (n = 40, 20 %) displayed methylation profiles similar to those of either low-grade gliomas or pleomorphic xanthoastrocytomas (PXA). These tumors showed a markedly better prognosis, with molecularly PXA-like tumors frequently harboring BRAF V600E mutations and 9p21 (CDKN2A) homozygous deletion. The remaining 162 tumors with pedGBM molecular signatures comprised four subgroups: H3.3 G34-mutant (15 %), H3.3/H3.1 K27-mutant (43 %), IDH1-mutant (6 %), and H3/IDH wild-type (wt) GBM (36 %). These subgroups were associated with specific cytogenetic aberrations, MGMT methylation patterns and clinical outcomes. Analysis of follow-up data identified a set of biomarkers feasible for use in risk stratification: pedGBM with any oncogene amplification and/or K27M mutation (n = 124) represents a particularly unfavorable group, with 3-year overall survival (OS) of 5 %, whereas tumors without these markers (n = 38) define a more favorable group (3-year OS ~70 %).Combined with the lower grade-like lesions, almost 40 % of pedGBM cases had distinct molecular features associated with a more favorable outcome. This refined prognostication method for pedGBM using a molecular risk algorithm may allow for improved therapeutic choices and better planning of clinical trial stratification for this otherwise devastating disease.
    Acta Neuropathologica 03/2015; DOI:10.1007/s00401-015-1405-4 · 9.78 Impact Factor