title: Manganese superoxide dismutase (MnSOD) is a malignant astrocytoma specific biomarker and associated with adverse prognosis in p53 expressing glioblastoma.
abstract: BACKGROUND
  Manganese super oxide dismutase (MnSOD) has been previously identified as one of the top regulated genes associated with poor survival in glioblastoma (GBM) patients. In the current study we have evaluated the protein expression of MnSOD across various grades of astrocytoma, studied its influence on survival of GBM patients and following recurrence.
  
  
  METHODS
  The protein expression of MnSOD was analyzed on tumor tissue sections by immunohistochemistry on 30 diffuse astrocytomas (DA), 50 anaplastic astrocytomas (AA), 30 paired (primary and recurrent) GBM samples and 30 non-tumor brain tissues. The protein expression among the different grades of diffusely infiltrating astrocytoma (DIA) was evaluated by Kruskal-Wallis one-way ANOVA followed by post hoc test. Wilcoxon matched pair test was employed to assess MnSOD protein expression across 30 paired GBM samples (primary and recurrent). The prognostic impact of MnSOD protein expression individually and following stratification with p53 expression was evaluated in a cohort of 123 GBM patients. Both over-all survival (OS) and progression free survival (PFS) analysis were performed by employing Cox regression analysis and Kaplan-Meier survival analysis on GBM patients.
  
  
  RESULTS
  A significantly increased protein expression of MnSOD was observed among malignant astrocytomas (GBM and AA) in comparison with either DA or non-tumor brain tissues (p<0.05). Among the GBM cases it was noted that the IDH1 immunopositive tumors (R132H mutant protein; n=17) had a low MnSOD expression as opposed to IDH1 immunonegative tumors (n=106), which had high expression of MnSOD (p=0.0307). Further, a statistically significant increase (p=0.010) in extent of MnSOD protein expression was also noted in GBM tumors following recurrence. Protein expression of MnSOD was associated with both poor OS (HR: 1.021; p=0.011) and early PFS (HR: 1.022; p=0.006) on univariate analysis. Multivariate Cox regression analysis as well as Kaplan-Meier survival analysis demonstrated similar poor prognostic association. Stratification of GBM cases based on p53 expression status revealed a strong association of MnSOD with OS (HR: 1.042; p=0.002) and PFS (HR: 1.044; p=0.001) in p53 positive tumor tissue samples. Similar findings were noted on multivariate Cox regression analysis and K-M survival analysis, while no such association was noted in tumor tissues staining negative for p53 expression.
  
  
  CONCLUSIONS
  Our study shows an increased expression of MnSOD in anaplastic astrocytoma and GBM compared to low grade astrocytoma and control brain. An increase in MnSOD expression following GBM tumor recurrence strengthens its putative role in tumor aggressiveness. Further, MnSOD emerges as a poor prognostic biomarker in p53 expressing GBMs, rendering this molecule as a potential therapeutic target in such patients.
authors.affiliation: Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bangalore, India.
authors.forename: Shivayogi D
authors.initials: SD
authors.lastname: Shwetha
authors.affiliation: Department of Clinical Neurosciences, National Institute of Mental Health and Neurosciences, Bangalore, India.
authors.forename: Arun H
authors.initials: AH
authors.lastname: Shastry
authors.affiliation: Department of Neurosurgery, National Institute of Mental Health and Neurosciences, Bangalore, India. Electronic address: arivazhagan.a@gmail.com.
authors.forename: Arimappamagan
authors.initials: A
authors.lastname: Arivazhagan
authors.affiliation: Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bangalore, India; Department of Clinical Neurosciences, National Institute of Mental Health and Neurosciences, Bangalore, India.
authors.forename: Vani
authors.initials: V
authors.lastname: Santosh
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001254:Astrocytoma / Q000175:diagnosis / Q000378:metabolism*; D001932:Brain Neoplasms / Q000175:diagnosis / Q000473:pathology; D005260:Female; D016158:Genes, p53 / Q000235:genetics*; D005909:Glioblastoma / Q000175:diagnosis / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D013482:Superoxide Dismutase / Q000378:metabolism*; D055815:Young Adult; D000099156:Superoxide Dismutase 2
chemical_list: D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2
keywords: Glioblastoma; MnSOD; Prognosis; Recurrent GBM; p53