PARP1 expression and its correlation with survival is tumour molecular subtype dependent in glioblastoma

Oncotarget. 2017 Jul 11;8(28):46348-46362. doi: 10.18632/oncotarget.18013.

Abstract

Overexpression of PARP1 exists in various cancers, including glioblastoma (GBM). Although PARP1 inhibition is a promising therapeutic target, no comprehensive study has addressed PARP1's expression characteristics and prognostic role regarding molecular heterogeneity in astrocytomas including GBM. Our aim was to evaluate PARP1's associations with survival, WHO grade, lineage specific markers, and GBM transcriptomic subtypes. We collected genomic and clinical data from the latest glioma datasets of The Cancer Genome Atlas and performed PARP1, ATRX, IDH1, and p53 immunohistochemistry on GBM tissue samples. We demonstrated that PARP1 gain and increased mRNA expression are characteristics of high-grade astrocytomas, particularly of Proneural and Classical GBM subtypes. Additionally, higher PARP1 levels exhibited an inverse correlation with patient survival (p<0.005) in the Classical subgroup. ATRX (p=0.006), and TP53 (p=0.015) mutations were associated with increased PARP1 expression and PARP1 protein level correlated with ATRX loss and p53 overexpression. Furthermore, higher PARP1 expression together with wildtype TP53 indicated shorter survival (p=0.039). Therefore, due to subtype specificity, PARP1 expression level and TP53 mutation status are reliable marker candidates to distinguish Proneural and Classical subtypes, with prognostic and therapeutic implications in GBM.

Keywords: PARP1; glioblastoma; glioma; p53.

MeSH terms

  • Adult
  • Aged
  • Biomarkers, Tumor
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / mortality*
  • Brain Neoplasms / pathology
  • Female
  • Gene Dosage
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Glioblastoma / genetics*
  • Glioblastoma / mortality*
  • Glioblastoma / pathology
  • Humans
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Mutation
  • Neoplasm Grading
  • Poly (ADP-Ribose) Polymerase-1 / genetics*
  • Prognosis
  • Protein Binding
  • Signal Transduction
  • Tumor Suppressor Protein p53 / metabolism
  • X-linked Nuclear Protein / metabolism
  • Young Adult

Substances

  • Biomarkers, Tumor
  • Tumor Suppressor Protein p53
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • X-linked Nuclear Protein