Laboratory Investigation

Journal of Neuro-Oncology

, Volume 80, Issue 3, pp 261-274

First online:

Increased Expression of Thymidylate Synthetase (TS), Ubiquitin Specific Protease 10 (USP10) and Survivin is Associated with Poor Survival in Glioblastoma Multiforme (GBM)

  • Jessica M. GrundaAffiliated withDepartments of Pharmacology and Toxicology, Division of Clinical Pharmacology, University of Alabama at Birmingham
  • , L. Burton NaborsAffiliated withDepartment of Neurology, Division of Neuro-oncology, University of Alabama at Birmingham
  • , Cheryl A. PalmerAffiliated withDepartment of Pathology, Division of Neuropathology, University of Alabama at Birmingham
  • , David C. ChhiengAffiliated withDepartment of Pathology, University of Alabama at Birmingham
  • , Adam StegAffiliated withDepartments of Pharmacology and Toxicology, Division of Clinical Pharmacology, University of Alabama at Birmingham
  • , Tom MikkelsenAffiliated withDepartment of Neurosurgery, Henry Ford Hospital, Brain Tumor Center
  • , Robert B. DiasioAffiliated withDepartments of Pharmacology and Toxicology, Division of Clinical Pharmacology, University of Alabama at Birmingham
  • , Kui ZhangAffiliated withDepartment of Biostatistics, University of Alabama at Birmingham
  • , David AllisonAffiliated withDepartment of Biostatistics, University of Alabama at Birmingham
    • , William E. GrizzleAffiliated withDepartment of Pathology, University of Alabama at Birmingham
    • , Wenquan WangAffiliated withDepartment of Biostatistics, Biostatistics and Bioinformatics Unit, University of Alabama at Birmingham
    • , G. Yancey GillespieAffiliated withDepartment of Surgery, Division of Neurosurgery, University of Alabama at Birmingham
    • , Martin R. JohnsonAffiliated withDepartments of Pharmacology and Toxicology, Division of Clinical Pharmacology, University of Alabama at BirminghamDepartment of Clinical Pharmacology, University of Alabama at Birmingham Email author 

Rent the article at a discount

Rent now

* Final gross prices may vary according to local VAT.

Get Access

Abstract

Background

The limited success of empirically designed treatment paradigms for patients diagnosed with glioblastoma multiforme (GBM) emphasizes the need for rationally designed treatment strategies based on the molecular profile of tumor samples and their correlation to clinical parameters.

Methods

In the current study, we utilize a novel real-time quantitative low density array (RTQ-LDA) to identify differentially expressed genes in de novo GBM tissues obtained from patients with distinctly different clinical outcomes. Total RNA was isolated from a cohort of 21 GBM specimens obtained from patients with either good (long-term survival (LTS) >36 months post surgery, n = 8) or poor (died of the disease (DOD) <24 months post surgery, n = 13) prognosis. Non-neoplastic brain tissue (n = 5) was obtained from patients who underwent surgery for refractory epilepsy. Demographic data was assessed for correlation with survival using Cox proportional hazards models. Sufficient RNA was available to use RTQ-LDA to quantify the expression of 93 independent genes in 5␣LTS, 4 DOD, and 5 non-neoplastic brain samples. The eight differentially expressed genes identified by RTQ-LDA in LTS versus DOD (P ≤ 0.050) were subsequently quantified in all 21 GBM samples by real-time quantitative PCR (RTQ).

Results

A correlation between younger patients and good prognosis was demonstrated (P ≤ 0.05). The combination of RTQ-LDA and RTQ identified thymidylate synthetase (TS), ubiquitin specific protease 10 (USP10), and survivin as significantly over-expressed (P ≤ 0.050) in DOD compared to LTS patients. Ribonucleotide reductase subunit M2 (RRM2) was identified as tumor-specific, but not associated with survival.

Conclusions

Taken collectively, TS, USP10, survivin and RRM2 may be useful as prognostic indicators and/or in the development of rationally designed treatment protocols.

Keywords

Glioblastoma multiforme Glioma Low density array Real-time quantitative PCR Ribonucleotide reductase subunit M2 Survival Survivin Thymidylate synthetase Ubiquitin specific protease 10