Increased expression of thymidylate synthetase (TS), ubiquitin specific protease 10 (USP10) and survivin is associated with poor survival in glioblastoma multiforme (GBM).
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 <or= 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 <or= 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 <or= 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.
Grunda
Jessica M
JM
Departments of Pharmacology and Toxicology, Division of Clinical Pharmacology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
Nabors
L Burton
LB
Palmer
Cheryl A
CA
Chhieng
David C
DC
Steg
Adam
A
Mikkelsen
Tom
T
Diasio
Robert B
RB
Zhang
Kui
K
Allison
David
D
Grizzle
William E
WE
Wang
Wenquan
W
Gillespie
G Yancey
GY
Johnson
Martin R
MR
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism* / Q000401:mortality; D002648:Child; D018572:Disease-Free Survival; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism* / Q000401:mortality; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D012313:RNA / Q000032:analysis; D012189:Retrospective Studies; D018709:Statistics, Nonparametric; D000077022:Survivin; D013940:Thymidylate Synthase / Q000235:genetics / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase
C107489:BIRC5 protein, human; D014408:Biomarkers, Tumor; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; C431363:USP10 protein, human; D012313:RNA; D013940:Thymidylate Synthase; D010450:Endopeptidases; D043222:Ubiquitin Thiolesterase