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Journal of Neuro-Oncology
https://doi.org/10.1007/s11060-018-2911-8
CLINICAL STUDY
G6PD as a predictive marker for glioma risk, prognosis
and chemosensitivity
Chin‑An Yang
1,2,3
· Hsi‑Yuan Huang
1
· Cheng‑Li Lin
4
· Jan‑Gowth Chang
1,3
Received: 28 March 2018 / Accepted: 19 May 2018
© Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract
Purpose Glucose-6-phosphate dehydrogenase (G6PD) is a key enzyme preventing cells from oxidative damage and has
been reported to have tumor-promoting roles. This study aims to comprehensively evaluate the predictive values of G6PD
on brain tumor risk, prognosis and chemo-resistance.
Methods A retrospective 13-year cohort study analyzing cancer risk using the Taiwan National Health Insurance Research
Database (4066 G6PD deficiency patients and 16,264 controls) was conducted. Furthermore, RNAseq and clinical data of
grade II–III glioma (LGG, n = 515) and glioblastoma (GBM, n = 155) were downloaded from The Cancer Genome Atlas
(TCGA) and analyzed. Bioinformatics methods were applied to build a glioma prognostication model and to predict response
to chemotherapy based on tumor G6PD-related gene expressions. The predicted results were validated in another glioma
cohort GSE 16011 and in KALS1 cell line.
Results G6PD-dificient patients were found to have an increased risk for cancers, especially for brain tumor (adjusted hazard
ratio (HR) 10.5, 95% CI 1.03–7.60). Furthermore, higher tumor G6PD expression was associated with poor patient survival
in LGG, but not in GBM. A prognostication model using expression levels of G6PD and 9 related genes (PSMA2, PSMB8,
SHFM1, GSS, GSTK1, MGST2, POLD3, MSH2, MSH6) could independently predict LGG patient survival. Boosted decision
tree analysis on 213 cancer cell line database revealed predictive values of G6PD expression on response to gemcitabine and
bortezomib. Knockdown of G6PD in KALS1 cell line enhanced its sensitivity to both chemotherapeutic agents.
Conclusions Our study suggests that G6PD could be a marker predicting glioma risk, prognosis and chemo-sensitivity.
Keywords Glucose-6-phosphate dehydrogenase · Glucose-6-phosphate dehydrogenase deficiency · Glioma ·
Prognostication · Chemosensitivity
Introduction
Glucose-6-phosphate dehydrogenase (G6PD) is the key
enzyme generating reduced nicotinamide adenine dinucleo-
tide phosphate (NADPH) and reduced glutathione (GSH),
combating cellular oxidative stress [1]. Brain is particularly
vulnerable to cell damage mediated by oxidative stress, such
as reactive oxygen species (ROS), because of its higher met-
abolic activity and lower regeneration capacity. The resulting
neuron loss has been implicated in the pathogenesis of brain
ischemia–reperfusion injury and neurodegenerative diseases
[2, 3]. Furthermore, accumulation of ROS-mediated geno-
toxicity has been reported in tumorigenesis and progression
of gliomas [4, 5]. G6PD deficient mice was found to be
prone to neurodegeneration [3]. However, whether G6PD
deficiency (G6PDD) predispose human in a lifespan to risk
of brain tumor remains unclear. Previous studies focused on
Electronic supplementary material The online version of this
article (https ://doi.org/10.1007/s1106 0-018-2911-8) contains
supplementary material, which is available to authorized users.
* Jan-Gowth Chang
d6781@mail.cmuh.org.tw
1
Department of Laboratory Medicine, China Medical
University Hospital, #2 Yude Road, Taichung 40447,
Taiwan, ROC
2
Division of General Pediatrics, China Medical University
Children’s Hospital, Taichung, Taiwan, ROC
3
College of Medicine, China Medical University, Taichung,
Taiwan, ROC
4
Management Office for Health Data, China Medical
University Hospital, Taichung, Taiwan, ROC
@Phil_Robichaud
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