Screening recurrent glioblastoma-related genes and analyzing their gene expressions in association with clinicopathological parameters and prognosis

Yi LIN; Ce WANG; Xun KANG; Zhuang KANG; Feng CHEN; Bo JIANG; Wenbin LI

doi:10.19401/j.cnki.1007-3639.2022.01.002

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Screening recurrent glioblastoma-related genes and analyzing their gene expressions in association with clinicopathological parameters and prognosis

Article | 更新时间：2025-12-31

- Screening recurrent glioblastoma-related genes and analyzing their gene expressions in association with clinicopathological parameters and prognosis
- China Oncology Vol. 32, Issue 1, Pages: 13-23(2022)
- 作者机构：
  
  首都医科大学附属北京天坛医院肿瘤综合治疗中心,北京 100070
- 作者简介：
- 基金信息：
- DOI：10.19401/j.cnki.1007-3639.2022.01.002
  CLC： R739.41
- Received：05 July 2021，
  
  Revised：2021-12-09，
  
  Published：30 January 2022
- 稿件说明：
移动端阅览
Yi LIN, Ce WANG, Xun KANG, et al. Screening recurrent glioblastoma-related genes and analyzing their gene expressions in association with clinicopathological parameters and prognosis[J]. China Oncology, 2022, 32(1): 13-23.
DOI：

Yi LIN, Ce WANG, Xun KANG, et al. Screening recurrent glioblastoma-related genes and analyzing their gene expressions in association with clinicopathological parameters and prognosis[J]. China Oncology, 2022, 32(1): 13-23. DOI： 10.19401/j.cnki.1007-3639.2022.01.002.

摘要

背景与目的：

脑胶质瘤是常见的中枢神经系统原发性恶性脑肿瘤之一

胶质母细胞瘤恶性程度高、侵袭性强、容易复发

复发后患者的预后极差。筛选胶质母细胞瘤复发相关的基因

并分析其在胶质瘤中的表达、临床病理学参数和预后的关系。

方法：

通过对GEO数据库中胶质母细胞瘤相关数据集进行挖掘

筛选包含胶质母细胞瘤原发和复发病例的相关数据集

并分析胶质母细胞瘤原发病例和复发病例样本间的差异表达基因（differentially expressed gene

DEG）。对DEG进行基因本体功能和信号富集分析

构架蛋白质相互作用（protein-protein interaction

PPI）网络

筛选Hub基因。通过PPI网络和Venn图筛选关键基因

而后研究使用基因表达谱数据动态分析（Gene Expression Profiling Interactive Analysis

GEPIA）和中国脑胶质瘤基因组图谱（Chinese Glioma Genome Atlas

CGGA）数据库进行关键基因的生存分析和表达分析

分析其表达与胶质瘤临床病理学参数的关系。

结果：

GSE62153数据集筛选到40个DEG

上调基因34个

下调基因6个。GSE58399数据集筛选到19个DEG

上调基因16个

下调基因3个。GO功能分析结果提示GSE62153的DEG主要参与中枢神经系统发育、髓鞘、肌动蛋白结合及中枢神经系统髓鞘形成等11个生理过程。而GSE58399的DEG主要参与上皮细胞迁移的正调控。京都基因和基因组百科全书（Kyoto Encyclopedia of Genes and Genomes

KEGG）通路富集分析结果显示

GSE62153和GSE58399的DEG存在共同富集

#x02014;组氨酸代谢。通过STRING数据库

将20个蛋白分子构建成为核心PPI

Hub基因共筛选出10个

分别为

MOBP

、

OPALIN

、

ERMN

、

PLP

1、

MOG

、

CLDN

11、

ASPA

、

TMEM

125、

KLK

6和

NKX

6-2基因。胶质母细胞瘤复发关键基因筛选结果显示

共有3个基因：

ERMN

、

MOG

和

MOBP

基因。基于癌症基因组图谱（The Cancer Genome Atlas

TCGA）和CGGA数据库胶质瘤数据分析

ERMN

、

MOG

和

MOBP

基因高表达者预后均优于低表达组

ERMN

、

MOG

和

MOBP

基因在胶质母细胞瘤组织内表达水平低于对照组织（

0.001）。

ERMN

、

MOG

和

MOBP

基因在不同世界卫生组织（World Health Organization

WHO）分级（WHO

#x02161;、

#x02162;和

#x02163;级）组织内表达差异有统计学意义（

0.001）

且随着胶质母细胞瘤的级别升高

ERMN

、

MOG

和

MOBP

基因的表达逐渐降低。

ERMN

、

MOG

和

MOBP

基因表达与WHO分级、异柠檬酸脱氢酶（isocitrate dehydrogenase

IDH）状态及临床病理学参数相关（

0.001）。而

MOBP

基因表达与患者年龄（

0.001）及MGMT甲基化状态（

=0.022）相关。

结论：

ERMN

、

MOG

和

MOBP

基因可能发挥抑癌基因作用参与胶质瘤复发过程

组氨酸代谢途径可能与甲氨蝶呤治疗敏感性相关。

Abstract

Background and purpose:

Glioma is the most common and malignant primary brain tumor in the central nervous system (CNS). Glioblastoma is highly malignant and aggressive

and the prognosis of patients with recurrent glioblastoma is very poor. This study aimed to screen the genes related to the recurrent glioblastoma

and analyze the relationship between their expressions

clinicopathological parameters and prognosis in glioma.

Methods:

By mining the relevant datasets of the primary and recurrent cases of glioblastoma in the GEO database

the differentially expressed gene (DEG) in the samples of primary and recurrent glioblastomas were screened and analyzed. All DEGs analyses were carried out in ontology function and pathway enrichment. Protein-protein interaction (PPI) network was constructed and used for screening Hub gene. Key genes were intersected by PPI network and Venn diagram

and the Gene Expression Profiling Interactive Analysis (GEPIA) and Chinese Glioma Genome Atlas (CGGA) database were analyzed for association of key gene expressions and survival status. Key genes were furtherly analyzed to determine the relationship between their expressions and clinicopathological parameters of glioma.

Results:

There were 40 DEG screened in the dataset GSE62153

including 34 up-regulated genes and 6 down-regulated genes. There were 19 DEG screened in the dataset GSE58399

including 16 up-regulated genes and 3 down-regulated genes. Go functional analyses showed that the DEG of GSE62153 were mainly involved in 11 physiological processes

such as central nervous system development

myelin sheath

actin binding

central nervous system myelination. The DEG of GSE58399 were mainly enriched in the positive regulation of epithelial cell migration. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment showed tha

t the datasets GSE62153 and GSE58399 were both enriched in histidine metabolism. By using the STRING database

the core of PPI network was constructed with 20 protein molecules. A total of 10 hub genes were screened

including

MOBP

OPALIN

ERMN

PLP

MOG

CLDN

ASPA

TMEM

125

KLK

6 and

NKX

6-2 gene. The key genes for recurrent glioblastoma were

ERMN

MOG

and

MOBP

gene. Based on analyses using The Cancer Genome Atlas (TCGA) and CGGA databases

the prognosis of patients with high expressions of

ERMN

MOG

and

MOBP

was favorable compared with the low expression group. The expression levels of key genes in glioblastoma were lower compared with the control tissues (

0.001). There were significant differences in the expressions of

ERMN

MOG

and

MOBP

gene among different World Health Organization (WHO) grades (WHO

#x02161;

#x02162; and

#x02163;) (

0.001). As the grade of glioblastoma increased

the expressions of

ERMN

MOG

and

MOBP

were decreased gradually. The expressions of

ERMN

MOG

and

MOBP

gene were correlated with WHO classification

isocitrate dehydrogenase (IDH) status and clinicopathological characteristics (

0.001). The expression of

MOBP

gene was correlated with age (

0.001) and MGMT methylation status (

=0.022).

Conclusion:

ERMN

MOG

and

MOBP

gene may function as tumor suppressor genes and participate in the recurrence of glioblastoma. The histidine metabolism pathway may be related to the sensit

ivity of methotrexate treatment.

关键词

Keywords

references

OSTROM Q T , PATIL N , CIOFFI G , et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2013-2017 [J ] . Neuro Oncol , 2020 , 22 ( 12 suppl 2 ): iv1 - iv96 . DOI: 10.1093/neuonc/noaa200 http://doi.org/10.1093/neuonc/noaa200 https://academic.oup.com/neuro-oncology/article/22/Supplement_1/iv1/5943281 https://academic.oup.com/neuro-oncology/article/22/Supplement_1/iv1/5943281

MEYER M A . Malignant gliomas in adults [J ] . N Engl J Med , 2008 , 359 ( 17 ): 1850 .

GRUBER M L , BUSTER W P . Temozolomide in combination with irinotecan for treatment of recurrent malignant glioma [J ] . Am J Clin Oncol , 2004 , 27 ( 1 ): 33 - 38 . DOI: 10.1097/01.coc.0000045852.88461.80 http://doi.org/10.1097/01.coc.0000045852.88461.80 https://journals.lww.com/00000421-200402000-00007 https://journals.lww.com/00000421-200402000-00007

BAO Z S , CHEN H M , YANG M Y , et al. RNA-seq of 272 gliomas revealed a novel, recurrent PTPRZ1-MET fusion transcript in secondary glioblastomas [J ] . Genome Res , 2014 , 24 ( 11 ): 1765 - 1773 . DOI: 10.1101/gr.165126.113 http://doi.org/10.1101/gr.165126.113 http://genome.cshlp.org/lookup/doi/10.1101/gr.165126.113 http://genome.cshlp.org/lookup/doi/10.1101/gr.165126.113

ZHAO Z , MENG F , WANG W , et al. Comprehensive RNA-seq transcriptomic profiling in the malignant progression of gliomas [J ] . Sci Data , 2017 , 4 : 170024 . DOI: 10.1038/sdata.2017.24 http://doi.org/10.1038/sdata.2017.24 https://doi.org/10.1038/sdata.2017.24 https://doi.org/10.1038/sdata.2017.24

NIEDER C , GROSU A L , MOLLS M . A comparison of treatment results for recurrent malignant gliomas [J ] . Cancer Treat Rev , 2000 , 26 ( 6 ): 397 - 409 . DOI: 10.1053/ctrv.2000.0191 http://doi.org/10.1053/ctrv.2000.0191 https://linkinghub.elsevier.com/retrieve/pii/S0305737200901919 https://linkinghub.elsevier.com/retrieve/pii/S0305737200901919

STUPP R , HEGI M E , MASON W P , et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase Ⅲ study: 5-year analysis of the EORTC-NCIC trial [J ] . Lancet Oncol , 2009 , 10 ( 5 ): 459 - 466 . DOI: 10.1016/S1470-2045(09)70025-7 http://doi.org/10.1016/S1470-2045(09)70025-7 https://linkinghub.elsevier.com/retrieve/pii/S1470204509700257 https://linkinghub.elsevier.com/retrieve/pii/S1470204509700257

AZOULAY M , SANTOS F , SHENOUDA G , et al. Benefit of re-operation and salvage therapies for recurrent glioblastoma multiforme: results from a single institution [J ] . J Neurooncol , 2017 , 132 ( 3 ): 419 - 426 . DOI: 10.1007/s11060-017-2383-2 http://doi.org/10.1007/s11060-017-2383-2 http://link.springer.com/10.1007/s11060-017-2383-2 http://link.springer.com/10.1007/s11060-017-2383-2

FRIEDMAN H S , PRADOS M D , WEN P Y , et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma [J ] . J Clin Oncol , 2009 , 27 ( 28 ): 4733 - 4740 . DOI: 10.1200/JCO.2008.19.8721 http://doi.org/10.1200/JCO.2008.19.8721 http://ascopubs.org/doi/10.1200/JCO.2008.19.8721 http://ascopubs.org/doi/10.1200/JCO.2008.19.8721

KONG D S , LEE J I , PARK K , et al. Efficacy of stereotactic radiosurgery as a salvage treatment for recurrent malignant gliomas [J ] . Cancer , 2008 , 112 ( 9 ): 2046 - 2051 . DOI: 10.1002/(ISSN)1097-0142 http://doi.org/10.1002/(ISSN)1097-0142 http://doi.wiley.com/10.1002/%28ISSN%291097-0142 http://doi.wiley.com/10.1002/%28ISSN%291097-0142

SCHNELL O , THORSTEINSDOTTIR J , FLEISCHMANN D F , et al. Re-irradiation strategies in combination with bevacizumab for recurrent malignant glioma [J ] . J Neurooncol , 2016 , 130 ( 3 ): 591 - 599 . DOI: 10.1007/s11060-016-2267-x http://doi.org/10.1007/s11060-016-2267-x http://link.springer.com/10.1007/s11060-016-2267-x http://link.springer.com/10.1007/s11060-016-2267-x

STUPP R , WONG E T , KANNER A A , et al. NovoTTF-100A versus physician's choice chemotherapy in recurrent glioblastoma: a randomised phase Ⅲ trial of a novel treatment modality [J ] . Eur J Cancer , 2012 , 48 ( 14 ): 2192 - 2202 . DOI: 10.1016/j.ejca.2012.04.011 http://doi.org/10.1016/j.ejca.2012.04.011 https://linkinghub.elsevier.com/retrieve/pii/S0959804912003528 https://linkinghub.elsevier.com/retrieve/pii/S0959804912003528

WANG J G , CAZZATO E , LADEWIG E , et al. Clonal evolution of glioblastoma under therapy [J ] . Nat Genet , 2016 , 48 ( 7 ): 768 - 776 . DOI: 10.1038/ng.3590 http://doi.org/10.1038/ng.3590 https://doi.org/10.1038/ng.3590 https://doi.org/10.1038/ng.3590

NANDEESH B N , NASKAR S , SHASHTRI A H , et al. Recurrent glioblastomas exhibit higher expression of biomarkers with stem-like properties [J ] . J Neurosci Rural Pract , 2018 , 9 ( 1 ): 86 - 91 . DOI: 10.4103/jnrp.jnrp_417_17 http://doi.org/10.4103/jnrp.jnrp_417_17 http://www.thieme-connect.de/DOI/DOI?10.4103/jnrp.jnrp_417_17 http://www.thieme-connect.de/DOI/DOI?10.4103/jnrp.jnrp_417_17

ZHANG R R , POINTER K B , KUO J S , et al. Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma [J ] . Neurosurgery , 2014 , 75 ( 6 ): N9 - 10 .

KIM J , LEE I H , CHO H J , et al. Spatiotemporal evolution of the primary glioblastoma genome [J ] . Cancer Cell , 2015 , 28 ( 3 ): 318 - 328 . DOI: 10.1016/j.ccell.2015.07.013 http://doi.org/10.1016/j.ccell.2015.07.013 https://linkinghub.elsevier.com/retrieve/pii/S1535610815002652 https://linkinghub.elsevier.com/retrieve/pii/S1535610815002652

SALEK ESFAHANI B , GHARESOURAN J , GHAFOURI-FARD S , et al. Down-regulation of ERMN expression in relapsing remitting multiple sclerosis [J ] . Metab Brain Dis , 2019 , 34 ( 5 ): 1261 - 1266 . DOI: 10.1007/s11011-019-00429-w http://doi.org/10.1007/s11011-019-00429-w https://doi.org/10.1007/s11011-019-00429-w https://doi.org/10.1007/s11011-019-00429-w

ZHANG L , XUE Z Y , LIU Q D , et al. Disrupted folate metabolism with anesthesia leads to myelination deficits mediated by epigenetic regulation of ERMN [J ] . EBioMedicine , 2019 , 43 : 473 - 486 . DOI: 10.1016/j.ebiom.2019.04.048 http://doi.org/10.1016/j.ebiom.2019.04.048 https://linkinghub.elsevier.com/retrieve/pii/S2352396419302877 https://linkinghub.elsevier.com/retrieve/pii/S2352396419302877

HOMS A , CODINA-SOLÀ M , RODRÍGUEZ-SANTIAGO B , et al. Genetic and epigenetic methylation defects and implication of the ERMN gene in autism spectrum disorders [J ] . Transl Psychiatry , 2016 , 6 ( 7 ): e855 . DOI: 10.1038/tp.2016.120 http://doi.org/10.1038/tp.2016.120 https://doi.org/10.1038/tp.2016.120 https://doi.org/10.1038/tp.2016.120

LINNINGTON C , WEBB M , WOODHAMS P L . A novel myelin-associated glycoprotein defined by a mouse monoclonal antibody [J ] . J Neuroimmunol , 1984 , 6 ( 6 ): 387 - 396 . DOI: 10.1016/0165-5728(84)90064-X http://doi.org/10.1016/0165-5728(84)90064-X https://linkinghub.elsevier.com/retrieve/pii/016557288490064X https://linkinghub.elsevier.com/retrieve/pii/016557288490064X

VOURC'H P , ANDRES C . Oligodendrocyte myelin glycoprotein (OMgp): evolution, structure and function [J ] . Brain Res Brain Res Rev , 2004 , 45 ( 2 ): 115 - 124 . DOI: 10.1016/j.brainresrev.2004.01.003 http://doi.org/10.1016/j.brainresrev.2004.01.003 https://linkinghub.elsevier.com/retrieve/pii/S0165017304000190 https://linkinghub.elsevier.com/retrieve/pii/S0165017304000190

KIM S M , WOODHALL M R , KIM J S , et al. Antibodies to MOG in adults with inflammatory demyelinating disease of the CNS [J ] . Neurol Neuroimmunol Neuroinflamm , 2015 , 2 ( 6 ): e163 . DOI: 10.1212/NXI.0000000000000163 http://doi.org/10.1212/NXI.0000000000000163 http://nn.neurology.org/lookup/doi/10.1212/NXI.0000000000000163 http://nn.neurology.org/lookup/doi/10.1212/NXI.0000000000000163

KANAREK N , KEYS H R , CANTOR J R , et al. Histidine catabolism is a major determinant of methotrexate sensitivity [J ] . Nature , 2018 , 559 ( 7715 ): 632 - 636 . DOI: 10.1038/s41586-018-0316-7 http://doi.org/10.1038/s41586-018-0316-7 https://doi.org/10.1038/s41586-018-0316-7 https://doi.org/10.1038/s41586-018-0316-7

ROMODANOV A P , ZOZULJA J A , SOSNOV J D , et al. Regional chemotherapy of malignant brain tumors with endolumbar methotrexate injection [J ] . Zentralbl Neurochir , 1976 , 37 ( 3 ): 161 - 167 .

NIERENBERG D , HARBAUGH R , MAURER L H , et al. Continuous intratumoral infusion of methotrexate for recurrent glioblastoma: a pilot study [J ] . Neurosurgery , 1991 , 28 ( 5 ): 752 - 761 . DOI: 10.1227/00006123-199105000-00023 http://doi.org/10.1227/00006123-199105000-00023 https://academic.oup.com/neurosurgery/article/28/5/752/2748857 https://academic.oup.com/neurosurgery/article/28/5/752/2748857

李丰展 , 盖立平 , 杨艳敏 , 等 . 胶质母细胞瘤术后甲氨蝶呤间质化疗同步放化疗临床观察 [J ] . 中国实用神经疾病杂志 , 2020 , 23 ( 17 ): 1544 - 1548 .

LI F Z , GAI L P , YANG Y M , et al. Clinical observation on simultaneous sadiotherapy and chemotherapy of methotrexate interstitial chemotherapy after glioblastoma [J ] . Chin J Pract Nerv Dis , 2020 , 23 ( 17 ): 1544 - 1548 .

白玥 , 钟晓松 , 李文斌 . 甲氨蝶呤通过RAS/MAPK/ERK/MYC/CD47信号通路抑制胶质母细胞瘤的生长 [J ] . 肿瘤代谢与营养电子杂志 , 2018 , 5 ( 2 ): 144 - 150 .

BAI Y , ZHONG X S , LI W B . Glioblastoma progression is inhibited by methotrexate via RAS/MEK/ERK/MYC/CD47 signaling pathways [J ] . Electron J Metab Nutr Cancer , 2018 , 5 ( 2 ): 144 - 150 .

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