整合基因的拷贝数与表达信息识别胶质瘤风险通路区域内的生存标志物

doi:10.3969/j.issn.1004-616x.2017.01.005

摘要/Abstract

摘要：

目的：识别胶质瘤风险区域，并预测风险区域内与生存高度相关的基因。方法：从TCGA和GISTIC 2.0网站分别获取胶质瘤病人拷贝数变异数据和人类参考基因组数据。根据胶质瘤患者的基因拷贝数变异和mRNA表达谱，形成新的基因表达谱。将样本按是否发生拷贝数变异分为两组，将由t检验获得差异的基因注释到KEGG PATHWAY database的300个通路，运用Subpathway-GM方法，挖掘得到风险子通路。结合Kaplan-Meier方法和Log-rank检验，预测与胶质瘤生存高度相关的基因。结果：由t检验获得2 219个差异基因，通过Subpathway-GM方法挖掘出48个风险子通路。我们研究预测得到的14个胶质瘤生存相关的基因与排名前10的风险子通路的关系，发现MDH2、YWHAE、SHB2B、CACNG4和CACNA1G可作为胶质瘤的生存标志物。结论：整合胶质瘤患者的拷贝数变异信息和表达信息，有效利用通路的拓扑结构，对识别可能用于胶质瘤的诊断和治疗的生存标志物具有重要意义。

关键词: 胶质瘤, 拷贝数变异, Subpathway-GM方法, 信号通路, 标志物

Abstract:

OBJECTIVE: To identify the relationship among gene copy number and their expression with survival of glioma. METHODS: Based on the gene copy number variation data and mRNA expression information of 95 glioma patients,we organized a new expression profile. Samples were divided into two groups by the copy number variation and by using t test differential genes. The data were annotated into 300 pathways from KEGG pathway database. Applying with the Subpathway-GM method,we identified risky subpathways. Kaplan-Meier method and Log-rank test were used to predict genes which were highly related to the survival of glioma. RESULTS: 2 219 differential genes were obtained by using t test,as well as 48 risky subpathways by Subpathway-GM method. Studying the relathion between the 14 genes precticted by using survival method and the top 10 risky subpathways,we found that MDH2,YWHAE,SHB2B, CACNG4 and CACNA1G could be regard as survival markers of glioma. CONCLUSION: By combining glioma patients' copy number variation of gene,their expression information and the topological structure of the pathways,we identified some survival markers for the diagnosis and treatment of glioma.

Key words: glioma, copy number variation, Subpathway-GM method, subpathways, markers

中图分类号:

R318.04

潘奇, 李萌, 钱凤翠, 汤治东, 赵越, 王秋毓, 李春权. 整合基因的拷贝数与表达信息识别胶质瘤风险通路区域内的生存标志物[J]. 癌变·畸变·突变, 2017, 29(1): 23-30,36.

PAN Qi, LI Meng, QIAN Fengcui, TANG Zhidong, ZHAO Yue, WANG Qiuyu, LI Chunquan. Copy number of gene and their expression as survival markers for glioma[J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2017, 29(1): 23-30,36.

参考文献

[1] OMURO A,DEANGELIS L M. Glioblastoma and other malignant gliomas:a clinical review[J]. JAMA,2013,310(17):1842-1850.

[2] DEORAH S,LYNCH C F,SIBENALLER Z A,et al. Trends in brain cancer incidence and survival in the United States:surveillance,epidemiology,and end results program,1973 to 2001[J]. Neurosurg Focus,2006,20(4):E1.

[3] FURNARI F B,FENTON T,BACHOO R M,et al. Malignant astrocytic glioma:genetics,biology,and paths to treatment[J]. Genes Dev,2007,21(21):2683-2710.

[4] OHGAKI H,DESSEN P,JOURDE B,et al. Genetic pathways to glioblastoma:a population-based study[J]. Cancer Res,2004, 64(19):6892-6899.

[5] BEROUKHIM R,MERMEL C H,PORTER D,et al. The landscape of somatic copy-number alteration across human cancers[J]. Nature, 2010,463(7283):899-905.

[6] YOSHIHARA K,TAJIMA A,ADACHI S,et al. Germline copy number variations in BRCA1-associated ovarian cancer patients[J]. Genes Chrom Cancer,2011,50(3):167-177.

[7] LI C,HAN J,YAO Q,et al. Subpathway-GM:identification of metabolic subpathways via joint power of interesting genes and metabolites and their topologies within pathways[J]. Nucleic Acids Res,2013,41(9):e101.

[8] MERMEL C H,SCHUMACHER S E,HILL B,et al. GISTIC 2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers[J]. Genome Biol,2011,12(4):R41.

[9] LI C,LI X,MIAO Y,et al. Subpathway miner:a software package for flexible identification of pathways[J]. Nucleic Acids Res,2009,37(19):e131.

[10] PAN H C,JIANG Q,Y U Y,et al. Quercetin promotes cell apoptosis and inhibits the expression of MMP-9 and fibronectin via the AKT and ERK signalling pathways in human glioma cells[J]. Neurochem Int,2015,80:60-71.

[11] WANG G P,HAN X F. CD9 modulates proliferation of human glioblastoma cells via epidermal growth factor receptor signaling[J]. Mol Med Rep,2015,12(1):1381-1386.

[12] ZHAO L. Hirudin inhibits cell growth via ERK/MAPK signaling in human glioma[J]. Int J Clin Exp Med,2015,8(11):20983-20987.

[13] YANG N,WANG Y,HUI L,et al. Silencing SOX2 expression by RNA interference inhibits proliferation,invasion and metastasis,and induces apoptosis through MAP4K4/JNK signaling pathway in human laryngeal cancer TU212 cells[J]. J Histochem Cytochem,2015,63(9):721-733.

[14] HALATSCH M E,LOW S,MURSCH K,et al. Candidate genes for sensitivity and resistance of human glioblastoma multiforme cell lines to erlotinib. Laboratory investigation[J]. J Neurosurg, 2009,111(2):211-218.

[15] CHEUNG H C,BAGGERLY K A,TSAVACHIDIS S,et al. Global analysis of aberrant pre-mRNA splicing in glioblastoma using exon expression arrays[J]. BMC Genomics,2008,9:216.

[16] LIU X,CHONG Y,TU Y,et al. CRM1/XPO1 is associated with clinical outcome in glioma and represents a therapeutic target by perturbing multiple core pathways[J]. J Hematol Oncol,2016, 9(1):108.

[17] JIN Y,XIAO W,SONG T,et al. Expression and prognostic significance of p53 in glioma patients:A meta-analysis[J]. Neurochem Res,2016,41(7):1723-1731.

[18] CHOU T T,TROJANOWSKI J Q,LEE VM. Neurotrophin signal transduction in medulloblastoma[J]. J Neurosci Res, 1997, 49(5):522-527.

[19] WASHIYAMA K,MURAGAKI Y,RORKE L B,et al. Neurotrophin and neurotrophin receptor proteins in medullo-blastomas and other primitive neuroectodermal tumors of the pediatric central nervous system[J]. Am J Pathol,1996,148(3):929-940.

[20] LUKASHOVA-V ZANGEN I,KNEITZ S,MONORANU C M,et al. Ependymoma gene expression profiles associated with histological subtype,proliferation,and patient survival[J]. Acta Neuropathol,2007,113(3):325-337.

[21] CVEKL A,J R.,ZAVADIL J,BIRSHTEIN B K,et al. Analysis of transcripts from 17p13.3 in medulloblastoma suggests ROX/MNT as a potential tumour suppressor gene[J]. Eur J Cancer,2004, 40(16):2525-2532.

[22] CUPPENS T,TUYAERTS S,AMANT F. Potential therapeutic targets in uterine sarcomas[J]. Sarcoma,2015,2015:243298.

[23] KARLSSON J,VALIND A,GISSELSSON D. BCOR internal tandem duplication and YWHAE-NUTM2B/E fusion are mutually exclusive events in clear cell sarcoma of the kidney[J]. Genes Chrom Cancer,2016,55(2):120-123.

[24] JOCHMANOVA I,ZHUANG Z,PACAK K. Pheochro-mocytoma:Gasping for air[J]. Horm Cancer,2015, 6(5/6):191-205.

[25] CASCóN A,COMINO-MéNDEZ I,CURRáS-FREIXES M, et al. Whole-exome sequencing identifies MDH2 as a new familial paraganglioma gene[J]. J Natl Cancer Inst,2015. doi:10.1093/jnci/djv053.

[26] LIU Q,HARVEY C T,GENG H,et al. Malate dehydrogenase 2 confers docetaxel resistance via regulations of JNK signaling and oxidative metabolism[J]. Prostate,2013,73(10):1028-1037.

[27] LO Y W,LIN S T,CHANG S J,et al. Mitochondrial proteomics with siRNA knockdown to reveal ACAT1 and MDH2 in the development of doxorubicin-resistant uterine cancer[J]. J Cell Mol Med,2015,19(4):744-759.

[28] SCHULZ D M,BOLLNER C,THOMAS G,et al. Identification of differentially expressed proteins in triple-negative breast carcinomas using DIGE and mass spectrometry[J]. J Proteome Res,2009,8(7):3430-3438.

[29] KAUSHIK N K,KAUSHIK N,YOO K C,et al. Low doses of PEG-coated gold nanoparticles sensitize solid tumors to cold plasma by blocking the PI3K/AKT-driven signaling axis to suppress cellular transformation by inhibiting growth and EMT[J]. Biomaterials,2016,87:118-130.

[30] YAO C,LI P,SONG H,et al. CXCL12/CXCR4 axis upregulates twist to induce EMT in human glioblastoma[J]. Mol Neurobiol, 2016,53:3948.

[31] CHANG Y,LI L,ZHANG L,et al. Plexin-B1 indirectly affects glioma invasiveness and angiogenesis by regulating the RhoA/alphavbeta3 signaling pathway and SRPK1[J]. Tumour Biol,2016:11225-11236.

[32] NI W,FANG Y,TONG L,et al. Girdin regulates the migration and invasion of glioma cells via the PI3K-Akt signaling pathway[J]. Mol Med Rep,2015,12(4):5086-5092.

[33] MA Q,ZHANG Y,MENG R,et al. MAGI3 suppresses glioma cell proliferation via upregulation of PTEN expression[J]. Biomed Environ Sci,2015,28(7):502-509.

[34] DUZGUN Z,EROGLU Z,BIRAY A C. Role of mTOR in glioblastoma[J]. Gene,2016,575(2 Sup 1):187-190.