Full Text:   <1673>

Summary:  <1253>

Suppl. Mater.: 

CLC number: 

On-line Access: 2021-08-20

Received: 2020-08-30

Revision Accepted: 2021-01-25

Crosschecked: 0000-00-00

Cited: 0

Clicked: 3052

Citations:  Bibtex RefMan EndNote GB/T7714


Jianguang QIU


-   Go to

Article info.
Open peer comments

Journal of Zhejiang University SCIENCE B 2021 Vol.22 No.8 P.664-681


Integrative analysis of prognostic long non-coding RNAs with copy number variation in bladder cancer

Author(s):  Wenwen ZHONG, Dejuan WANG, Bing YAO, Xiaoxia CHEN, Zhongyang WANG, Hu QU, Bo MA, Lei YE, Jianguang QIU

Affiliation(s):  Department of Urology, the Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510655, China; more

Corresponding email(s):   qiujg@mail.sysu.edu.cn

Key Words:  Bladder cancer, Copy number variation (CNV), Long non-coding RNA (lncRNA), Prognosis

Wenwen ZHONG, Dejuan WANG, Bing YAO, Xiaoxia CHEN, Zhongyang WANG, Hu QU, Bo MA, Lei YE, Jianguang QIU. Integrative analysis of prognostic long non-coding RNAs with copy number variation in bladder cancer[J]. Journal of Zhejiang University Science B, 2021, 22(8): 664-681.

@article{title="Integrative analysis of prognostic long non-coding RNAs with copy number variation in bladder cancer",
author="Wenwen ZHONG, Dejuan WANG, Bing YAO, Xiaoxia CHEN, Zhongyang WANG, Hu QU, Bo MA, Lei YE, Jianguang QIU",
journal="Journal of Zhejiang University Science B",
publisher="Zhejiang University Press & Springer",

%0 Journal Article
%T Integrative analysis of prognostic long non-coding RNAs with copy number variation in bladder cancer
%A Wenwen ZHONG
%A Dejuan WANG
%A Bing YAO
%A Xiaoxia CHEN
%A Zhongyang WANG
%A Hu QU
%A Bo MA
%A Lei YE
%A Jianguang QIU
%J Journal of Zhejiang University SCIENCE B
%V 22
%N 8
%P 664-681
%@ 1673-1581
%D 2021
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B2000494

T1 - Integrative analysis of prognostic long non-coding RNAs with copy number variation in bladder cancer
A1 - Wenwen ZHONG
A1 - Dejuan WANG
A1 - Bing YAO
A1 - Xiaoxia CHEN
A1 - Zhongyang WANG
A1 - Hu QU
A1 - Bo MA
A1 - Lei YE
A1 - Jianguang QIU
J0 - Journal of Zhejiang University Science B
VL - 22
IS - 8
SP - 664
EP - 681
%@ 1673-1581
Y1 - 2021
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B2000494

Copy number variations (CNVs), which can affect the role of long non-coding RNAs (lncRNAs), are important genetic changes seen in some malignant tumors. We analyzed lncRNAs with CNV to explore the relationship between lncRNAs and prognosis in bladder cancer (BLCA). Messenger RNA (mRNA) expression levels, DNA methylation, and DNA copy number data of 408 BLCA patients were subjected to integrative bioinformatics analysis. Cluster analysis was performed to obtain different subtypes and differently expressed lncRNAs and coding genes. Weighted gene co-expression network analysis (WGCNA) was performed to identify the co-expression gene and lncRNA modules. CNV-associated lncRNA data and their influence on cancer prognosis were assessed with Kaplan-Meier survival curve. Multi-omics integration analysis revealed five prognostic lncRNAs with CNV, namely NR2F1-AS1, LINC01138, THUMPD3-AS1, LOC101928489, and TMEM147-AS1, and a risk-score signature related to overall survival in BLCA was identified. Moreover, validated results in another independent Gene Expression Omnibus (GEO) dataset, GSE31684, were consistent with these results. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that the mitogen-activated protein kinase (MAPK) signaling pathway, focal adhesion pathway, and Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling pathway were enriched in a high-risk score pattern, suggesting that imbalance in these pathways is closely related to tumor development. We revealed the prognosis-related lncRNAs by analyzing the expression profiles of lncRNAs and CNVs, which can be used as prognostic biomarkers for BLCA.


目的:探讨伴有拷贝数变异(copy number variation (CNV))的长非编码RNA(long non-coding RNAs (LncRNAs))在膀胱癌中的作用。
方法:对The Cancer Genome Atlas(TCGA)数据库中408例膀胱癌患者的mRNA、DNA甲基化和DNA拷贝数数据进行综合生物信息学分析,筛选获得不同的亚型、差异表达lncRNAs和编码基因,采用加权基因共表达网络分析(weighted gene co-expression network analysis(WGCNA))方法鉴定共表达基因和lncRNA模块。使用Kaplan-Meier生存曲线评估CNV相关的lncRNAs对膀胱癌预后的影响,并用GSE31684数据集进行验证。


Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article


[1]AngCE, MaQ, WapinskiOL, et al., 2019. The novel lncRNA lnc-NR2F1 is pro-neurogenic and mutated in human neurodevelopmental disorders. Elife, 8:e41770.

[2]BeroukhimR, MermelCH, PorterD, et al., 2010. The landscape of somatic copy-number alteration across human cancers. Nature, 463(7283):899-905.

[3]BlancheP, DartiguesJF, Jacqmin-GaddaH, 2013. Estimating and comparing time-dependent areas under receiver operating characteristic curves for censored event times with competing risks. Stat Med, 32(30):5381-5397.

[4]BrayF, FerlayJ, SoerjomataramI, et al., 2018. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 68(6):394-424.

[5]ChappellG, SilvaGO, UeharaT, et al., 2016. Characterization of copy number alterations in a mouse model of fibrosis‐associated hepatocellular carcinoma reveals concordance with human disease. Cancer Med, 5(3):574-585.

[6]ChenG, WangZY, WangDQ, et al., 2013. LncRNADisease: a database for long-non-coding RNA-associated diseases. Nucleic Acids Res, 41(D1):D983-D986.

[7]ChenXJ, ChangCW, SpoerkeJM, et al., 2019. Low-pass whole-genome sequencing of circulating cell-free DNA demonstrates dynamic changes in genomic copy number in a squamous lung cancer clinical cohort. Clin Cancer Res, 25(7):2254-2263.

[8]ChenYA, LemireM, ChoufaniS, et al., 2013. Discovery of cross-reactive probes and polymorphic CpGs in the Illumina Infinium HumanMethylation450 microarray. Epigenetics, 8(2):203-209.

[9]ChengLJ, PandyaPH, LiuEZ, et al., 2019. Integration of genomic copy number variations and chemotherapy-response biomarkers in pediatric sarcoma. BMC Med Genomics, 12(S1):23.

[10]CibulskisK, LawrenceMS, CarterSL, et al., 2013. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat Biotechnol, 31(3):213-219.

[11]DuZ, FeiT, VerhaakRGW, et al., 2013. Integrative genomic analyses reveal clinically relevant long noncoding RNAs in human cancer. Nat Struct Mol Biol, 20(7):908-913.

[12]EggersS, DeBoerKD, van den BergenJ, et al., 2015. Copy number variation associated with meiotic arrest in idiopathic male infertility. Fertil Steril, 103(1):214-219.

[13]ErriquezJ, BeccoP, OliveroM, et al., 2015. TOP2A gene copy gain predicts response of epithelial ovarian cancers to pegylated liposomal doxorubicin: TOP2A as marker of response to PLD in ovarian cancer. Gynecol Oncol, 138(3):627-633.

[14]FeukL, CarsonAR, SchererSW, 2006. Structural variation in the human genome. Nat Rev Genet, 7(2):85-97.

[15]GudenasBL, WangJ, KuangSZ, et al., 2019. Genomic data mining for functional annotation of human long noncoding RNAs. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 20(6):476-487.

[16]GuoF, FuQF, WangY, et al., 2019. Long non-coding RNA NR2F1-AS1 promoted proliferation and migration yet suppressed apoptosis of thyroid cancer cells through regulating miRNA-338-3p/CCND1 axis. J Cell Mol Med, 23(9):5907-5919.

[17]HänzelmannS, CasteloR, GuinneyJ, 2013. GSVA: gene set variation analysis for microarray and RNA‐Seq data. BMC Bioinformatics, 14:7.

[18]HayashiT, GustKM, WyattAW, et al., 2016. Not all NOTCH is created equal: the oncogenic role of NOTCH2 in bladder cancer and its implications for targeted therapy. Clin Cancer Res, 22(12):2981-2992.

[19]HenrichsenCN, ChaignatE, ReymondA, 2009. Copy number variants, diseases and gene expression. Hum Mol Genet, 18(R1):R1-R8.

[20]HuJ, ChenY, LiX, et al., 2019. THUMPD3-AS1 is correlated with non-small cell lung cancer and regulates self-renewal through miR-543 and ONECUT2. OncoTargets Ther, 12:9849-9860.

[21]HuLW, WuYY, TanDL, et al., 2015. Up-regulation of long noncoding RNA MALAT1 contributes to proliferation and metastasis in esophageal squamous cell carcinoma. J Exp Clin Cancer Res, 34(1):7.

[22]HuXW, FengY, ZhangDM, et al., 2014. A functional genomic approach identifies FAL1 as an oncogenic long noncoding RNA that associates with BMI1 and represses p21 expression in cancer. Cancer Cell, 26(3):344-357.

[23]HuY, WangJL, QianJ, et al., 2014. Long noncoding RNA GAPLINC regulates CD44-dependent cell invasiveness and associates with poor prognosis of gastric cancer. Cancer Res, 74(23):6890-6902.

[24]HuangH, ChenJ, DingCM, et al., 2018. LncRNA NR2F1-AS1 regulates hepatocellular carcinoma oxaliplatin resistance by targeting ABCC1 via miR-363. J Cell Mol Med, 22(6):3238-3245.

[25]HussainSA, JamesND, 2003. The systemic treatment of advanced and metastatic bladder cancer. Lancet Oncol, 4(8):489-497.

[26]KimJS, ChaeY, HaYS, et al., 2012. Ras association domain family 1A: a promising prognostic marker in recurrent nonmuscle invasive bladder cancer. Clin Genitourin Cancer, 10(2):114-120.

[27]LangfelderP, HorvathS, 2008. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics, 9:559.

[28]LedetEM, HuXF, SartorO, et al., 2013. Characterization of germline copy number variation in high-risk African American families with prostate cancer. Prostate, 73(6):614-623.

[29]LiSL, ZhengK, PeiY, et al., 2019. Long noncoding RNA NR2F1-AS1 enhances the malignant properties of osteosarcoma by increasing forkhead box A1 expression via sponging of microRNA-483-3p. Aging, 11(23):11609-11623.

[30]LiZ, ZhangJW, LiuXY, et al., 2018. The LINC01138 drives malignancies via activating arginine methyltransferase 5 in hepatocellular carcinoma. Nat Commun, 9:1572.

[31]LiuD, XuXY, WenJM, et al., 2018. Integrated genome-wide analysis of gene expression and DNA copy number variations highlights stem cell-related pathways in small cell esophageal carcinoma. Stem Cells Int, 2018:3481783.

[32]MalhotraD, SebatJ, 2012. CNVs: harbingers of a rare variant revolution in psychiatric genetics. Cell, 148(6):1223-1241.

[33]Martin-DoyleW, LeowJJ, OrsolaA, et al., 2015. Improving selection criteria for early cystectomy in high-grade T1 bladder cancer: a meta-analysis of 15 215 patients. J Clin Oncol, 33(6):643-650.

[34]Martínez-FernándezM, FeberA, DueñasM, et al., 2015. Analysis of the polycomb-related lncRNAs HOTAIR and ANRIL in bladder cancer. Clin Epigenetics, 7:109.

[35]McCarrollSA, HuettA, KuballaP, et al., 2008. Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn’s disease. Nat Genet, 40(9):1107-1112.

[36]MengQT, WangKL, BrunettiT, et al., 2018. The DGCR5 long noncoding RNA may regulate expression of several schizophrenia-related genes. Sci Transl Med, 10(472):eaat6912.

[37]MermelCH, SchumacherSE, HillB, et al., 2011. GISTIC 2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol, 12(4):R41.

[38]MitraAP, CoteRJ, 2009. Molecular pathogenesis and diagnostics of bladder cancer. Annu Rev Pathol Mech Dis, 4:251-285.

[39]MoranVA, PereraRJ, KhalilAM, 2012. Emerging functional and mechanistic paradigms of mammalian long non-coding RNAs. Nucleic Acids Res, 40(14):6391-6400.

[40]NakamuraY, 2009. DNA variations in human and medical genetics: 25 years of my experience. J Hum Genet, 54(1):1-8.

[41]NingSW, ZhangJZ, WangP, et al., 2016. Lnc2Cancer: a manually curated database of experimentally supported lncRNAs associated with various human cancers. Nucleic Acids Res, 44(D1):D980-D985.

[42]NørskovMS, Frikke-SchmidtR, BojesenSE, et al., 2011. Copy number variation in glutathione-S-transferase T1 and M1 predicts incidence and 5-year survival from prostate and bladder cancer, and incidence of corpus uteri cancer in the general population. Pharmacogenom J, 11(4):292-299.

[43]PeterS, BorkowskaE, DraytonRM, et al., 2014. Identification of differentially expressed long noncoding RNAs in bladder cancer. Clin Cancer Res, 20(20):5311-5321.

[44]PotockiL, BiWM, Treadwell-DeeringD, et al., 2007. Characterization of Potocki-Lupski Syndrome (dup(17)(p11.2p11.2)) and delineation of a dosage-sensitive critical interval that can convey an autism phenotype. Am J Hum Genet, 80(4):633-649.

[45]RedonR, IshikawaS, FitchKR, et al., 2006. Global variation in copy number in the human genome. Nature, 444(7118):444-454.

[46]RobinsonMD, McCarthyDJ, SmythGK, 2010. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics, 26(1):139-140.

[47]RossJS, WangK, KhairaD, et al., 2016. Comprehensive genomic profiling of 295 cases of clinically advanced urothelial carcinoma of the urinary bladder reveals a high frequency of clinically relevant genomic alterations. Cancer, 122(5):702-711.

[48]RubinsteinJC, BrownTC, GohG, et al., 2016. Chromosome 19 amplification correlates with advanced disease in adrenocortical carcinoma. Surgery, 159(1):296-301.

[49]ShenRL, OlshenAB, LadanyiM, 2009. Integrative clustering of multiple genomic data types using a joint latent variable model with application to breast and lung cancer subtype analysis. Bioinformatics, 25(22):2906-2912.

[50]SubramanianA, TamayoP, MoothaVK, et al., 2005. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA, 102(43):15545-15550.

[51]The Wellcome Trust Case Control Consortium, 2010. Genome-wide association study of CNVs in 16 000 cases of eight common diseases and 3000 shared controls. Nature, 464(7289):713-720.

[52]XuHT, ZhuX, XuZL, et al., 2015. Non-invasive analysis of genomic copy number variation in patients with hepatocellular carcinoma by next generation DNA sequencing. J Cancer, 6(3):247-253.

[53]YangCJ, LiuZ, ChangXY, et al., 2020. NR2F1‐AS1 regulated miR‐423‐5p/SOX12 to promote proliferation and invasion of papillary thyroid carcinoma. J Cell Biochem, 121(2):2009-2018.

[54]YuGC, WangLG, HanYY, et al., 2012. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS, 16(5):284-287.

[55]ZackTI, SchumacherSE, CarterSL, et al., 2013. Pan-cancer patterns of somatic copy number alteration. Nat Genet, 45(10):1134-1140.

[56]ZhangX, WuJ, WuCC, et al., 2018. The LINC01138 interacts with PRMT5 to promote SREBP1-mediated lipid desaturation and cell growth in clear cell renal cell carcinoma. Biochem Biophys Res Commun, 507(1-4):337-342.

[57]ZhangYW, ZhengAP, XuRP, et al., 2019. NR2F1-induced NR2F1-AS1 promotes esophageal squamous cell carcinoma progression via activating Hedgehog signaling pathway. Biochem Biophys Res Commun, 519(3):497-504.

Open peer comments: Debate/Discuss/Question/Opinion


Please provide your name, email address and a comment

Journal of Zhejiang University-SCIENCE, 38 Zheda Road, Hangzhou 310027, China
Tel: +86-571-87952783; E-mail: cjzhang@zju.edu.cn
Copyright © 2000 - 2022 Journal of Zhejiang University-SCIENCE