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Integrative genomic analyses reveal clinically relevant long noncoding RNAs in human cancer

Abstract

Despite growing appreciation of the importance of long noncoding RNAs (lncRNAs) in normal physiology and disease, our knowledge of cancer-related lncRNAs remains limited. By repurposing microarray probes, we constructed expression profiles of 10,207 lncRNA genes in approximately 1,300 tumors over four different cancer types. Through integrative analysis of the lncRNA expression profiles with clinical outcome and somatic copy-number alterations, we identified lncRNAs that are associated with cancer subtypes and clinical prognosis and predicted those that are potential drivers of cancer progression. We validated our predictions by experimentally confirming prostate cancer cell growth dependence on two newly identified lncRNAs. Our analysis provides a resource of clinically relevant lncRNAs for the development of lncRNA biomarkers and the identification of lncRNA therapeutic targets. It also demonstrates the power of integrating publically available genomic data sets and clinical information for discovering disease-associated lncRNAs.

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Figure 1: Human Exon array reannotation and lncRNA classification.
Figure 2: The numbers and expression profiles of lncRNAs that have disease-specific or subtype-specific expression in prostate cancer, GBM, OvCa or lung SCC.
Figure 3: lncRNAs associated with prognosis or located in the genomic regions of SCNAs.
Figure 4: The genetic alteration and expression profiles of PCAN-R1 and PCAN-R2 in normal prostate tissues or prostate tumors and their transcript structures in cell lines.
Figure 5: Functional validation of PCAN-R1 and PCAN-R2.

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References

  1. Ota, T. et al. Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat. Genet. 36, 40–45 (2004).

    Article  Google Scholar 

  2. Guttman, M. et al. Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature 458, 223–227 (2009).

    Article  CAS  Google Scholar 

  3. Khalil, A.M. et al. Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc. Natl. Acad. Sci. USA 106, 11667–11672 (2009).

    Article  CAS  Google Scholar 

  4. Guttman, M. et al. Ab initio reconstruction of cell type-specific transcriptomes in mouse reveals the conserved multi-exonic structure of lincRNAs. Nat. Biotechnol. 28, 503–510 (2010).

    Article  CAS  Google Scholar 

  5. Cabili, M.N. et al. Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. Genes Dev. 25, 1915–1927 (2011).

    Article  CAS  Google Scholar 

  6. Prensner, J.R. & Chinnaiyan, A.M. The emergence of lncRNAs in cancer biology. Cancer Discov. 1, 391–407 (2011).

    Article  CAS  Google Scholar 

  7. Wapinski, O. & Chang, H.Y. Long noncoding RNAs and human disease. Trends Cell Biol. 21, 354–361 (2011).

    Article  CAS  Google Scholar 

  8. Lee, G.L., Dobi, A. & Srivastava, S. Prostate cancer: diagnostic performance of the PCA3 urine test. Nat. Rev. Urol. 8, 123–124 (2011).

    Article  Google Scholar 

  9. Liao, Q. et al. Large-scale prediction of long non-coding RNA functions in a coding–non-coding gene co-expression network. Nucleic Acids Res. 39, 3864–3878 (2011).

    Article  CAS  Google Scholar 

  10. Mercer, T.R., Dinger, M.E., Sunkin, S.M., Mehler, M.F. & Mattick, J.S. Specific expression of long noncoding RNAs in the mouse brain. Proc. Natl. Acad. Sci. USA 105, 716–721 (2008).

    Article  CAS  Google Scholar 

  11. Michelhaugh, S.K. et al. Mining Affymetrix microarray data for long non-coding RNAs: altered expression in the nucleus accumbens of heroin abusers. J. Neurochem. 116, 459–466 (2011).

    Article  CAS  Google Scholar 

  12. Gellert, P., Ponomareva, Y., Braun, T. & Uchida, S. Noncoder: a web interface for exon array-based detection of long non-coding RNAs. Nucleic Acids Res. 41, e20 (2013).

    Article  CAS  Google Scholar 

  13. Johnson, R. Long non-coding RNAs in Huntington's disease neurodegeneration. Neurobiol. Dis. 46, 245–254 (2012).

    Article  CAS  Google Scholar 

  14. Zhang, X. et al. Long non-coding RNA expression profiles predict clinical phenotypes in glioma. Neurobiol. Dis. 48, 1–8 (2012).

    Article  Google Scholar 

  15. Raghavachari, N. et al. A systematic comparison and evaluation of high density exon arrays and RNA-seq technology used to unravel the peripheral blood transcriptome of sickle cell disease. BMC Med. Genomics 5, 28 (2012).

    Article  CAS  Google Scholar 

  16. Xu, W. et al. Human transcriptome array for high-throughput clinical studies. Proc. Natl. Acad. Sci. USA 108, 3707–3712 (2011).

    Article  CAS  Google Scholar 

  17. Levin, J.Z. et al. Comprehensive comparative analysis of strand-specific RNA sequencing methods. Nat. Methods 7, 709–715 (2010).

    Article  CAS  Google Scholar 

  18. Taylor, B.S. et al. Integrative genomic profiling of human prostate cancer. Cancer Cell 18, 11–22 (2010).

    Article  CAS  Google Scholar 

  19. The Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008).

  20. Derrien, T. et al. The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res. 22, 1775–1789 (2012).

    Article  CAS  Google Scholar 

  21. Kapur, K., Xing, Y., Ouyang, Z. & Wong, W.H. Exon arrays provide accurate assessments of gene expression. Genome Biol. 8, R82 (2007).

    Article  Google Scholar 

  22. Prensner, J.R. et al. Transcriptome sequencing across a prostate cancer cohort identifies PCAT-1, an unannotated lincRNA implicated in disease progression. Nat. Biotechnol. 29, 742–749 (2011).

    Article  CAS  Google Scholar 

  23. Wang, Z., Gerstein, M. & Snyder, M. RNA-Seq: a revolutionary tool for transcriptomics. Nat. Rev. Genet. 10, 57–63 (2009).

    Article  CAS  Google Scholar 

  24. Petrovics, G. et al. Elevated expression of PCGEM1, a prostate-specific gene with cell growth-promoting function, is associated with high-risk prostate cancer patients. Oncogene 23, 605–611 (2004).

    Article  CAS  Google Scholar 

  25. Mourtada-Maarabouni, M., Pickard, M.R., Hedge, V.L., Farzaneh, F. & Williams, G.T. GAS5, a non-protein-coding RNA, controls apoptosis and is downregulated in breast cancer. Oncogene 28, 195–208 (2009).

    Article  CAS  Google Scholar 

  26. Clemson, C.M. et al. An architectural role for a nuclear noncoding RNA: NEAT1 RNA is essential for the structure of paraspeckles. Mol. Cell 33, 717–726 (2009).

    Article  CAS  Google Scholar 

  27. Kretz, M. et al. Suppression of progenitor differentiation requires the long noncoding RNA ANCR. Genes Dev. 26, 338–343 (2012).

    Article  CAS  Google Scholar 

  28. Wang, K.C. et al. A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature 472, 120–124 (2011).

    Article  CAS  Google Scholar 

  29. Szegedi, K. et al. The anti-apoptotic protein G1P3 is overexpressed in psoriasis and regulated by the non-coding RNA, PRINS. Exp. Dermatol. 19, 269–278 (2010).

    Article  CAS  Google Scholar 

  30. Wagner, L.A. et al. EGO, a novel, noncoding RNA gene, regulates eosinophil granule protein transcript expression. Blood 109, 5191–5198 (2007).

    Article  CAS  Google Scholar 

  31. The Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 474, 609–615 (2011).

  32. Hammerman, P.S. et al. Comprehensive genomic characterization of squamous cell lung cancers. Nature 489, 519–525 (2012).

    Article  CAS  Google Scholar 

  33. Ishii, N. et al. Identification of a novel non-coding RNA, MIAT, that confers risk of myocardial infarction. J. Hum. Genet. 51, 1087–1099 (2006).

    Article  CAS  Google Scholar 

  34. Rapicavoli, N.A., Poth, E.M. & Blackshaw, S. The long noncoding RNA RNCR2 directs mouse retinal cell specification. BMC Dev. Biol. 10, 49 (2010).

    Article  Google Scholar 

  35. Chan, A.S., Thorner, P.S., Squire, J.A. & Zielenska, M. Identification of a novel gene NCRMS on chromosome 12q21 with differential expression between rhabdomyosarcoma subtypes. Oncogene 21, 3029–3037 (2002).

    Article  CAS  Google Scholar 

  36. Gupta, R.A. et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature 464, 1071–1076 (2010).

    Article  CAS  Google Scholar 

  37. Rinn, J.L. et al. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell 129, 1311–1323 (2007).

    Article  CAS  Google Scholar 

  38. Kogo, R. et al. Long noncoding RNA HOTAIR regulates polycomb-dependent chromatin modification and is associated with poor prognosis in colorectal cancers. Cancer Res. 71, 6320–6326 (2011).

    Article  CAS  Google Scholar 

  39. Beroukhim, R. et al. The landscape of somatic copy-number alteration across human cancers. Nature 463, 899–905 (2010).

    Article  CAS  Google Scholar 

  40. Garraway, L.A. et al. Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature 436, 117–122 (2005).

    Article  CAS  Google Scholar 

  41. Akavia, U.D. et al. An integrated approach to uncover drivers of cancer. Cell 143, 1005–1017 (2010).

    Article  CAS  Google Scholar 

  42. Tran, V.G. et al. H19 antisense RNA can up-regulate Igf2 transcription by activation of a novel promoter in mouse myoblasts. PLoS ONE 7, e37923 (2012).

    Article  CAS  Google Scholar 

  43. Califano, A., Butte, A.J., Friend, S., Ideker, T. & Schadt, E. Leveraging models of cell regulation and GWAS data in integrative network-based association studies. Nat. Genet. 44, 841–847 (2012).

    Article  CAS  Google Scholar 

  44. Pe'er, D. & Hacohen, N. Principles and strategies for developing network models in cancer. Cell 144, 864–873 (2011).

    Article  CAS  Google Scholar 

  45. Zhao, J. et al. Genome-wide identification of polycomb-associated RNAs by RIP-seq. Mol. Cell 40, 939–953 (2010).

    Article  CAS  Google Scholar 

  46. Syvänen, A.C. Accessing genetic variation: genotyping single nucleotide polymorphisms. Nat. Rev. Genet. 2, 930–942 (2001).

    Article  Google Scholar 

  47. Meyerson, M., Gabriel, S. & Getz, G. Advances in understanding cancer genomes through second-generation sequencing. Nat. Rev. Genet. 11, 685–696 (2010).

    Article  CAS  Google Scholar 

  48. Flicek, P. et al. Ensembl 2012. Nucleic Acids Res. 40, D84–D90 (2012).

    Article  CAS  Google Scholar 

  49. Jiang, H. & Wong, W.H. SeqMap: mapping massive amount of oligonucleotides to the genome. Bioinformatics 24, 2395–2396 (2008).

    Article  CAS  Google Scholar 

  50. Kuhn, R.M., Haussler, D. & Kent, W.J. The UCSC genome browser and associated tools. Brief. Bioinform. 14, 144–161 (2013).

    Article  CAS  Google Scholar 

  51. Seok, J., Xu, W., Gao, H., Davis, R.W. & Xiao, W. JETTA: junction and exon toolkits for transcriptome analysis. Bioinformatics 28, 1274–1275 (2012).

    Article  CAS  Google Scholar 

  52. Johnson, W.E., Li, C. & Rabinovic, A. Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics 8, 118–127 (2007).

    Article  Google Scholar 

  53. Trapnell, C. et al. Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat. Biotechnol. 28, 511–515 (2010).

    Article  CAS  Google Scholar 

  54. Beroukhim, R. et al. Assessing the significance of chromosomal aberrations in cancer: methodology and application to glioma. Proc. Natl. Acad. Sci. USA 104, 20007–20012 (2007).

    Article  CAS  Google Scholar 

  55. Mermel, C.H. et al. GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol. 12, R41 (2011).

    Article  Google Scholar 

  56. Taylor, B.S. et al. Functional copy-number alterations in cancer. PLoS ONE 3, e3179 (2008).

    Article  Google Scholar 

  57. Lin, M.F., Jungreis, I. & Kellis, M. PhyloCSF: a comparative genomics method to distinguish protein coding and non-coding regions. Bioinformatica 27, 275–282 (2011).

    Article  Google Scholar 

  58. Lindblad-Toh, K. et al. A high-resolution map of human evolutionary constraint using 29 mammals. Nature 478, 476–482 (2011).

    Article  CAS  Google Scholar 

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Acknowledgements

This work was partially funded by the National Natural Science Foundation of China (31028011) (X.S.L.), the National Basic Research (973) Program of China (2010CB944904; Y.Z.) and US National Institutes of Health grant GM099409 (X.S.L.).

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Authors

Contributions

Y.C. conceived the project. Z.D. and Y.C. designed the algorithms and performed computational analyses. R.G.W.V. contributed to the subtype analyses of ovarian cancer. T.F. performed all the experimental validation. Z.D., T.F., Z.S., Y.Z., M.B., Y.C. and X.S.L. participated in the discussions and contributed to the analysis of the intermediate results throughout the project. Y.C., M.B. and X.S.L. supervised the project. Z.D., T.F., Y.C. and X.S.L. wrote the manuscript with the help from other coauthors.

Corresponding authors

Correspondence to Myles Brown, Yiwen Chen or X Shirley Liu.

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The authors declare no competing financial interests.

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Du, Z., Fei, T., Verhaak, R. et al. Integrative genomic analyses reveal clinically relevant long noncoding RNAs in human cancer. Nat Struct Mol Biol 20, 908–913 (2013). https://doi.org/10.1038/nsmb.2591

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