Transcriptome instability as a molecular pan-cancer characteristic of carcinomas

BMC Genomics

Rolf I Skotheim¹  Ragnhild A Lothe¹  Manuel R Teixeira²  Bjarne Johannessen¹  Anita Sveen¹ 

[1] Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, P.O. Box 1078 Blindern, Oslo NO-0316, Norway;Institute of Biomedical Sciences Abel Salazar, University of Porto, Rua de Jorge Viterbo Ferreira n.° 228, Porto 4050-313, Portugal

关键词: Tissue specificity;    Splicing factor;    Exon microarray;    Carcinomas;    Alternative splicing;   

Others  :  1216277
DOI  :  10.1186/1471-2164-15-672

 received in 2014-04-25, accepted in 2014-08-06,  发布年份 2014

【 摘 要 】

Background

We have previously proposed transcriptome instability as a genome-wide, pre-mRNA splicing-related characteristic of colorectal cancer. Here, we explore the hypothesis of transcriptome instability being a general characteristic of cancer.

Results

Exon-level microarray expression data from ten cancer datasets were analyzed, including breast cancer, cervical cancer, colorectal cancer, gastric cancer, lung cancer, neuroblastoma, and prostate cancer (555 samples), as well as paired normal tissue samples from the colon, lung, prostate, and stomach (93 samples). Based on alternative splicing scores across the genomes, we calculated sample-wise relative amounts of aberrant exon skipping and inclusion. Strong and non-random (P < 0.001) correlations between these estimates and the expression levels of splicing factor genes (n = 280) were found in most cancer types analyzed (breast-, cervical-, colorectal-, lung- and prostate cancer). This suggests a biological explanation for the splicing variation. Surprisingly, these associations prevailed in pan-cancer analyses. This is in contrast to the tissue and cancer specific patterns observed in comparisons across healthy tissue samples from the colon, lung, prostate, and stomach, and between paired cancer-normal samples from the same four tissue types.

Conclusion

Based on exon-level expression profiling and computational analyses of alternative splicing, we propose transcriptome instability as a molecular pan-cancer characteristic. The affected cancers show strong and non-random associations between low expression levels of splicing factor genes, and high amounts of aberrant exon skipping and inclusion, and vice versa, on a genome-wide scale.

【 授权许可】

   
2014 Sveen et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM: Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010, 127:2893-2917.
• [2]Lengauer C, Kinzler KW, Vogelstein B: Genetic instabilities in human cancers. Nature 1998, 396:643-649.
• [3]Hanahan D, Weinberg RA: Hallmarks of cancer: the next generation. Cell 2011, 144:646-674.
• [4]Fishel R, Lescoe MK, Rao MR, Copeland NG, Jenkins NA, Garber J, Kane M, Kolodner R: The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 1993, 75:1027-1038.
• [5]Leach FS, Nicolaides NC, Papadopoulos N, Liu B, Jen J, Parsons R, Peltomaki P, Sistonen P, Aaltonen LA, Nystrom-Lahti M: Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 1993, 75:1215-1225.
• [6]Fishel R, Kolodner RD: Identification of mismatch repair genes and their role in the development of cancer. Curr Opin Genet Dev 1995, 5:382-395.
• [7]Aaltonen LA, Peltomaki P, Leach FS, Sistonen P, Pylkkanen L, Mecklin JP, Jarvinen H, Powell SM, Jen J, Hamilton SR: Clues to the pathogenesis of familial colorectal cancer. Science 1993, 260:812-816.
• [8]Ionov Y, Peinado MA, Malkhosyan S, Shibata D, Perucho M: Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 1993, 363:558-561.
• [9]Lothe RA, Peltomaki P, Meling GI, Aaltonen LA, Nystrom-Lahti M, Pylkkanen L, Heimdal K, Andersen TI, Moller P, Rognum TO: Genomic instability in colorectal cancer: relationship to clinicopathological variables and family history. Cancer Res 1993, 53:5849-5852.
• [10]Lothe RA: Microsatellite instability in human solid tumors. Mol Med Today 1997, 3:61-68.
• [11]Peltomaki P, Lothe RA, Aaltonen LA, Pylkkanen L, Nystrom-Lahti M, Seruca R, David L, Holm R, Ryberg D, Haugen A: Microsatellite instability is associated with tumors that characterize the hereditary non-polyposis colorectal carcinoma syndrome. Cancer Res 1993, 53:5853-5855.
• [12]Merok MA, Ahlquist T, Røyrvik EC, Tufteland KF, Hektoen M, Sjo OH, Mala T, Svindland A, Lothe RA, Nesbakken A: Microsatellite instability has a positive prognostic impact on stage II colorectal cancer after complete resection: results from a large, consecutive Norwegian series. Ann Oncol 2012, 24:1274-1282.
• [13]Popat S, Hubner R, Houlston RS: Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol 2005, 23:609-618.
• [14]Choi CM, Seo KW, Jang SJ, Oh YM, Shim TS, Kim WS, Lee DS, Lee SD: Chromosomal instability is a risk factor for poor prognosis of adenocarcinoma of the lung: Fluorescence in situ hybridization analysis of paraffin-embedded tissue from Korean patients. Lung Cancer 2009, 64:66-70.
• [15]Smid M, Hoes M, Sieuwerts AM, Sleijfer S, Zhang Y, Wang Y, Foekens JA, Martens JW: Patterns and incidence of chromosomal instability and their prognostic relevance in breast cancer subtypes. Breast Cancer Res Treat 2011, 128:23-30.
• [16]Walther A, Houlston R, Tomlinson I: Association between chromosomal instability and prognosis in colorectal cancer: A meta-analysis. Gut 2008, 57:941-950.
• [17]Pretorius ME, Waehre H, Abeler VM, Davidson B, Vlatkovic L, Lothe RA, Giercksky KE, Danielsen HE: Large scale genomic instability as an additive prognostic marker in early prostate cancer. Cell Oncol 2009, 31:251-259.
• [18]Issa JP: CpG island methylator phenotype in cancer. Nat Rev Cancer 2004, 4:988-993.
• [19]Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB, Issa JP: CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci U S A 1999, 96:8681-8686.
• [20]Sveen A, Ågesen TH, Nesbakken A, Rognum TO, Lothe RA, Skotheim RI: Transcriptome instability in colorectal cancer identified by exon microarray analyses: Associations with splicing factor expression levels and patient survival. Genome Med 2011, 3:32.
• [21]Barash Y, Calarco JA, Gao W, Pan Q, Wang X, Shai O, Blencowe BJ, Frey BJ: Deciphering the splicing code. Nature 2010, 465:53-59.
• [22]Salzman J, Gawad C, Wang PL, Lacayo N, Brown PO: Circular RNAs are the predominant transcript isoform from hundreds of human genes in diverse cell types. PLoS One 2012, 7:e30733.
• [23]Li H, Wang J, Mor G, Sklar J: A neoplastic gene fusion mimics trans-splicing of RNAs in normal human cells. Science 2008, 321:1357-1361.
• [24]Blencowe BJ: Alternative splicing: new insights from global analyses. Cell 2006, 126:37-47.
• [25]Pan Q, Shai O, Lee LJ, Frey BJ, Blencowe BJ: Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nat Genet 2008, 40:1413-1415.
• [26]Bernstein BE, Birney E, Dunham I, Green ED, Gunter C, Snyder M, ENCODE Project Consortium: An integrated encyclopedia of DNA elements in the human genome. Nature 2012, 489:57-74.
• [27]Venables JP: Aberrant and alternative splicing in cancer. Cancer Res 2004, 64:7647-7654.
• [28]Karni R, De Stanchina E, Lowe SW, Sinha R, Mu D, Krainer AR: The gene encoding the splicing factor SF2/ASF is a proto-oncogene. Nat Struct Mol Biol 2007, 14:185-193.
• [29]Skotheim RI, Nees M: Alternative splicing in cancer: noise, functional, or systematic? Int J Biochem Cell Biol 2007, 39:1432-1449.
• [30]Yoshida K, Sanada M, Shiraishi Y, Nowak D, Nagata Y, Yamamoto R, Sato Y, Sato-Otsubo A, Kon A, Nagasaki M, Chalkidis G, Suzuki Y, Shiosaka M, Kawahata R, Yamaguchi T, Otsu M, Obara N, Sakata-Yanagimoto M, Ishiyama K, Mori H, Nolte F, Hofmann WK, Miyawaki S, Sugano S, Haferlach C, Koeffler HP, Shih LY, Haferlach T, Chiba S, Nakauchi H, et al.: Frequent pathway mutations of splicing machinery in Myelodysplasia. Nature 2011, 478:64-69.
• [31]Imielinski M, Berger AH, Hammerman PS, Hernandez B, Pugh TJ, Hodis E, Cho J, Suh J, Capelletti M, Sivachenko A, Sougnez C, Auclair D, Lawrence MS, Stojanov P, Cibulskis K, Choi K, De WL, Sharifnia T, Brooks A, Greulich H, Banerji S, Zander T, Seidel D, Leenders F, Ansen S, Ludwig C, Engel-Riedel W, Stoelben E, Wolf J, Goparju C, et al.: Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 2012, 150:1107-1120.
• [32]The Cancer Genome Atlas Network: Comprehensive molecular portraits of human breast tumours. Nature 2012, 490:61-70.
• [33]Wang ET, Sandberg R, Luo S, Khrebtukova I, Zhang L, Mayr C, Kingsmore SF, Schroth GP, Burge CB: Alternative isoform regulation in human tissue transcriptomes. Nature 2008, 456:470-476.
• [34]Chen M, Manley JL: Mechanisms of alternative splicing regulation: insights from molecular and genomics approaches. Nat Rev Mol Cell Biol 2009, 10:741-754.
• [35]Weinstein JN, Collisson EA, Mills GB, Shaw KR, Ozenberger BA, Ellrott K, Shmulevich I, Sander C, Stuart JM, Cancer Genome Atlas Research Network: The cancer genome atlas pan-cancer analysis project. Nat Genet 2013, 45:1113-1120.
• [36]Gonzalez-Perez A, Perez-Llamas C, Deu-Pons J, Tamborero D, Schroeder MP, Jene-Sanz A, Santos A, Lopez-Bigas N: IntOGen-mutations identifies cancer drivers across tumor types. Nat Methods 2013, 10:1081-1082.
• [37]Brooks AN, Choi PS, De WL, Sharifnia T, Imielinski M, Saksena G, Pedamallu CS, Sivachenko A, Rosenberg M, Chmielecki J, Lawrence MS, DeLuca DS, Getz G, Meyerson M: A pan-cancer analysis of transcriptome changes associated with somatic mutations in U2AF1 reveals commonly altered splicing events. PLoS One 2014, 9:e87361.
• [38]Huelga SC, Vu AQ, Arnold JD, Liang TY, Liu PP, Yan BY, Donohue JP, Shiue L, Hoon S, Brenner S, Ares M Jr, Yeo GW: Integrative genome-wide analysis reveals cooperative regulation of alternative splicing by hnRNP proteins. Cell Rep 2012, 1:167-178.
• [39]Quesada V, Conde L, Villamor N, Ordonez GR, Jares P, Bassaganyas L, Ramsay AJ, Bea S, Pinyol M, Martinez-Trillos A, Lopez-Guerra M, Colomer D, Navarro A, Baumann T, Aymerich M, Rozman M, Delgado J, Gine E, Hernandez JM, Gonzalez-Diaz M, Puente DA, Velasco G, Freije JM, Tubio JM, Royo R, Gelpi JL, Orozco M, Pisano DG, Zamora J, Vazquez M, et al.: Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia. Nat Genet 2011, 44:47-52.
• [40]Wang L, Lawrence MS, Wan Y, Stojanov P, Sougnez C, Stevenson K, Werner L, Sivachenko A, DeLuca DS, Zhang L, Zhang W, Vartanov AR, Fernandes SM, Goldstein NR, Folco EG, Cibulskis K, Tesar B, Sievers QL, Shefler E, Gabriel S, Hacohen N, Reed R, Meyerson M, Golub TR, Lander ES, Neuberg D, Brown JR, Getz G, Wu CJ: SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N Engl J Med 2011, 365:2497-2506.
• [41]Clark F, Thanaraj TA: Categorization and characterization of transcript-confirmed constitutively and alternatively spliced introns and exons from human. Hum Mol Genet 2002, 11:451-464.
• [42]Jass JR: Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology 2006, 50:113-130.
• [43]Guo X, Chen QR, Song YK, Wei JS, Khan J: Exon array analysis reveals neuroblastoma tumors have distinct alternative splicing patterns according to stage and MYCN amplification status. BMC Med Genomics 2011, 4:35.
• [44]Hall JS, Leong HS, Armenoult LS, Newton GE, Valentine HR, Irlam JJ, Moller-Levet C, Sikand KA, Pepper SD, Miller CJ, West CM: Exon-array profiling unlocks clinically and biologically relevant gene signatures from formalin-fixed paraffin-embedded tumour samples. Br J Cancer 2011, 104:971-981.
• [45]Lin E, Li L, Guan Y, Soriano R, Rivers CS, Mohan S, Pandita A, Tang J, Modrusan Z: Exon array profiling detects EML4-ALK fusion in breast, colorectal, and non-small cell lung cancers. Mol Cancer Res 2009, 7:1466-1476.
• [46]Paulo P, Ribeiro FR, Santos J, Mesquita D, Almeida M, Barros-Silva JD, Itkonen H, Henrique R, Jeronimo C, Sveen A, Mills IG, Skotheim RI, Lothe RA, Teixeira MR: Molecular subtyping of primary prostate cancer reveals specific and shared target genes of different ETS rearrangements. Neoplasia 2012, 14:600-611.
• [47]Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, Arora VK, Kaushik P, Cerami E, Reva B, Antipin Y, Mitsiades N, Landers T, Dolgalev I, Major JE, Wilson M, Socci ND, Lash AE, Heguy A, Eastham JA, Scher HI, Reuter VE, Scardino PT, Sander C, Sawyers CL, Gerald WL: Integrative genomic profiling of human prostate cancer. Cancer Cell 2010, 18:11-22.
• [48]Xi L, Feber A, Gupta V, Wu M, Bergemann AD, Landreneau RJ, Litle VR, Pennathur A, Luketich JD, Godfrey TE: Whole genome exon arrays identify differential expression of alternatively spliced, cancer-related genes in lung cancer. Nucleic Acids Res 2008, 36:6535-6547.
• [49]Ågesen TH, Sveen A, Merok MA, Lind GE, Nesbakken A, Skotheim RI, Lothe RA: ColoGuideEx: a robust gene classifier specific for stage II colorectal cancer prognosis. Gut 2012, 61:1560-1567.
• [50]Purdom E, Simpson KM, Robinson MD, Conboy JG, Lapuk AV, Speed TP: FIRMA: a method for detection of alternative splicing from exon array data. Bioinformatics 2008, 24:1707-1714.
• [51]Purdom E: HuEx-1_0-st-v2,coreR3,A20071112,EP.cdf. http://aroma-project.org/data/annotationData/chipTypes/HuEx-1_0-st-v2/HuEx-1_0-st-v2 webcite,coreR3,A20071112,EP.cdf.gz
• [52]R Core Team: R: A language and environment for statistical computing. http://www.R-project.org/ webcite
• [53]Irizarry RA, Hobbs B, Collin F, Beazer-Barclay YD, Antonellis KJ, Scherf U, Speed TP: Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 2003, 4:249-264.
• [54]Langfelder P, Horvath S: WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics 2008, 9:559.
• [55]Affymetrix Inc: Quality assessment of exon and gene arrays. [http://www.affymetrix.com/support/technical/whitepapers/exon_gene_arrays_qa_whitepaper.pdf webcite]
• [56]Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, Harris MA, Hill DP, Issel-Tarver L, Kasarskis A, Lewis S, Matese JC, Richardson JE, Ringwald M, Rubin GM, Sherlock G: Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 2000, 25:25-29.
• [57]Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP: Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 2005, 102:15545-15550.