Alternative RNA Splicing as a Potential Major …...2019/02/12 · trans-acting splicing factors (proteins or RNAs) that enhance or silence the use of splice sites. Variation in cis-acting
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1
Alternative RNA Splicing as a Potential Major Source of Untapped Molecular
Targets in Precision Oncology and Cancer Disparities
Timothy J. Robinson1,, Jennifer A. Freedman2,3,, Muthana Al Abo3, April E. Deveaux2,
Bonnie LaCroix2, Brendon M. Patierno2, Daniel J. George2,3 and Steven R. Patierno2,3,*
1Department of Radiation Oncology, Moffitt Cancer Center, Tampa, FL, 33612, USA
2Department of Medicine, Division of Medical Oncology, Duke University Medical
Center, Durham, NC, 27710, USA
3Duke Cancer Institute, Duke University Medical Center, Durham, NC, 27710, USA
Running title: RNA splicing in precision oncology and cancer disparities
Keywords: alternative RNA splicing, biomarkers, therapeutic agents, oncology, cancer
disparities
Financial support: This work was partially supported by a RSNA Resident Research
Grant to TJR PI and SRP Mentor, a DoD Prostate Cancer Research Program Health
Disparity Research Award PC131972 to SRP PI and JAF Co-I, a NIH Feasibility Studies
to Build Collaborative Partnerships in Cancer Research P20 Award 1P20-CA202925-
01A1 to SRP Overall PI and JAF PI of Pilot Project One, and a NIH Basic Research in
Cancer Health Disparities R01 Award R01CA220314 to SRP PI and JAF Co-I.
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2019; DOI: 10.1158/1078-0432.CCR-18-2445
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2019; DOI: 10.1158/1078-0432.CCR-18-2445
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2019; DOI: 10.1158/1078-0432.CCR-18-2445
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2019; DOI: 10.1158/1078-0432.CCR-18-2445
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2019; DOI: 10.1158/1078-0432.CCR-18-2445
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2019; DOI: 10.1158/1078-0432.CCR-18-2445
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2019; DOI: 10.1158/1078-0432.CCR-18-2445
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2019; DOI: 10.1158/1078-0432.CCR-18-2445
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2019; DOI: 10.1158/1078-0432.CCR-18-2445
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2019; DOI: 10.1158/1078-0432.CCR-18-2445
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2019; DOI: 10.1158/1078-0432.CCR-18-2445
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2019; DOI: 10.1158/1078-0432.CCR-18-2445
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2019; DOI: 10.1158/1078-0432.CCR-18-2445
1. The Cancer Genome Atlas, National Institutes of Health, 2018 2. Kou T, Kanai M, Matsumoto S, et al: The possibility of clinical sequencing in the management of cancer. Jpn J Clin Oncol 46:399-406, 2016 3. Spratt DE, Chan T, Waldron L, et al: Racial/Ethnic Disparities in Genomic Sequencing. JAMA Oncol 2:1070-4, 2016 4. Tan DS, Mok TS, Rebbeck TR: Cancer Genomics: Diversity and Disparity Across Ethnicity and Geography. J Clin Oncol 34:91-101, 2016 5. Hanahan D, Weinberg RA: Hallmarks of cancer: the next generation. Cell 144:646-74, 2011 6. Berget SM, Moore C, Sharp PA: Spliced segments at the 5' terminus of adenovirus 2 late mRNA. Proc Natl Acad Sci U S A 74:3171-5, 1977 7. Urbanski LM, Leclair N, Anczukow O: Alternative-splicing defects in cancer: Splicing regulators and their downstream targets, guiding the way to novel cancer therapeutics. Wiley Interdiscip Rev RNA 9:e1476, 2018 8. Barbosa-Morais NL, Irimia M, Pan Q, et al: The evolutionary landscape of alternative splicing in vertebrate species. Science 338:1587-93, 2012 9. Pentony MM, Jones DT: Modularity of intrinsic disorder in the human proteome. Proteins 78:212-21, 2010 10. Chen J, Weiss WA: Alternative splicing in cancer: implications for biology and therapy. Oncogene 34:1-14, 2015 11. Baralle FE, Giudice J: Alternative splicing as a regulator of development and tissue identity. Nat Rev Mol Cell Biol 18:437-451, 2017 12. Wang GS, Cooper TA: Splicing in disease: disruption of the splicing code and the decoding machinery. Nat Rev Genet 8:749-61, 2007 13. Sibley CR, Blazquez L, Ule J: Lessons from non-canonical splicing. Nat Rev Genet 17:407-421, 2016 14. Jung H, Lee D, Lee J, et al: Intron retention is a widespread mechanism of tumor-suppressor inactivation. Nat Genet 47:1242-8, 2015 15. Pearson JL, Robinson TJ, Munoz MJ, et al: Identification of the cellular targets of the transcription factor TCERG1 reveals a prevalent role in mRNA processing. J Biol Chem 283:7949-61, 2008 16. Robinson TJ, Dinan MA, Dewhirst M, et al: SplicerAV: A tool for mining microarray expression data for changes in RNA processing. BMC Bioinformatics 11:108, 2010 17. Robinson TJ, Forte E, Salinas RE, et al: SplicerEX: a tool for the automated detection and classification of mRNA changes from conventional and splice-sensitive microarray expression data. RNA 18:1435-45, 2012 18. Robinson TJ, Chi JT, Dewhirst M: Hypoxia Induces mRNA 3’UTR Truncation in Multiple Cell Types In Vitro. Abstract. IJROBP. 90:S824, 2014 19. Wang BD, Ceniccola K, Hwang S, et al: Alternative splicing promotes tumour aggressiveness and drug resistance in African American prostate cancer. Nat Commun 8:15921, 2017 20. Liu S, Cheng C: Alternative RNA splicing and cancer. Wiley Interdiscip Rev RNA 4:547-66, 2013 21. Sveen A, Johannessen B, Teixeira MR, et al: Transcriptome instability as a molecular pan-cancer characteristic of carcinomas. BMC Genomics 15:672, 2014
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2019; DOI: 10.1158/1078-0432.CCR-18-2445
22. Bullock N, Potts J, Simpkin AJ, et al: Serine-arginine protein kinase 1 (SRPK1), a determinant of angiogenesis, is upregulated in prostate cancer and correlates with disease stage and invasion. J Clin Pathol, 2015 23. Lu ZX, Huang Q, Park JW, et al: Transcriptome-wide landscape of pre-mRNA alternative splicing associated with metastatic colonization. Mol Cancer Res 13:305-18, 2015 24. Rao AR, Sahu TK, Singh N: Spliceomics: The OMICS of RNA Splicing, in Barh D, Zambare V, Azevedo V (eds): OMICS Applications in Biomedical, Agricultural, and Environmental Sciences (ed 1st Edition). Boca Raton, Taylor & Francis Group, 2013 25. Sowalsky AG, Xia Z, Wang L, et al: Whole transcriptome sequencing reveals extensive unspliced mRNA in metastatic castration-resistant prostate cancer. Mol Cancer Res 13:98-106, 2015 26. Tsai YS, Dominguez D, Gomez SM, et al: Transcriptome-wide identification and study of cancer-specific splicing events across multiple tumors. Oncotarget 6:6825-39, 2015 27. Antonarakis ES, Lu C, Wang H, et al: AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med 371:1028-38, 2014 28. Anczukow O, Krainer AR: The spliceosome, a potential Achilles heel of MYC-driven tumors. Genome Med 7:107, 2015 29. Chen J, Crutchley J, Zhang D, et al: Identification of a DNA Damage-Induced Alternative Splicing Pathway That Regulates p53 and Cellular Senescence Markers. Cancer Discov 7:766-781, 2017 30. Han J, Li J, Ho JC, et al: Hypoxia is a Key Driver of Alternative Splicing in Human Breast Cancer Cells. Sci Rep 7:4108, 2017 31. Wang Y, Freedman JA, Liu H, et al: Associations between RNA splicing regulatory variants of stemness-related genes and racial disparities in susceptibility to prostate cancer. Int J Cancer, 2017 32. Freedman JA, Wang Y, Li X, et al: Single Nucleotide Polymorphisms of Stemness Genes Predicted to Regulate RNA Splicing, microRNA and Oncogenic Signaling are Associated with Prostate Cancer Survival. Carcinogenesis, 2018 33. Rebbeck TR, Mitra N, Wan F, et al: Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer. JAMA 313:1347-61, 2015 34. Haffty BG, Silber A, Matloff E, et al: Racial differences in the incidence of BRCA1 and BRCA2 mutations in a cohort of early onset breast cancer patients: African American compared to white women. J Med Genet 43:133-7, 2006 35. Bejar R: Splicing Factor Mutations in Cancer. Adv Exp Med Biol 907:215-28, 2016 36. Li X, Manley JL: Inactivation of the SR protein splicing factor ASF/SF2 results in genomic instability. Cell 122:365-78, 2005 37. Karni R, de Stanchina E, Lowe SW, et al: The gene encoding the splicing factor SF2/ASF is a proto-oncogene. Nat Struct Mol Biol 14:185-93, 2007 38. Silipo M, Gautrey H, Tyson-Capper A: Deregulation of splicing factors and breast cancer development. J Mol Cell Biol, 2015 39. Bauman J, Jearawiriyapaisarn N, Kole R: Therapeutic potential of splice-switching oligonucleotides. Oligonucleotides 19:1-13, 2009 40. Zanetta C, Nizzardo M, Simone C, et al: Molecular therapeutic strategies for spinal muscular atrophies: current and future clinical trials. Clin Ther 36:128-40, 2014 41. Zammarchi F, de Stanchina E, Bournazou E, et al: Antitumorigenic potential of STAT3 alternative splicing modulation. Proc Natl Acad Sci U S A 108:17779-84, 2011 42. Hong D, Kurzrock R, Kim Y, et al: AZD9150, a next-generation antisense oligonucleotide inhibitor of STAT3 with early evidence of clinical activity in lymphoma and lung cancer. Sci Transl Med 7:314ra185, 2015
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2019; DOI: 10.1158/1078-0432.CCR-18-2445
43. Younis I, Berg M, Kaida D, et al: Rapid-response splicing reporter screens identify differential regulators of constitutive and alternative splicing. Mol Cell Biol 30:1718-28, 2010 44. Pawellek A, McElroy S, Samatov T, et al: Identification of small molecule inhibitors of pre-mRNA splicing. J Biol Chem 289:34683-98, 2014 45. ClinicalTrials.gov: An Open Label Study of LMI070 (Branaplam) in Type 1 Spinal Muscular Atrophy (SMA), 2014 46. Scanlan MJ, Chen YT, Williamson B, et al: Characterization of human colon cancer antigens recognized by autologous antibodies. Int J Cancer 76:652-8, 1998 47. Cifola I, Pietrelli A, Consolandi C, et al: Comprehensive genomic characterization of cutaneous malignant melanoma cell lines derived from metastatic lesions by whole-exome sequencing and SNP array profiling. PLoS One 8:e63597, 2013 48. Berger MF, Hodis E, Heffernan TP, et al: Melanoma genome sequencing reveals frequent PREX2 mutations. Nature 485:502-6, 2012 49. Volpe G, Cignetti A, Panuzzo C, et al: Alternative BCR/ABL splice variants in Philadelphia chromosome-positive leukemias result in novel tumor-specific fusion proteins that may represent potential targets for immunotherapy approaches. Cancer Res 67:5300-7, 2007 50. Smart AC, Margolis CA, Pimentel H, et al: Intron retention is a source of neoepitopes in cancer. Nat Biotechnol, 2018 51. Stoilov P, Lin CH, Damoiseaux R, et al: A high-throughput screening strategy identifies cardiotonic steroids as alternative splicing modulators. Proc Natl Acad Sci U S A 105:11218-23, 2008 52. Zardavas D, Irrthum A, Swanton C, et al: Clinical management of breast cancer heterogeneity. Nat Rev Clin Oncol 12:381-94, 2015 53. Jamal-Hanjani M, Wilson GA, McGranahan N, et al: Tracking the Evolution of Non-Small-Cell Lung Cancer. N Engl J Med 376:2109-2121, 2017 54. Garman B, Anastopoulos IN, Krepler C, et al: Genetic and genomic characterization of 462 melanoma patient-derived xenografts, tumor biopsies and cell lines. Cell Rep 21:1936-52, 2017 55. Frampton GM, Ali SM, Rosenzweig M, et al: Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov, 2015 56. Liu R, Loraine AE, Dickerson JA: Comparisons of computational methods for differential alternative splicing detection using RNA-seq in plant systems. BMC Bioinformatics 15:364, 2014 57. Jayasinghe RG, Cao S, Gao Q, et al: Systematic Analysis of Splice-Site-Creating Mutations in Cancer. Cell Rep 23:270-281 e3, 2018 58. Jian X, Boerwinkle E, Liu X: In silico tools for splicing defect prediction: a survey from the viewpoint of end users. Genet Med 16:497-503, 2014 59. Soreq L, Guffanti A, Salomonis N, et al: Long non-coding RNA and alternative splicing modulations in Parkinson's leukocytes identified by RNA sequencing. PLoS Comput Biol 10:e1003517, 2014 60. Ernst C, Morton CC: Identification and function of long non-coding RNA. Front Cell Neurosci 7:168, 2013 61. Niland CN, Merry CR, Khalil AM: Emerging Roles for Long Non-Coding RNAs in Cancer and Neurological Disorders. Front Genet 3:25, 2012 62. Gao Y, Wang H, Zhang H, et al: PRAPI: post-transcriptional regulation analysis pipeline for Iso-Seq. Bioinformatics 34:1580-1582, 2018 63. Han S, Kim D, Kim Y, et al: CAS-viewer: web-based tool for splicing-guided integrative analysis of multi-omics cancer data. BMC Med Genomics 11:25, 2018
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2019; DOI: 10.1158/1078-0432.CCR-18-2445
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2019; DOI: 10.1158/1078-0432.CCR-18-2445
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2019; DOI: 10.1158/1078-0432.CCR-18-2445
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2019; DOI: 10.1158/1078-0432.CCR-18-2445
Published OnlineFirst February 12, 2019.Clin Cancer Res Timothy J Robinson, Jennifer A Freedman, Muthana Al Abo, et al. DisparitiesUntapped Molecular Targets in Precision Oncology and Cancer Alternative RNA Splicing as a Potential Major Source of
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Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 12, 2019; DOI: 10.1158/1078-0432.CCR-18-2445