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Transcriptome sequencing to detect gene fusions in cancer

Nature volume 458, pages 97–101 (2009)Cite this article

Abstract

Recurrent gene fusions, typically associated with haematological malignancies and rare bone and soft-tissue tumours1, have recently been described in common solid tumours2,3,4,5,6,7,8,9. Here we use an integrative analysis of high-throughput long- and short-read transcriptome sequencing of cancer cells to discover novel gene fusions. As a proof of concept, we successfully used integrative transcriptome sequencing to ‘re-discover’ the BCR–ABL1 (ref. 10) gene fusion in a chronic myelogenous leukaemia cell line and the TMPRSS2–ERG2,3 gene fusion in a prostate cancer cell line and tissues. Additionally, we nominated, and experimentally validated, novel gene fusions resulting in chimaeric transcripts in cancer cell lines and tumours. Taken together, this study establishes a robust pipeline for the discovery of novel gene chimaeras using high-throughput sequencing, opening up an important class of cancer-related mutations for comprehensive characterization.

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Figure 1: Using massively parallel sequencing to discover chimaeric transcripts in cancer.
Figure 2: Representative gene fusions characterized in the prostate cancer cell line VCaP.
Figure 3: Schematic of MIPOL1–DGKB gene fusion in the prostate cancer cell line LNCaP.
Figure 4: Discovery of the recurrent SLC45A3–ELK4 chimaera in prostate cancer and a general classification system for chimaeric transcripts in cancer.

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Primary accessions

GenBank/EMBL/DDBJ

Data deposits

Sequences of the gene fusion chimaeras are deposited in GenBank under accession numbers FJ423742–FJ423755.

References

  1. Mitelman, F., Johansson, B. & Mertens, F. Fusion genes and rearranged genes as a linear function of chromosome aberrations in cancer. Nature Genet. 36, 331–334 (2004)

    Article  CAS  PubMed  Google Scholar 

  2. Tomlins, S. A. et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310, 644–648 (2005)

    Article  ADS  CAS  PubMed  Google Scholar 

  3. Tomlins, S. A. et al. Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer. Nature 448, 595–599 (2007)

    Article  ADS  CAS  PubMed  Google Scholar 

  4. Kumar-Sinha, C., Tomlins, S. A. & Chinnaiyan, A. M. Recurrent gene fusions in prostate cancer. Nature Rev. Cancer 8, 497–511 (2008)

    Article  CAS  Google Scholar 

  5. Choi, Y. L. et al. Identification of novel isoforms of the EML4-ALK transforming gene in non-small cell lung cancer. Cancer Res. 68, 4971–4976 (2008)

    Article  CAS  PubMed  Google Scholar 

  6. Koivunen, J. P. et al. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin. Cancer Res. 14, 4275–4283 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Perner, S. et al. EML4-ALK fusion lung cancer: a rare acquired event. Neoplasia 10, 298–302 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Rikova, K. et al. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 131, 1190–1203 (2007)

    Article  CAS  PubMed  Google Scholar 

  9. Soda, M. et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448, 561–566 (2007)

    Article  ADS  CAS  PubMed  Google Scholar 

  10. Rowley, J. D. Chromosome translocations: dangerous liaisons revisited. Nature Rev. Cancer 1, 245–250 (2001)

    Article  CAS  Google Scholar 

  11. Lynch, T. J. et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 350, 2129–239 (2004)

    Article  CAS  PubMed  Google Scholar 

  12. Slamon, D. J. et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 344, 783–792 (2001)

    Article  CAS  PubMed  Google Scholar 

  13. Demetri, G. D. et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N. Engl. J. Med. 347, 472–480 (2002)

    Article  CAS  PubMed  Google Scholar 

  14. Druker, B. J. et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N. Engl. J. Med. 355, 2408–2417 (2006)

    Article  CAS  PubMed  Google Scholar 

  15. Futreal, P. A. et al. A census of human cancer genes. Nature Rev. Cancer 4, 177–183 (2004)

    Article  CAS  Google Scholar 

  16. Shtivelman, E., Lifshitz, B., Gale, R. P. & Canaani, E. Fused transcript of abl and bcr genes in chronic myelogenous leukaemia. Nature 315, 550–554 (1985)

    Article  ADS  CAS  PubMed  Google Scholar 

  17. Takahara, T., Tasic, B., Maniatis, T., Akanuma, H. & Yanagisawa, S. Delay in synthesis of the 3′ splice site promotes trans-splicing of the preceding 5′ splice site. Mol. Cell 18, 245–251 (2005)

    Article  CAS  PubMed  Google Scholar 

  18. Communi, D., Suarez-Huerta, N., Dussossoy, D., Savi, P. & Boeynaems, J. M. Cotranscription and intergenic splicing of human P2Y11 and SSF1 genes. J. Biol. Chem. 276, 16561–16566 (2001)

    Article  CAS  PubMed  Google Scholar 

  19. Gleave, M. et al. The effects of the dual 5α-reductase inhibitor dutasteride on localized prostate cancer – results from a 4-month pre-radical prostatectomy study. Prostate 66, 1674–1685 (2006)

    Article  CAS  PubMed  Google Scholar 

  20. Han, B. et al. A fluorescence in situ hybridization screen for E26 transformation-specific aberrations: identification of DDX5–ETV4 fusion protein in prostate cancer. Cancer Res. 68, 7629–7637 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Barber, T. D., Vogelstein, B., Kinzler, K. W. & Velculescu, V. E. Somatic mutations of EGFR in colorectal cancers and glioblastomas. N. Engl. J. Med. 351, 2883 (2004)

    Article  CAS  PubMed  Google Scholar 

  22. Cheung, V. G. et al. Integration of cytogenetic landmarks into the draft sequence of the human genome. Nature 409, 953–958 (2001)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  23. Greenman, C. et al. Patterns of somatic mutation in human cancer genomes. Nature 446, 153–158 (2007)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  24. Stephens, P. et al. A screen of the complete protein kinase gene family identifies diverse patterns of somatic mutations in human breast cancer. Nature Genet. 37, 590–592 (2005)

    Article  CAS  PubMed  Google Scholar 

  25. Strausberg, R. L., Buetow, K. H., Emmert-Buck, M. R. & Klausner, R. D. The cancer genome anatomy project: building an annotated gene index. Trends Genet. 16, 103–106 (2000)

    Article  CAS  PubMed  Google Scholar 

  26. Weir, B. A. et al. Characterizing the cancer genome in lung adenocarcinoma. Nature 450, 893–898 (2007)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wood, L. D. et al. The genomic landscapes of human breast and colorectal cancers. Science 318, 1108–1113 (2007)

    Article  ADS  CAS  PubMed  Google Scholar 

  28. Korenchuk, S. et al. VCaP, a cell-based model system of human prostate cancer. In Vivo 15, 163–168 (2001)

    CAS  PubMed  Google Scholar 

  29. Rubin, M. A. et al. Rapid (‘warm’) autopsy study for procurement of metastatic prostate cancer. Clin. Cancer Res. 6, 1038–1045 (2000)

    CAS  PubMed  Google Scholar 

  30. Karolchik, D. et al. The UCSC Table Browser data retrieval tool. Nucleic Acids Res. 32 (Database issue). D493–D496 (2004)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Abouelhoda, M. I., Kurtz, S. & Ohlebusch, E. Replacing suffix trees with enhanced suffix arrays. J. Discrete Algorithms 2, 53–86 (2004)

    Article  MathSciNet  Google Scholar 

  32. Kent, W. J. BLAT – the BLAST-like alignment tool. Genome Res. 12, 656–664 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Vandesompele, J. et al. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 3, 34–50 (2002)

    Article  Google Scholar 

Download references

Acknowledgements

We thank Illumina and 454 for technical support, R. Mehra and J. Siddiqui for providing tissue samples, Y. Gong, S. Shankar, X. Wang and A. Menon for technical assistance, J. Yu for help with the Illumina Genome Analyzer, and R. J. Lonigro for discussions. C.A.M. was supported by a National Institutes of Health Ruth L. Kirschstein post-doctoral training grant, and currently derives support from the American Association of Cancer Research Amgen Fellowship in Clinical/Translational Research, the Canary Foundation and American Cancer Society Early Detection Postdoctoral Fellowship. This work was supported in part by the National Institutes of Health (to A.M.C.), the Department of Defense (to A.M.C.), the Early Detection Research Network (to A.M.C.), and NCIBI (grant number U54 DA 021519).

Author Contributions C.A.M., C.K.-S. and A.M.C. wrote the manuscript. C.K.-S., X.C., X.J., B.H. and N.P. performed the sequencing and biochemical experiments. C.A.M., S.K.-S., L.S. and T.B. performed bioinformatics analysis.

Author information

Author notes

  1. Christopher A. Maher and Chandan Kumar-Sinha: These authors contributed equally to this work.

Authors and Affiliations

  1. Michigan Center for Translational Pathology,,

    Christopher A. Maher, Chandan Kumar-Sinha, Xuhong Cao, Shanker Kalyana-Sundaram, Bo Han, Xiaojun Jing, Lee Sam, Terrence Barrette, Nallasivam Palanisamy & Arul M. Chinnaiyan

  2. Howard Hughes Medical Institute,,

    Xuhong Cao & Arul M. Chinnaiyan

  3. Department of Pathology,,

    Christopher A. Maher, Chandan Kumar-Sinha, Shanker Kalyana-Sundaram, Bo Han, Xiaojun Jing, Lee Sam, Terrence Barrette, Nallasivam Palanisamy & Arul M. Chinnaiyan

  4. Department of Urology,,

    Arul M. Chinnaiyan

  5. Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA ,

    Arul M. Chinnaiyan

Authors
  1. Christopher A. Maher
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Correspondence to Arul M. Chinnaiyan.

Supplementary information

Supplementary Information

This file contains a Supplementary Discussion, Supplementary Materials and Methods, Supplementary Tables 1-9, Supplementary Figures 1-15 with Legends and Supplementary References (PDF 9467 kb)

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Maher, C., Kumar-Sinha, C., Cao, X. et al. Transcriptome sequencing to detect gene fusions in cancer. Nature 458, 97–101 (2009). https://doi.org/10.1038/nature07638

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