Transcriptome sequencing to detect gene fusions in cancer (original) (raw)
- Letter
- Published: 11 January 2009
- Chandan Kumar-Sinha1,3 na1,
- Xuhong Cao1,2,
- Shanker Kalyana-Sundaram1,3,
- Bo Han1,3,
- Xiaojun Jing1,3,
- Lee Sam1,3,
- Terrence Barrette1,3,
- Nallasivam Palanisamy1,3 &
- …
- Arul M. Chinnaiyan1,2,3,4,5
Nature volume 458, pages 97–101 (2009)Cite this article
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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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Data deposits
Sequences of the gene fusion chimaeras are deposited in GenBank under accession numbers FJ423742–FJ423755.
References
- 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 - Rowley, J. D. Chromosome translocations: dangerous liaisons revisited. Nature Rev. Cancer 1, 245–250 (2001)
Article CAS Google Scholar - 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 - 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 - 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 - 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 - Futreal, P. A. et al. A census of human cancer genes. Nature Rev. Cancer 4, 177–183 (2004)
Article CAS Google Scholar - 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 - Korenchuk, S. et al. VCaP, a cell-based model system of human prostate cancer. In Vivo 15, 163–168 (2001)
CAS PubMed Google Scholar - 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 - 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 - 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 - Kent, W. J. BLAT – the BLAST-like alignment tool. Genome Res. 12, 656–664 (2002)
Article CAS PubMed PubMed Central Google Scholar - 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
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.
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Author notes
- Christopher A. Maher and Chandan Kumar-Sinha: These authors contributed equally to this work.
Authors and Affiliations
- 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 - Howard Hughes Medical Institute,,
Xuhong Cao & Arul M. Chinnaiyan - 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 - Department of Urology,,
Arul M. Chinnaiyan - Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA ,
Arul M. Chinnaiyan
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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
- Received: 21 July 2008
- Accepted: 10 November 2008
- Published: 11 January 2009
- Issue Date: 05 March 2009
- DOI: https://doi.org/10.1038/nature07638
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Prostate cancer link
Recurrent gene fusions, typically associated with haematological malignancies and rare bone and soft-tissue tumours, have recently been described in common solid tumours. Using a combination of new-generation long- and short-read sequencing technologies, Chinnaiyan and colleagues analyse cancer samples for gene fusion transcripts. The approach uncovers transcripts arising from known gene fusions in leukaemia and prostate cancer, as well as novel ones in prostate cancer, including a recurrent transcript SCL45A3-ELK4 that would not have been found using conventional methods.