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Transcriptome sequencing to detect gene fusions in cancer


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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Data deposits

Sequences of the gene fusion chimaeras are deposited in GenBank under accession numbers FJ423742FJ423755.


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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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Correspondence to 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).

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