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The emerging complexity of gene fusions in cancer

Abstract

Structural chromosome rearrangements may result in the exchange of coding or regulatory DNA sequences between genes. Many such gene fusions are strong driver mutations in neoplasia and have provided fundamental insights into the disease mechanisms that are involved in tumorigenesis. The close association between the type of gene fusion and the tumour phenotype makes gene fusions ideal for diagnostic purposes, enabling the subclassification of otherwise seemingly identical disease entities. In addition, many gene fusions add important information for risk stratification, and increasing numbers of chimeric proteins encoded by the gene fusions serve as specific targets for treatment, resulting in dramatically improved patient outcomes. In this Timeline article, we describe the spectrum of gene fusions in cancer and how the methods to identify them have evolved, and also discuss conceptual implications of current, sequencing-based approaches for detection.

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Figure 1: Major discoveries from research on gene fusions and cancer.
Figure 2: The chromosomal basis of gene fusions.
Figure 3: Gene fusion networks in AML.
Figure 4: Gene fusion reports.
Figure 5: Gene fusion networks in ovarian cancer.

References

  1. Boveri, T. Zur Frage der Entstehung maligner Tumoren (Gustav Fischer, 1914).

    Google Scholar 

  2. Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Vogelstein, B. et al. Cancer genome landscapes. Science 339, 1546–1558 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Watson, I. R., Takahashi, K., Futreal, A. P. & Chin, L. Emerging patterns of somatic mutations in cancer. Nature Reviews Genet. 14, 703–718 (2013).

    Article  CAS  Google Scholar 

  5. Mitelman, F., Johansson, B. & Mertens, F. Mitelman database of chromosome aberrations and gene fusions in cancer. National Cancer Institute [online], (2015).

    Google Scholar 

  6. Mitelman, F., Johansson, B. & Mertens, F. The impact of translocations and gene fusions on cancer causation. Nature Reviews Cancer 7, 233–245 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Nowell, P. C. & Hungerford, D. A. A minute chromosome in human chronic granulocytic leukemia. Science 132, 1497 (1960).

    Google Scholar 

  8. Caspersson, T., Zech, L. & Johansson, C. Differential binding of alkylating fluorochromes in human chromosomes. Exp. Cell Res. 60, 315–319 (1970).

    Article  CAS  PubMed  Google Scholar 

  9. Rowley, J. D. A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 243, 290–293 (1973).

    Article  CAS  PubMed  Google Scholar 

  10. Rowley, J. D. Identification of a translocation with quinacrine fluorescence in a patient with acute leukemia. Ann. Genet. 16, 109–112 (1973).

    CAS  PubMed  Google Scholar 

  11. Zech, L., Haglund, U., Nilsson, K. & Klein, G. Characteristic chromosomal abnormalities in biopsies and lymphoid-cell lines from patients with Burkitt and non-Burkitt lymphomas. Int. J. Cancer 17, 47–56 (1976).

    Article  CAS  PubMed  Google Scholar 

  12. Berger, R. et al. A new translocation in Burkitt's tumor cells. Hum. Genet. 53, 111–112 (1979).

    Article  CAS  PubMed  Google Scholar 

  13. Miyoshi, I., Hiraki, S., Kimura, I., Miyamoto, K. & Sato, J. 2/8 translocation in a Japanese Burkitt's lymphoma. Experientia 35, 742–743 (1979).

    Article  CAS  PubMed  Google Scholar 

  14. van den Berghe, H. et al. Variant translocation in Burkitt lymphoma. Cancer Genet. Cytogenet. 1, 9–14 (1979).

    Article  Google Scholar 

  15. Oshimura, M., Freeman, A. I. & Sandberg, A. A. Chromosomes and causation of human cancer and leukemia. XXVI. Banding studies in acute lymphoblastic leukemia (ALL). Cancer 40, 1161–1172 (1977).

    Article  CAS  PubMed  Google Scholar 

  16. Rowley, J. D., Golomb, H. M. & Dougherty, C. 15/17 translocation, a consistent chromosomal change in acute promyelocytic leukaemia. Lancet 1, 549–550 (1977).

    Article  CAS  PubMed  Google Scholar 

  17. Fukuhara, S., Rowley, J. D., Variakojis, D. & Golomb, H. M. Chromosome abnormalities in poorly differentiated lymphocytic lymphoma. Cancer Res. 39, 3119–3128 (1979).

    CAS  PubMed  Google Scholar 

  18. Ohno, S. et al. Nonrandom chromosome changes involving the Ig gene-carrying chromosomes 12 and 6 in pristane-induced mouse plasmacytomas. Cell 18, 1001–1007 (1979).

    Article  CAS  PubMed  Google Scholar 

  19. Seidal, T., Mark, J., Hagmar, B. & Angervall, L. Alveolar rhabdomyosarcoma: a cytogenetic and correlated cytological and histological study. APMIS 90, 345–354 (1982).

    CAS  Google Scholar 

  20. Aurias, A., Rimbaut, C., Buffe, D., Dubousset, J. & Mazabraud, A. Chromosomal translocations in Ewing's sarcoma. N. Engl. J. Med. 309, 496–497 (1983).

    Google Scholar 

  21. Turc-Carel, C., Philip, I., Berger, M.-P., Philip, T. & Lenoir, G. M. Chromosomal translocations in Ewing's sarcoma. N. Engl. J. Med. 309, 497–498 (1983).

    Google Scholar 

  22. de Jong, B., Molenaar, I. M., Leeuw, J. A., Idenberg, V. J. S. & Oosterhuis, J. W. Cytogenetics of a renal adenocarcinoma in a 2-year-old child. Cancer Genet. Cytogenet. 21, 165–169 (1986).

    Article  CAS  PubMed  Google Scholar 

  23. Stenman, G., Sandros, J., Dahlenfors, R., Juberg-Ode, M. & Mark, J. 6q- and loss of the Y chromosome — two common deviations in malignant human salivary gland tumors. Cancer Genet. Cytogenet. 22, 283–293 (1986).

    Article  CAS  PubMed  Google Scholar 

  24. Mark, J., Dahlenfors, R., Ekedahl, C. & Stenman, G. The mixed salivary gland tumor — a normally benign human neoplasm frequently showing specific chromosomal abnormalities. Cancer Genet. Cytogenet. 2, 231–241 (1980).

    Article  Google Scholar 

  25. Heim, S. et al. Reciprocal translocation t(3;12)(q27;q13) in lipoma. Cancer Genet. Cytogenet. 23, 301–304 (1986).

    Article  CAS  PubMed  Google Scholar 

  26. Turc-Carel, C., Dal Cin, P., Rao, U., Karakousis, C. & Sandberg, A. A. Cytogenetic studies of adipose tissue tumors. I. A benign lipoma with reciprocal translocation t(3;12)(q28;q14). Cancer Genet. Cytogenet. 23, 283–289 (1986).

    Article  CAS  PubMed  Google Scholar 

  27. Speicher, M. R. & Carter, N. P. The new cytogenetics: blurring the boundaries with molecular biology. Nature Reviews Genet. 6, 782–792 (2005).

    Article  CAS  Google Scholar 

  28. Pinkel, D. & Albertson, D. G. Array comparative genomic hybridization and its application in cancer. Nature Genet. 37, S11–S17 (2005).

    Article  CAS  PubMed  Google Scholar 

  29. Wachtel, M. et al. Gene expression signatures identify rhabdomyosarcoma subtypes and detect a novel t(2;2)(q35;p23) translocation fusing PAX3 to NCOA1. Cancer Res. 64, 5539–5545 (2004).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  31. West, R. B. et al. A landscape effect in tenosynovial giant-cell tumor from activation of CSF1 expression by a translocation in a minority of tumor cells. Proc. Natl Acad. Sci. USA 103, 690–695 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 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 

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

    Article  CAS  PubMed  Google Scholar 

  34. Wang, L. et al. Identification of a novel, recurrent HEY1–NCOA2 fusion in mesenchymal chondrosarcoma based on a genome-wide screen of exon-level expression data. Genes Chromosomes Cancer 51, 127–139 (2012).

    Article  CAS  PubMed  Google Scholar 

  35. Bernard, O. et al. Two site-specific deletions and t(1;14) translocation restricted to human T-cell acute leukemias disrupt the 5′ part of the tal-1 gene. Oncogene 6, 1477–1488 (1991).

    CAS  PubMed  Google Scholar 

  36. Barr, F. G. et al. In vivo amplification of the PAX3FKHR and PAX7FKHR fusion genes in alveolar rhabdomyosarcoma. Hum. Mol. Genet. 5, 15–21 (1996).

    Article  CAS  PubMed  Google Scholar 

  37. Simon, M.-P. et al. Deregulation of the platelet-derived growth factor B-chain gene via fusion with collagen gene COL1A1 in dermatofibrosarcoma protuberans and giant-cell fibroblastoma. Nature Genet. 15, 95–98 (1997).

    Article  CAS  PubMed  Google Scholar 

  38. Sinclair, P. B. et al. Large deletions at the t(9;22) breakpoint are common and may identify a poor-prognosis subgroup of patients with chronic myeloid leukemia. Blood 95, 738–744 (2000).

    CAS  PubMed  Google Scholar 

  39. Möller, E. et al. FUS–CREB3L2/L1-positive sarcomas show a specific gene expression profile with upregulation of CD24 and FOXL1. Clin. Cancer Res. 17, 2646–2656 (2011).

    Article  CAS  PubMed  Google Scholar 

  40. Gelsi-Boyer, V. et al. Genome profiling of chronic myelomonocytic leukemia: frequent alterations of RAS and RUNX1 genes. BMC Cancer 8, 299 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Van Vlierberghe, P. et al. The recurrent SETNUP214 fusion as a new HOXA activation mechanism in pediatric T-cell acute lymphoblastic leukemia. Blood 111, 4668–4680 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Mullighan, C. G. et al. Rearrangement of CRLF2 in B-progenitor- and Down syndrome-associated acute lymphoblastic leukemia. Nature Genet. 41, 1243–1246 (2009).

    Article  CAS  PubMed  Google Scholar 

  43. Santo, E. E. et al. Oncogenic activation of FOXR1 by 11q23 intrachromosomal deletion-fusions in neuroblastoma. Oncogene 31, 1571–1581 (2012).

    Article  CAS  PubMed  Google Scholar 

  44. Plaszczyca, A. et al. Fusions involving protein kinase C and membrane-associated proteins in benign fibrous histiocytoma. Int. J. Biochem. Cell. Biol. 53, 475–481 (2014).

    Article  CAS  PubMed  Google Scholar 

  45. Campbell, P. et al. Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing. Nature Genet. 40, 722–729 (2008).

    Article  CAS  PubMed  Google Scholar 

  46. Maher, C. A. et al. Transcriptome sequencing to detect gene fusions in cancer. Nature 458, 97–101 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Maher, C. A. et al. Chimeric transcript discovery by paired-end transcriptome sequencing. Proc. Natl Acad. Sci. USA 106, 12353–12358 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Stephens, P. J. et al. Complex landscapes of somatic rearrangement in human breast cancer genomes. Nature 462, 1005–1010 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hammerman, P. S. et al. Comprehensive genomic characterization of squamous cell lung cancers. Nature 489, 519–525 (2012).

    Article  CAS  Google Scholar 

  50. The Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330–337 (2012).

  51. Kandoth, C. et al. Integrated genomic characterization of endometrial carcinoma. Nature 497, 67–73 (2013).

    Article  CAS  PubMed  Google Scholar 

  52. Steidl, C. et al. MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers. Nature 471, 377–381 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Welch, J. S. et al. Use of whole-genome sequencing to diagnose a cryptic fusion oncogene. JAMA 305, 1577–1584 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Roberts, K. G. et al. Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia. Cancer Cell 22, 153–166 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Yoshihara, K. et al. The landscape and therapeutic relevance of cancer-associated transcript fusions. Oncogene http://dx.doi.org/10.1038/onc.2014.406 (2015).

  56. The Cancer Genome Atlas Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N. Engl. J. Med. 368, 2059–2074 (2013).

  57. The Cancer Genome Atlas Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499, 43–49 (2013).

  58. The Cancer Genome Atlas Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 507, 315–322 (2014).

  59. The Cancer Genome Atlas Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014).

  60. The Cancer Genome Atlas Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513, 202–209 (2014).

  61. Bass, A. J. et al. Genomic sequencing of colorectal adenocarcinomas identifies a recurrent VTI1A–TCF7L2 fusion. Nature Genet. 43, 964–968 (2011).

    Article  CAS  PubMed  Google Scholar 

  62. Chmielecki, J. et al. Whole-exome sequencing identifies a recurrent NAB2–STAT6 fusion in solitary fibrous tumors. Nature Genet. 45, 131–132 (2013).

    Article  CAS  PubMed  Google Scholar 

  63. Mohajeri, A. et al. Comprehensive genetic analysis identifies a pathognomonic NAB2/STAT6 fusion gene, nonrandom secondary genomic imbalances, and a characteristic gene expression profile in solitary fibrous tumor. Genes Chromosomes Cancer 52, 873–886 (2013).

    Article  CAS  PubMed  Google Scholar 

  64. Robinson, D. R. et al. Identification of recurrent NAB2–STAT6 gene fusions in solitary fibrous tumor by integrative sequencing. Nature Genet. 45, 180–185 (2013).

    Article  CAS  PubMed  Google Scholar 

  65. Kalyana-Sundaram, S. et al. Gene fusions associated with recurrent amplicons represent a class of passenger aberrations in breast cancer. Neoplasia 14, 702–708 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Lou, D. I. et al. High-throughput DNA sequencing errors are reduced by orders of magnitude using circle sequencing. Proc. Natl Acad. Sci. USA 110, 19872–19877 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Sleep, J. A., Schreiber, A. W. & Baumann, U. Sequencing error correction without a reference genome. BMC Bioinformatics 14, 367 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Bourgon, R. et al. High-throughput detection of clinically relevant mutations in archived tumor samples by multiplexed PCR and next-generation sequencing. Clin. Cancer Res. 20, 2080–2091 (2014).

    Article  CAS  PubMed  Google Scholar 

  69. Shiroguchi, K., Jia, T. Z., Sims, P. A. & Xie, X. S. Digital RNA sequencing minimizes sequence-dependent bias and amplification noise with optimized single-molecule barcodes. Proc. Natl Acad. Sci. USA 109, 1347–1352 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Carrara, M. et al. State-of-the-art fusion-finder algorithms sensitivity and specificity. Biomed. Res. Int. 2013, 340620 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Hedegaard, J. et al. Next-generation sequencing of RNA and DNA isolated from paired fresh-frozen and formalin-fixed paraffin-embedded samples of human cancer and normal tissue. PLoS ONE 9, e98187 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Kim, D. & Salzberg, S. L. TopHat-Fusion: an algorithm for discovery of novel fusion transcripts. Genome Biol. 12, R72 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Ozsolak, F. & Milos, P. M. RNA sequencing: advances, challenges and opportunities. Nature Reviews Genet. 12, 87–98 (2011).

    Article  CAS  Google Scholar 

  74. Nacu, S. et al. Deep RNA sequencing analysis of readthrough gene fusions in human prostate adenocarcinoma and reference samples. BMC Med. Genom. 4, 11 (2011).

    Article  CAS  Google Scholar 

  75. Rickman, D. S. et al. SLC45A3ELK4 is a novel and frequent erythroblast transformation-specific fusion transcript in prostate cancer. Cancer Res. 69, 2734–2738 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Gingeras, T. R. Implications of chimaeric non-co-linear transcripts. Nature 461, 206–211 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Zaphiropoulos, P. G. Trans-splicing in higher eukaryotes: implications for cancer development? Frontiers Genet. 2, 1–4 (2011).

    Article  Google Scholar 

  78. Jividen, K. & Li, H. Chimeric RNAs generated by intergenic splicing in normal and cancer cells. Genes Chromosomes Cancer 53, 963–971 (2014).

    Article  CAS  PubMed  Google Scholar 

  79. Panagopoulos, I. Absence of the JAZF1/SUZ12 chimeric transcript in the immortalized non-neoplastic endometrial stromal cell line T HESCs. Oncol. Lett. 1, 947–950 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Hayward, W. S., Neel, B. G. & Astrin, S. M. Activation of a cellular onc gene by promoter insertion in ALV-induced lymphoid leukosis. Nature 290, 475–480 (1981).

    Article  CAS  PubMed  Google Scholar 

  81. Neel, B. G., Hayward, W. S., Robinson, H. L., Fang, J. & Astrin, S. M. Avian leukosis virus-induced tumors have common proviral integration sites and synthesize discrete new RNAs: oncogenesis by promoter insertion. Cell 23, 323–334 (1981).

    Article  CAS  PubMed  Google Scholar 

  82. Payne, G. S. et al. Analysis of avian leukosis virus DNA and RNA in bursal tumours: viral gene expression is not required for maintenance of the tumor state. Cell 23, 311–322 (1981).

    Article  CAS  PubMed  Google Scholar 

  83. Cairns, J. The origin of human cancers. Nature 289, 353–357 (1981).

    Article  CAS  PubMed  Google Scholar 

  84. Klein, G. The role of gene dosage and genetic transpositions in carcinogenesis. Nature 294, 313–318 (1981).

    Article  CAS  PubMed  Google Scholar 

  85. Leder, P. et al. Translocations among antibody genes in human cancer. Science 222, 765–771 (1983).

    Article  CAS  PubMed  Google Scholar 

  86. Croce, C. M. & Nowell, P. C. Molecular basis of neoplasia. Blood 65, 1–7 (1985).

    CAS  PubMed  Google Scholar 

  87. Klein, G. & Klein, E. Conditioned tumorigenicity of activated oncogenes. Cancer Res. 46, 3211–3224 (1986).

    CAS  PubMed  Google Scholar 

  88. Tsujimoto, Y. et al. Molecular cloning of the chromosomal breakpoint of B-cell lymphomas and leukemias with the t(11;14) chromosome translocation. Science 224, 1403–1406 (1984).

    Article  CAS  PubMed  Google Scholar 

  89. Tsujimoto, Y., Finger, L. R., Yunis, J., Nowell, P. C. & Croce, C. M. Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation. Science 226, 1097–1099 (1984).

    Article  CAS  PubMed  Google Scholar 

  90. Grimaldi, J. C. & Meeker, T. C. The t(5;14) chromosomal translocation in a case of acute lymphocytic leukemia joins the interleukin-3 gene to the immunoglobulin heavy chain gene. Blood 73, 2081–2085 (1989).

    CAS  PubMed  Google Scholar 

  91. Korsmeyer, S. J. Chromosomal translocations in lymphoid malignancies reveal novel proto-oncogenes. Annu. Rev. Immunol. 10, 785–807 (1992).

    Article  CAS  PubMed  Google Scholar 

  92. Erikson, J. et al. Deregulation of c-myc by translocation of the α-locus of the T-cell receptor in T-cell leukemias. Science 232, 884–886 (1986).

    Article  CAS  PubMed  Google Scholar 

  93. Hayashi, Y., Yamamoto, K. & Kojima, S. T-cell acute lymphoblastic leukemias with a t(8;14) possibly involving a c-myc locus and T-cell-receptor α-chain genes. N. Engl. J. Med. 314, 650–651 (1986).

    Article  CAS  PubMed  Google Scholar 

  94. Mathieu-Mahul, D. et al. A t(8;14)(q24;q11) translocation in a T-cell leukemia (L1-ALL) with c-myc and TcR-α chain locus rearrangements. Int. J. Cancer 38, 835–840 (1986).

    Article  CAS  PubMed  Google Scholar 

  95. McKeithan, T. W. et al. Molecular cloning of the breakpoint junction of a human chromosomal 8;14 translocation involving the T-cell receptor α-chain gene and sequences on the 3′ side of MYC. Proc. Natl Acad. Sci. USA 83, 6636–6640 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Van Vlierberghe, P. & Ferrando, A. The molecular basis of T cell acute lymphoblastic leukemia. J. Clin. Invest. 122, 3398–3406 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Rabbitts, T. H. Chromosomal translocations in human cancer. Nature 372, 143–149 (1994).

    Article  CAS  PubMed  Google Scholar 

  98. O'Neil, J. & Look, A. T. Mechanisms of transcription factor deregulation in lymphoid cell transformation. Oncogene 26, 6838–6849 (2007).

    Article  CAS  PubMed  Google Scholar 

  99. Hatzi, K. & Melnick, A. Breaking bad in the germinal center: how deregulation of BCL6 contributes to lymphomagenesis. Trends Mol. Med. 20, 343–352 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Anderson, M. A., Huang, D. & Roberts, A. Targeting BCL2 for the treatment of lymphoid malignancies. Semin. Hematol. 51, 219–227 (2014).

    Article  CAS  PubMed  Google Scholar 

  101. Sonoki, T. et al. Cyclin D3 is a target gene of t(6;14)(p21.1;q32.3) of mature B-cell malignancies. Blood 98, 2837–2844 (2001).

    Article  CAS  PubMed  Google Scholar 

  102. Clappier, E. et al. Cyclin D2 dysregulation by chromosomal translocations to TCR loci in T-cell acute lymphoblastic leukemias. Leukemia 20, 82–86 (2006).

    Article  CAS  PubMed  Google Scholar 

  103. Hasanali, Z., Sharma, K. & Epner, E. Flipping the cyclin D1 switch in mantle cell lymphoma. Best Pract. Res. Clin. Haematol. 25, 143–152 (2012).

    Article  CAS  PubMed  Google Scholar 

  104. Russell, L. J. et al. Deregulated expression of cytokine receptor gene, CRLF2, is involved in lymphoid transformation in B-cell precursor acute lymphoblastic leukemia. Blood 114, 2688–2698 (2009).

    Article  CAS  PubMed  Google Scholar 

  105. Karrman, K. et al. The t(X;7)(q22;q34) in paediatric T-cell acute lymphoblastic leukaemia results in overexpression of the insulin receptor substrate 4 gene through illegitimate recombination with the T-cell receptor β locus. Br. J. Haematol. 144, 546–551 (2009).

    Article  CAS  PubMed  Google Scholar 

  106. Nagel, I. et al. Deregulation of the telomerase reverse transcriptase (TERT) gene by chromosomal translocations in B-cell malignancies. Blood 116, 1317–1320 (2010).

    Article  CAS  PubMed  Google Scholar 

  107. Kas, K. et al. Promoter swapping between the genes for a novel zinc finger protein and β-catenin in pleiomorphic adenomas with t(3;8)(p21;q12) translocations. Nature Genet. 15, 170–174 (1997).

    Article  CAS  PubMed  Google Scholar 

  108. Duhoux, F. P. et al. PRDM16 (1p36) translocations define a distinct entity of myeloid malignancies with poor prognosis but may also occur in lymphoid malignancies. Br. J. Haematol. 156, 76–88 (2012).

    Article  CAS  PubMed  Google Scholar 

  109. Oliveira, A. M. et al. Aneurysmal bone cyst variant translocations upregulate USP6 transcription by promoter swapping with the ZNF9, COL1A1, TRAP150, and OMD genes. Oncogene 24, 3419–3426 (2005).

    Article  CAS  PubMed  Google Scholar 

  110. 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  CAS  PubMed  Google Scholar 

  111. Stam, K. et al. Evidence of a new chimeric bcr/c-abl mRNA in patients with chronic myelocytic leukemia and the Philadelphia chromosome. N. Engl. J. Med. 313, 1429–1433 (1985).

    Article  CAS  PubMed  Google Scholar 

  112. Kamps, M. P., Murre, C., Sun, X. & Baltimore, D. A new homeobox gene contributes the DNA binding domain of the t(1;19) translocation protein in pre-B ALL. Cell 60, 547–555 (1990).

    Article  CAS  PubMed  Google Scholar 

  113. Nourse, J. et al. Chromosomal translocation t(1;19) results in synthesis of a homeobox fusion mRNA that codes for a potential chimeric transcription factor. Cell 60, 535–545 (1990).

    Article  CAS  PubMed  Google Scholar 

  114. von Lindern, M. et al. The translocation (6;9), associated with a specific subtype of acute myeloid leukemia, results in the fusion of two genes, dek and can, and the expression of a chimeric, leukemia-specific dek–can mRNA. Mol. Cell. Biol. 12, 1687–1697 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. de Thé, H., Chomienne, C., Lanotte, M., Degos, L. & Dejean, A. The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor α gene to a novel transcribed locus. Nature 347, 558–561 (1990).

    Article  PubMed  Google Scholar 

  116. Lemons, R. S. et al. Cloning and characterization of the t(15;17) translocation breakpoint region in acute promyelocytic leukemia. Genes Chromosomes Cancer 2, 79–87 (1990).

    Article  CAS  PubMed  Google Scholar 

  117. Delattre, O. et al. Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours. Nature 359, 162–165 (1992).

    Article  CAS  PubMed  Google Scholar 

  118. Pierotti, M. A. et al. Characterization of an inversion on the long arm of chromosome 10 juxtaposing D10S170 and RET and creating the oncogenic sequence RET/PTC. Proc. Natl Acad. Sci. USA 89, 1616–1620 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Santoro, M. et al. Ret oncogene activation in human thyroid neoplasms is restricted to the papillary cancer subtype. J. Clin. Invest. 89, 1517–1522 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Crozat, A., Aman, P., Mandahl, N. & Ron, D. Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma. Nature 363, 640–644 (1993).

    Article  CAS  PubMed  Google Scholar 

  121. Sorensen, P. H. & Triche, T. J. Gene fusions encoding chimaeric transcription factors in solid tumours. Semin. Cancer Biol. 7, 3–14 (1996).

    Article  CAS  PubMed  Google Scholar 

  122. Barr, F. G. Chromosomal translocations involving paired box transcription factors in human cancer. Int. J. Biochem. Cell Biol. 29, 1449–1461 (1997).

    Article  CAS  PubMed  Google Scholar 

  123. Slape, C. & Aplan, P. D. The role of NUP98 gene fusions in hematologic malignancy. Leuk. Lymphoma 45, 1341–1350 (2004).

    Article  CAS  PubMed  Google Scholar 

  124. Krivtsov, A. V. & Armstrong, S. A. MLL translocations, histone modofactions and leukaemia stem-cell development. Nature Reviews Cancer 7, 823–833 (2007).

    Article  CAS  PubMed  Google Scholar 

  125. Meyer, C. et al. The MLL recombinome of acute leukemias in 2013. Leukemia 27, 2165–2176 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Seshagiri, S. et al. Recurrent R-spondin fusions in colon cancer. Nature 488, 660–664 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Frattini, V. et al. The integrated landscape of driver genomic alterations in glioblastoma. Nature Genet. 45, 1141–1149 (2013).

    Article  CAS  PubMed  Google Scholar 

  128. Duro, D. et al. Inactivation of the P16INK4/MTS1 gene by a chromosome translocation t(9;14)(p21-22;q11) in an acute lymphoblastic leukemia of B-cell type. Cancer Res. 56, 848–854 (1996).

    CAS  PubMed  Google Scholar 

  129. Storlazzi, C. T., Von Steyern, F. V., Domanski, H. A., Mandahl, N. & Mertens, F. Biallelic somatic inactivation of the NF1 gene through chromosomal translocations in a sporadic neurofibroma. Int. J. Cancer 117, 1055–1057 (2005).

    Article  CAS  PubMed  Google Scholar 

  130. Coyaud, E. et al. Wide diversity of PAX5 alterations in B-ALL: a Groupe Francophone de Cytogenetique Hematologique study. Blood 115, 3089–3097 (2010).

    Article  CAS  PubMed  Google Scholar 

  131. Ågerstam, H. et al. Fusion gene-mediated truncation of RUNX1 as a potential mechanism underlying disease progression in the 8p11 myeloproliferative syndrome. Genes Chromosomes Cancer 46, 635–643 (2007).

    Article  CAS  PubMed  Google Scholar 

  132. Büschges, R. et al. Amplification and expression of cyclin D genes (CCND1, CCND2 and CCND3) in human malignant gliomas. Brain Pathol. 9, 435–442 (1999).

    Article  PubMed  Google Scholar 

  133. Bohlander, S. K. ETV6: a versatile player in leukemogenesis. Semin. Cancer. Biol. 15, 162–174 (2005).

    Article  CAS  PubMed  Google Scholar 

  134. Clappier, E. et al. The C-MYB locus is involved in chromosomal translocation and genomic duplications in human T-cell acute leukemia (T-ALL), the translocation defining a new T-ALL subtype in very young children. Blood 110, 1251–1261 (2007).

    Article  CAS  PubMed  Google Scholar 

  135. Mullighan, C. G. et al. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature 446, 758–764 (2007).

    Article  CAS  PubMed  Google Scholar 

  136. Tzoneva, G. & Ferrando, A. A. Recent advances on NOTCH signaling in T-ALL. Curr. Top. Microbiol. Immunol. 360, 163–182 (2012).

    CAS  PubMed  Google Scholar 

  137. Huether, R. et al. The landscape of somatic mutations in epigenetic regulators across 1,000 pediatric cancer genomes. Nature Commun. 5, 3630 (2014).

    Article  CAS  Google Scholar 

  138. Hofvander, J. et al. Recurrent PRDM10 gene fusions in undifferentiated pleomorphic sarcoma. Clin. Cancer Res. 21, 864–869 (2015).

    Article  CAS  PubMed  Google Scholar 

  139. Tomlins, S. A. et al. Urine TMPRSS2:ERG fusion transcript stratifies prostate cancer risk in men with elevated serum PSA. Sci. Transl. Med. 3, 94ra72 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Balgobind, B. V. et al. Novel prognostic subgroups in childhood 11q23/MLL-rearranged acute myeloid leukemia: results of an international retrospective study. Blood 114, 2489–2496 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Williamson, D. et al. Fusion gene-negative alveolar rhabdomyosarcoma is clinically and molecularly indistinguishable from embryonal rhabdomyosarcoma. J. Clin. Oncol. 28, 2151–2158 (2010).

    Article  PubMed  Google Scholar 

  142. Doyle, L. A. et al. MUC4 is a highly sensitive and specific marker for low-grade fibromyxoid sarcoma. Am. J. Surg. Pathol. 35, 733–741 (2011).

    Article  PubMed  Google Scholar 

  143. Minca, E. C. et al. ALK status testing in non-small cell lung carcinoma: correlation between ultrasensitive IHC and FISH. J. Mol. Diagn. 15, 341–346 (2013).

    Article  CAS  PubMed  Google Scholar 

  144. Shah, R. B. Clinical applications of novel ERG immunohistochemistry in prostate cancer diagnosis and management. Adv. Anat. Pathol. 20, 117–124 (2013).

    Article  CAS  PubMed  Google Scholar 

  145. Doyle, L. A. et al. Nuclear expression of STAT6 distinguishes solitary fibrous tumor from histologic mimics. Mod. Pathol. 27, 390–395 (2014).

    Article  CAS  PubMed  Google Scholar 

  146. Swerdlow, S. H. et al. (eds) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (IARC, 2008).

    Google Scholar 

  147. Fletcher, C. D. M., Bridge, J. A., Hogendoorn, P. C. W. & Mertens, F. (eds) WHO Classification of Tumours of Soft Tissue and Bone (IARC, 2013).

    Google Scholar 

  148. Hokland, P. & Ommen, H. B. Towards individualized follow-up in adult acute myeloid leukemia in remission. Blood 117, 2577–2584 (2011).

    Article  CAS  PubMed  Google Scholar 

  149. Crowley, E., Di Nicolantonio, F., Loupakis, F. & Bardelli, A. Liquid biopsy: monitoring cancer-genetics in the blood. Nature Reviews Clin. Oncol. 10, 472–484 (2013).

    Article  CAS  Google Scholar 

  150. Karabacak, N. M. et al. Microfluidic, marker-free isolation of circulating tumor cells from blood samples. Nature Protoc. 9, 694–710 (2014).

    Article  CAS  Google Scholar 

  151. Watanabe, M. et al. A novel flow cytometry-based cell capture platform for the detection, capture and molecular characterization of rare tumor cells in blood. J. Transl. Med. 12, 143 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  152. Yu, K. H. et al. Pharmacogenomic modeling of circulting and invasive cells for prediction of chemotherapy response and resistance in pancreatic cancer. Clin. Cancer Res. 20, 5281–5289 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Leary, R. J. et al. Development of personalized tumor biomarkers using massively parallel sequencing. Sci. Transl. Med. 2, 20ra14 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Druker, B. J. Translation of the Philadelphia chromosome into therapy for CML. Blood 112, 4808–4817 (2008).

    Article  CAS  PubMed  Google Scholar 

  155. Rutkowski, P. et al. Imatinib mesylate in advanced dermatofibrosarcoma protuberans: pooled analysis of two Phase II clinical trials. J. Clin. Oncol. 28, 1772–1779 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Lee, H. J., Thompson, J. E., Wang, E. S. & Wetzler, M. Philadelphia chromosome-positive acute lymphoblastic leukemia: current treatment and future perspectives. Cancer 117, 1583–1594 (2011).

    Article  PubMed  Google Scholar 

  157. Joensuu, H. Adjuvant treatment of GIST: patient selection and treatment strategies. Nature Reviews Clin. Oncol. 9, 351–358 (2012).

    Article  CAS  Google Scholar 

  158. Kohno, T. et al. RET fusion gene: translation to personalized lung cancer therapy. Cancer Sci. 104, 1396–1400 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Shaw, A. T. et al. Tyrosine kinase gene rearrangements in epithelial malignancies. Nature Reviews Cancer 13, 772–787 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Feng, F. Y., Brenner, J. C., Hussain, M. & Chinnaiyan, A. M. Molecular pathways: targeting ETS gene fusions in cancer. Clin. Cancer Res. 20, 4442–4448 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Parker, B. C., Engels, M., Annala, M. & Zhang, W. Emergence of FGFR family gene fusions as therapeutic targets in a wide spectrum of solid tumours. J. Pathol. 232, 4–15 (2014).

    Article  CAS  PubMed  Google Scholar 

  162. Højfeldt, J. W., Agger, K. & Helin, K. Histone lysine demethylases as targets for anticancer therapy. Nature Reviews Drug Discov. 12, 917–930 (2013).

    Article  CAS  Google Scholar 

  163. Sanger, F. et al. Nucleotide sequence of bacteriophage Φ X174 DNA. Nature 265, 687–695 (1977).

    Article  CAS  PubMed  Google Scholar 

  164. Sanger, F., Nicklen, S. & Coulson, A. R. DNA sequencing with chain-terminating inhibitors. Proc. Natl Acad. Sci. USA 74, 5463–5467 (1977).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Margulies, M. et al. Genome sequencing in microfabricated high-density picolitre reactors. Nature 437, 376–380 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Shendure, J. et al. Accurate multiplex polony sequencing of an evolved bacterial genome. Science 309, 1728–1732 (2005).

    Article  CAS  PubMed  Google Scholar 

  167. Volik, S. et al. End-sequence profiling: sequence-based analysis of aberrant genomes. Proc. Natl Acad. Sci. USA 100, 7696–7701 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  168. Volik, S. et al. Decoding the fine-scale structure of a breast cancer genome and transcriptome. Genome Res. 16, 394–404 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Ng, P. et al. Gene identification signature (GIS) analysis for transcriptome characterization and genomic annotation. Nature Methods 2, 105–111 (2005).

    Article  CAS  PubMed  Google Scholar 

  170. Ng, P. et al. Multiplex sequencing of paired-end ditags (MS-PET): a strategy for the ultra-high-throughput analysis of transcriptomes and genomes. Nucleic Acids Res. 34, e84 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Korbel, J. O. et al. Paired-end mapping reveals extensive structural variation in the human genome. Science 318, 420–426 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Schoenmakers, E. F. P. M. et al. Recurrent rearrangements in the high mobility group protein gene, HMGI-C, in benign mesenchymal tumours. Nature Genet. 10, 436–444 (1995).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors would like to acknowledge financial support from the Swedish Cancer Society, the Swedish Research Council and the Swedish Childhood Cancer Foundation.

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Mertens, F., Johansson, B., Fioretos, T. et al. The emerging complexity of gene fusions in cancer. Nat Rev Cancer 15, 371–381 (2015). https://doi.org/10.1038/nrc3947

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