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The impact of translocations and gene fusions on cancer causation

Key Points

  • Chromosome aberrations are a characteristic feature of neoplasia, and acquired chromosome changes have now been reported in more than 50,000 cases across all main cancer types.

  • Recurrent balanced chromosome rearrangements, in particular translocations, are strongly associated with distinct tumour entities, and there is compelling evidence that they represent an initial event in oncogenesis.

  • Balanced chromosome abnormalities result in the formation of gene fusions and exert their tumorigenic action by two alternative mechanisms: overexpression of a gene in one of the breakpoints or the creation of a hybrid gene through the fusion of two genes, one in each breakpoint.

  • A total of 358 gene fusions, involving 337 different genes, are known at present and have been described in all the main subtypes of human neoplasia.

  • The prevalence of gene fusions varies considerably, from 0–100%, among different tumour types. Among malignant disorders, the proportions of gene fusion-positive cases are similar in haematological disorders, sarcomas and carcinomas.

  • The gene fusions identified to date account for approximately 20% of human cancer morbidity.

  • A number of conceptually important questions remain to be answered: why, how and when do chromosome aberrations originate? Are the resulting gene fusions sufficient for tumorigenesis, and if not, what is the pathogenetic relationship between these gene rearrangements and the other genetic and epigenetic alterations that characterize neoplastic cells?

Abstract

Chromosome aberrations, in particular translocations and their corresponding gene fusions, have an important role in the initial steps of tumorigenesis; at present, 358 gene fusions involving 337 different genes have been identified. An increasing number of gene fusions are being recognized as important diagnostic and prognostic parameters in malignant haematological disorders and childhood sarcomas. The biological and clinical impact of gene fusions in the more common solid tumour types has been less appreciated. However, an analysis of available data shows that gene fusions occur in all malignancies, and that they account for 20% of human cancer morbidity. With the advent of new and powerful investigative tools that enable the detection of cytogenetically cryptic rearrangements, this proportion is likely to increase substantially.

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Figure 1: The number of cytogenetically abnormal neoplasms reported in the literature.
Figure 2: Gene fusion leading to gene upregulation.
Figure 3: Gene fusion leading to a chimeric gene.
Figure 4: Interconnected networks of gene fusions.
Figure 5: The distribution of 45,472 cytogenetically abnormal malignant disorders reported in the literature and the impact of gene fusions on cancer morbidity.

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References

  1. Boveri, T. Zur Frage der Entstehung maligner Tumoren. Gustav Fisher Verlag, Jena (1914).

    Google Scholar 

  2. Tjio, J. H. & Levan, A. The chromosome number of man. Hereditas 42, 1–6 (1956).

    Article  Google Scholar 

  3. Nowell, P. C. & Hungerford, D. A. A minute chromosome in human chronic granulocytic leukemia. Science 132, 1497 (1960). The first description of a specific cancer-associated chromosome abnormality.

    Google Scholar 

  4. 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 

  5. Vogelstein, B. & Kinzler, K. W. Cancer genes and the pathways they control. Nature Med. 10, 789–799 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. Rowley, J. D. A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 243, 290–293 (1973). The first report of a specific translocation in a human malignancy.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  8. Look, A. T. Oncogenic transcription factors in human acute leukemias. Science 278, 1059–1064 (1997).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. Mitelman, F., Johansson, B. & Mertens, F. Mitelman Database of Chromosome Aberrations in Cancer [online], http://cgap.nci.nih.gov/Chromosomes/Mitelman (2006). A comprehensive resource of all published neoplasia-associated karyotypes and their corresponding gene fusions.

  11. Kearney, L. & Horsley, S. W. Molecular cytogenetics in haematological malignancy: current technology and future prospects. Chromosoma 114, 286–294 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  15. Sjöblom, T. et al. The consensus coding sequences of human breast and colorectal cancers. Science 314, 268–274 (2006). A recent large-scale study showing an unexpectedly large number of mutations in breast and colon cancer.

    Article  PubMed  CAS  Google Scholar 

  16. Mandahl, N. Cytogenetics and molecular genetics of bone and soft tissue tumors. Adv. Cancer Res. 69, 63–99 (1996).

    Article  CAS  PubMed  Google Scholar 

  17. Harrison, C. J. & Foroni, L. Cytogenetics and molecular genetics of acute lymphoblastic leukemia. Rev. Clin. Exp. Hematol. 6, 91–113 (2002).

    Article  CAS  PubMed  Google Scholar 

  18. Borden, E. C. et al. Soft tissue sarcomas of adults: state of the translational science. Clin. Cancer Res. 9, 1941–1956 (2003).

    PubMed  Google Scholar 

  19. Johansson, B., Mertens, F. & Mitelman, F. Clinical and biological importance of cytogenetic abnormalities in childhood and adult acute lymphoblastic leukemia. Ann. Med. 36, 492–503 (2004).

    Article  CAS  PubMed  Google Scholar 

  20. Mrózek, K., Heerema, N. A. & Bloomfield, C. D. Cytogenetics in acute leukemia. Blood Rev. 18, 115–136 (2004).

    Article  PubMed  Google Scholar 

  21. Mitelman, F., Mertens, F. & Johansson B. Prevalence estimates of recurrent balanced cytogenetic aberrations and gene fusions in unselected patients with neoplastic disorders. Genes Chromosomes Cancer 43, 350–366 (2005).

    Article  CAS  PubMed  Google Scholar 

  22. Yeoh, E. J. et al. Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling. Cancer Cell 1, 133–143 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Andersson, A. et al. Molecular signatures in childhood acute leukemia and their correlations to expression patterns in normal hematopoietic subpopulations. Proc. Natl Acad. Sci. USA 102, 19069–19074 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Davicioni, E. et al. Identification of a PAX-FKHR gene expression signature that defines molecular classes and determines the prognosis of alveolar rhabdomyosarcomas. Cancer Res. 66, 6936–6946 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Nowell, P. C. The clonal evolution of tumor cell populations. Science 194, 23–28 (1976).

    Article  CAS  PubMed  Google Scholar 

  26. Heim, S., Mandahl, N. & Mitelman, F. Genetic convergence and divergence in tumor progression. Cancer Res. 48, 5911–5916 (1988).

    CAS  PubMed  Google Scholar 

  27. Johansson, B., Mertens, F. & Mitelman, F. Primary vs. secondary neoplasia-associated chromosomal abnormalities – balanced rearrangements vs. genomic imbalances? Genes Chromosomes Cancer 16, 155–163 (1996).

    Article  CAS  PubMed  Google Scholar 

  28. Nowell, P. C. Tumor progression: a brief historical perspective. Semin. Cancer Biol. 12, 261–266 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Hauschka, T. S. Cell population studies on mouse ascites tumors. Ann. NY Acad. Sci. 16, 64–73 (1953).

    CAS  Google Scholar 

  30. Levan, A. Chromosomal studies on some human tumors and tissues of normal origin, grown in vivo and in vitro at the Sloan-Kettering Institute. Cancer 9, 648–663 (1956).

    Article  CAS  PubMed  Google Scholar 

  31. Makino, S. Further evidence favoring the concept of the stem cell in ascites tumors of rats. Ann. NY Acad. Sci. 63, 818–830 (1956).

    Article  CAS  PubMed  Google Scholar 

  32. Heim, S. & Mitelman, F. Primary chromosome abnormalities in human neoplasia. Adv. Cancer Res. 52, 1–43 (1989).

    Article  CAS  PubMed  Google Scholar 

  33. 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, 738–743 (2000).

    Article  CAS  PubMed  Google Scholar 

  34. Kolomietz, E. et al. Primary chromosomal rearrangements of leukemia are frequently accompanied by extensive submicroscopic deletions and may lead to altered prognosis. Blood 97, 3581–3588 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. Aplan, P. D. Causes of oncogenic chromosomal translocation. Trends Genet. 22, 46–55 (2006). A recent review of mechanisms behind the origin of neoplasia-associated translocations and gene fusions.

    Article  CAS  PubMed  Google Scholar 

  36. Rego, E. M. & Pandolfi, P. P. Reciprocal products of chromosomal translocations in human cancer pathogenesis: key players or innocent bystanders? Trends Mol. Med. 8, 396–405 (2002).

    Article  CAS  PubMed  Google Scholar 

  37. Xia S. J. & Barr, F. G. Chromosome translocations in sarcomas and the emergence of oncogenic transcription factors. Eur. J. Cancer 41, 2513–2527 (2005).

    Article  CAS  PubMed  Google Scholar 

  38. Antonescu, C. R. The role of genetic testing in soft tissue sarcoma. Histopathology 48, 13–21 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Oehler, V. G. & Radich, J. P. Monitoring bcr-abl by polymerase chain reaction in the treatment of chronic myeloid leukemia. Curr. Oncol. Rep. 5, 426–435 (2003).

    Article  PubMed  Google Scholar 

  40. Avigad, S. et al. The predictive potential of molecular detection in the nonmetastatic Ewing family of tumors. Cancer 100, 1053–1058 (2004).

    Article  PubMed  Google Scholar 

  41. Deininger, M., Buchdunger, E. & Druker, B. J. The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood 105, 2640–2653 (2005). Provides an up-to-date review of targeted therapy in BCR ABL1 -positive leukaemia.

    Article  CAS  PubMed  Google Scholar 

  42. Kern, W., Schoch, C., Haferlach, T. & Schnittger, S. Monitoring of minimal residual disease in acute myeloid leukemia. Crit. Rev. Oncol. Hematol. 56, 283–309 (2005).

    Article  PubMed  Google Scholar 

  43. Adams, J. M. et al. The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature 318, 533–538 (1985).

    Article  CAS  PubMed  Google Scholar 

  44. Daley, G. Q., Van Etten, R. A. & Baltimore, D. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science 247, 824–830 (1990).

    Article  CAS  PubMed  Google Scholar 

  45. Elefanty, A. G., Hariharan, I. K. & Cory, S. bcr-abl, the hallmark of chronic myeloid leukaemia in man, induces multiple haemopoietic neoplasms in mice. EMBO J. 9, 1069–1078 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Heisterkamp, N. et al. Acute leukaemia in bcr/abl transgenic mice. Nature 344, 251–253 (1990).

    Article  CAS  PubMed  Google Scholar 

  47. Kamps, M. P. & Baltimore, D. E2A-Pbx1, the t(1;19) translocation protein of human pre-B-cell acute lymphocytic leukemia, causes acute myeloid leukemia in mice. Mol. Cell Biol. 13, 351–357 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Corral, J. et al. An Mll-AF9 fusion gene made by homologous recombination causes acute leukemia in chimeric mice: a method to create fusion oncogenes. Cell 85, 853–861 (1996).

    Article  CAS  PubMed  Google Scholar 

  49. Pérez-Losada, J. et al. The chimeric FUS/TLS-CHOP fusion protein specifically induces liposarcomas in transgenic mice. Oncogene 19, 2413–2422 (2000).

    Article  PubMed  Google Scholar 

  50. Rego, E. M. et al. Leukemia with distinct phenotypes in transgenic mice expressing PML/RARα, PLZF/RAR α or NPM/RAR α. Oncogene 25, 1974–1979 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Rodriguez-Garcia, A. et al. Selective destruction of tumor cells through specific inhibition of products resulting from chromosomal translocations. Curr. Cancer Drug Targets 1, 109–119 (2001).

    Article  CAS  PubMed  Google Scholar 

  52. Thomas, M., Greil, J. & Heidenreich, O. Targeting leukemic fusion proteins with small interfering RNAs: recent advances and therapeutic potentials. Acta Pharmacol. Sin. 27, 273–281 (2006).

    Article  CAS  PubMed  Google Scholar 

  53. Küppers, R. Mechanisms of B-cell lymphoma pathogenesis. Nature Rev. Cancer 5, 251–262 (2005).

    Article  CAS  Google Scholar 

  54. Sirvent, N., Maire, G. & Pedeutour, F. Genetics of dermatofibrosarcoma protuberans family of tumors: from ring chromosomes to tyrosine kinase inhibitor treatment. Genes Chromosomes Cancer 37, 1–19 (2003).

    Article  CAS  PubMed  Google Scholar 

  55. Kas, K. et al. Promoter swapping between the genes for a novel zinc finger protein and beta-catenin in pleiomorphic adenomas with t(3;8)(p21;q12) translocations. Nature Genet. 15, 170–174 (1997). First example of a translocation resulting in gene deregulation through promoter exchange in a solid tumour.

    Article  CAS  PubMed  Google Scholar 

  56. Dahlén, A. et al. Activation of the GLI oncogene through fusion with the β-actin gene (ACTB) in a group of distinctive pericytic neoplasms: pericytoma with t(7;12). Am. J. Pathol. 164, 1645–1653 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  57. 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 

  58. 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 

  59. Popovici, C. et al. Reciprocal translocations in breast tumor cell lines: cloning of a t(3;20) that targets the FHIT gene. Genes Chromosomes Cancer 35, 204–218 (2002).

    Article  CAS  PubMed  Google Scholar 

  60. Belloni, E. et al. A new complex rearrangement involving the ETV6, LOC115548, and MN1 genes in a case of acute myeloid leukemia. Genes Chromosomes Cancer 41, 272–277 (2004).

    Article  CAS  PubMed  Google Scholar 

  61. Karenko, L. et al. Primary cutaneous T-cell lymphomas show a deletion or translocation affecting NAV3, the human UNC-53 homologue. Cancer Res. 65, 8101–8110 (2005).

    Article  CAS  PubMed  Google Scholar 

  62. Berger, R. et al. Loss of the NPM1 gene in myeloid disorders with chromosome 5 rearrangements. Leukemia 20, 319–321 (2006).

    Article  CAS  PubMed  Google Scholar 

  63. Panagopoulos, I. et al. Fusion of ETV6 with an intronic sequence of the BAZ2A gene in a paediatric pre-B acute lymphoblastic leukaemia with a cryptic chromosome 12 rearrangement. Br. J. Haematol. 133, 270–275 (2006).

    Article  CAS  PubMed  Google Scholar 

  64. Deininger, M. W. N., Goldman, J. M. & Melo, J. V. The molecular biology of chronic myeloid leukemia. Blood 96, 3343–3356 (2000).

    Article  CAS  PubMed  Google Scholar 

  65. 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). An analysis of the impact of cytogenetic analyses on the detection of new gene fusions.

    Article  CAS  PubMed  Google Scholar 

  66. Lannon, C. L. & Sorensen, P. H. B. ETV6-NTRK3: a chimeric protein tyrosine kinase with transformation activity in multiple cell lineages. Semin. Cancer Biol. 15, 215–223 (2005). A review of the pathogenetic implications of a gene fusion involved in histogenetically distinct tumour types.

    Article  CAS  PubMed  Google Scholar 

  67. Meyer, C. et al. The MLL recombinome of acute leukemias. Leukemia 20, 777–784 (2006). A recent summary of partner genes involved in fusions with the MLL gene.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  69. Janknecht, R. EWS-ETS oncoproteins: the linchpin of Ewing tumors. Gene 363, 1–14 (2005).

    Article  CAS  PubMed  Google Scholar 

  70. Höglund, M., Frigyesi, A. & Mitelman, F. A gene fusion network in human neoplasia. Oncogene 25, 2674–2678 (2006).

    Article  PubMed  CAS  Google Scholar 

  71. Barabási, A.-L. & Oltvai, Z. N. Network biology: understanding the cell's functional organization. Nature Rev. Genet. 5, 101–113 (2004).

    Article  PubMed  CAS  Google Scholar 

  72. Ladanyi, M. et al. The der(17)t(X;17)(p11;q25) of human alveolar soft part sarcoma fuses the TFE3 transcription factor gene to ASPL, a novel gene at 17q25. Oncogene 20, 48–57 (2001).

    Article  CAS  PubMed  Google Scholar 

  73. Graux, C. et al. Fusion of NUP214 to ABL1 on amplified episomes in T-cell acute lymphoblastic leukemia. Nature Genet. 36, 1084–1089 (2004).

    Article  CAS  PubMed  Google Scholar 

  74. 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 

  75. Kourlas, P. J. et al. Identification of a gene at 11q23 encoding a guanine nucleotide exchange factor: evidence for its fusion with MLL in acute myeloid leukemia. Proc. Natl Acad. Sci. USA 97, 2145–2150 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Fu J.-F., Hsu J.-J., Tang T.-C. & Shih L.-Y. Identification of CBL, a proto-oncogene at 11q23. 3, as a novel MLL fusion partner in a patient with de novo acute myeloid leukemia. Genes Chromosomes Cancer 37, 214–219 (2003).

    Article  CAS  PubMed  Google Scholar 

  77. Meyer, C. et al. Diagnostic tool for the identification of MLL rearrangements including unknown partner genes. Proc. Natl Acad. Sci. USA 102, 449–454 (2005).

    Article  CAS  PubMed  Google Scholar 

  78. Pardanani, A. et al. CHIC2 deletion, a surrogate for FIP1L1-PDGFRA fusion, occurs in systemic mastocytosis associated with eosinophilia and predicts response to imatinib mesylate therapy. Blood 102, 3093–3096 (2003).

    Article  CAS  PubMed  Google Scholar 

  79. Hibbard, M. K. et al. PLAG1 fusion oncogenes in lipoblastoma. Cancer Res. 60, 4869–4872 (2000).

    CAS  PubMed  Google Scholar 

  80. Charest, A. et al. Fusion of FIG to the receptor tyrosine kinase ROS in a glioblastoma with an interstitial del(6)(q21q21). Genes Chromosomes Cancer 37, 58–71 (2003).

    Article  CAS  PubMed  Google Scholar 

  81. Perner, S. et al. TMPRSS2:ERG fusion-associated deletions provide insight into the heterogeneity of prostate cancer. Cancer Res. 66, 8337–8341 (2006).

    Article  CAS  PubMed  Google Scholar 

  82. Yoshimoto, M. et al. Three-color FISH analysis of TMPRSS2/ERG fusions in prostate cancer indicates that genomic microdeletion of chromosome 21 is associated with rearrangement. Neoplasia 8, 465–469 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Mitelman, F., Mertens, F. & Johansson, B. A breakpoint map of recurrent chromosomal rearrangements in human neoplasia. Nature Genet. 15, 417–474 (1997).

    Article  CAS  PubMed  Google Scholar 

  84. Pinkel, D. et al. High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays. Nature Genet. 20, 207–211 (1998).

    Article  CAS  PubMed  Google Scholar 

  85. Pollack, J. R. et al. Genome-wide analysis of DNA copy-number changes using cDNA microarrays. Natrue Genet. 23, 41–46 (1999).

    Article  CAS  Google Scholar 

  86. Cowell, J. K. & Nowak, N. J. High-resolution analysis of genetic events in cancer cells using bacterial artificial chromosome arrays and comparative genome hybridization. Adv. Cancer Res. 90, 91–125 (2003).

    Article  CAS  PubMed  Google Scholar 

  87. Bacher, U. et al. Population-based age-specific incidences of cytogenetic subgroups of acute myeloid leukemia. Haematologica 90, 1502–1510 (2005).

    CAS  PubMed  Google Scholar 

  88. Sanderson R. N. et al. Population-based demographic study of karyotypes in 1709 patients with adult acute myeloid leukemia. Leukemia 20, 444–450 (2006).

    Article  CAS  PubMed  Google Scholar 

  89. Gorunova, L. et al. Cytogenetic analysis of pancreatic carcinomas: intratumor heterogeneity and nonrandom pattern of chromosome aberrations. Genes Chromosomes Cancer 23, 81–99 (1998).

    Article  CAS  PubMed  Google Scholar 

  90. Johansson, B. et al. Cytogenetic polyclonality in hematologic malignancies. Genes Chromosomes Cancer 24, 222–229 (1999).

    Article  CAS  PubMed  Google Scholar 

  91. Han, J. Y., Theil, K. S. & Hoeltge, G. Frequencies and characterization of cytogenetically unrelated clones in various hematologic malignancies: seven years of experiences in a single institution. Cancer Genet. Cytogenet. 164, 128–132 (2006).

    Article  CAS  PubMed  Google Scholar 

  92. 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). The first description of a gene fusion in a solid tumour.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Pierotti, M. A. Chromosomal rearrangements in thyroid carcinomas: a recombination or death dilemma. Cancer Lett. 166, 1–7 (2001).

    Article  CAS  PubMed  Google Scholar 

  94. Behboudi, A. et al. Molecular classification of mucoepidermoid carcinomas- prognostic significance of the MECT1-MAML2 fusion oncogene. Genes Chromosomes Cancer 45, 470–481 (2006).

    Article  CAS  PubMed  Google Scholar 

  95. French, C. A. et al. Midline carcinoma of children and young adults with NUT rearrangement. J. Clin. Oncol. 22, 4135–4139 (2004).

    Article  CAS  PubMed  Google Scholar 

  96. Tomlins, S. A. et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310, 644–648 (2005). The first study to show a fusion gene that occurs in a large proportion of a common malignant solid tumour.

    Article  CAS  Google Scholar 

  97. Cerveira, N. et al. TMPRSS2-ERG gene fusion causing ERG overexpression precedes chromosome copy number changes in prostate carcinomas and paired HGPIN lesions. Neoplasia 8, 826–832 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Hermans, K. G. et al. TMPRSS2:ERG fusion by translocation or interstitial deletion is highly relevant in androgen-dependent prostate cancer, but is bypassed in late-stage androgen receptor-negative prostate cancer. Cancer Res. 66, 10658–10663 (2006).

    Article  CAS  PubMed  Google Scholar 

  99. Iljin, K. et al. TMPRSS2 fusions with oncogenic ETS factors in prostate cancer involve unbalanced genomic rearrangements and are associated with HDAC1 and epigenetic reprogramming. Cancer Res. 66, 10242–10246 (2006).

    Article  CAS  PubMed  Google Scholar 

  100. Soller, M. J. et al. Confirmation of the high frequency of the TMPRSS2/ERG fusion gene in prostate cancer. Genes Chromosomes Cancer 45, 717–719 (2006).

    Article  CAS  PubMed  Google Scholar 

  101. Wang, J., Cai, Y., Ren, C. & Ittmann, M. Expression of variant TMPRSS2/ERG fusion messenger RNAs is associated with aggressive prostate cancer. Cancer Res. 66, 8347–8351 (2006).

    Article  CAS  PubMed  Google Scholar 

  102. Tomlins, S. A. et al. TMPRSS2:ETV4 gene fusions define a third molecular subtype of prostate cancer. Cancer Res. 66, 3396–3400 (2006).

    Article  CAS  PubMed  Google Scholar 

  103. Parkin, D. M., Bray, F., Ferlay, J. & Pisani, P. Global cancer statistics, 2002. CA. Cancer J. Clin. 55, 74–108 (2005).

    Article  PubMed  Google Scholar 

  104. Kamanger, F., Dores, G. M. & Anderson, W. F. Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J. Clin. Oncol. 24, 2137–2150 (2006).

    Article  Google Scholar 

  105. Cancer Incidence in Sweden 2004. The National Board of Health and Welfare, Stockholm (2004).

  106. Novo, F. J. & Vizmanos, J. L. Chromosome translocations in cancer: computational evidence for the random generation of double-strand breaks. Trends Genet. 22, 193–196 (2006).

    Article  CAS  PubMed  Google Scholar 

  107. Povirk, L. F. Biochemical mechanisms of chromosomal translocations resulting from DNA double-strand breaks. DNA Repair 5, 1199–1212 (2006).

    Article  CAS  PubMed  Google Scholar 

  108. Obe, G. et al. Chromosomal aberrations: formation, identification and distribution. Mutat. Res. 504, 17–36 (2002).

    Article  CAS  PubMed  Google Scholar 

  109. Mitelman, F., Mark, J., Levan, G. & Levan, A. Tumor etiology and chromosome pattern. Science 176, 1340–1341 (1972).

    Article  CAS  PubMed  Google Scholar 

  110. Mitelman, F., Brandt, L. & Nilsson, P. G. Relation among occupational exposure to potential mutagenic/carcinogenic agents, clinical findings, and bone marrow chromosomes in acute nonlymphocytic leukemia. Blood 52, 1229–1237 (1978).

    Article  CAS  PubMed  Google Scholar 

  111. Mauritzson, N. et al. Pooled analysis of clinical and cytogenetic features in treatment-related and de novo adult acute myeloid leukemia and myelodysplastic syndromes based on a consecutive series of 761 patients analyzed 1976–1993 and on 5098 unselected cases reported in the literature 1974–2001. Leukemia 16, 2366–2378 (2002).

    Article  CAS  PubMed  Google Scholar 

  112. Pedersen-Bjergaard, J., Andersen, M. K., Christiansen, D. H. & Nerlov, C. Genetic pathways in therapy-related myelodysplasia and acute myeloid leukemia. Blood 99, 1909–1912 (2002).

    Article  CAS  PubMed  Google Scholar 

  113. Mistry, A. R. et al. DNA topoisomerase II in therapy-related acute promyelocytic leukemia. N. Engl. J. Med. 352, 1529–1538 (2005).

    Article  CAS  PubMed  Google Scholar 

  114. Zhang, Y. & Rowley, J. D. Chromatin structural elements and chromosomal translocations in leukemia. DNA Repair 5, 1282–1297 (2006).

    Article  CAS  PubMed  Google Scholar 

  115. Fugazzola, L. et al. Oncogenic rearrangements of the RET proto-oncogene in papillary thyroid carcinomas from children exposed to the Chernobyl nuclear accident. Cancer Res. 55, 5617–5620 (1995).

    CAS  PubMed  Google Scholar 

  116. Rabes, H. M. et al. Pattern of radiation-induced RET and NTRK1 rearrangements in 191 post-chernobyl papillary thyroid carcinomas: biological, phenotypic, and clinical implications. Clin. Cancer Res. 6, 1093–1103 (2000).

    CAS  PubMed  Google Scholar 

  117. Taylor, A. M. Chromosome instability syndromes. Best Pract. Res. Clin. Haematol. 14, 631–644 (2001).

    Article  CAS  PubMed  Google Scholar 

  118. Misteli, T. Concepts in nuclear architecture. BioEssays 27, 477–487 (2005).

    Article  CAS  PubMed  Google Scholar 

  119. Cremer, T. et al. Chromosome territories – a functional nuclear landscape. Curr. Opin. Cell Biol. 18, 307–316 (2006). References 118–119 provide comprehensive reviews of chromosome territories in interphase nuclei.

    Article  CAS  PubMed  Google Scholar 

  120. Kozubek, S. et al. The topological organization of chromosomes 9 and 22 in cell nuclei has a determinative role in the induction of t(9,22) translocations and in the pathogenesis of t(9,22) leukemias. Chromosoma 108, 426–435 (1999).

    Article  CAS  PubMed  Google Scholar 

  121. Neves, H., Ramos, C., da Silva, M. G., Parreira, A. & Parreira, L. The nuclear topography of ABL, BCR, PML, and RARalpha genes: evidence for gene proximity in specific phases of the cell cycle and stages of hematopoietic differentiation. Blood 93, 1197–1207 (1999).

    Article  CAS  PubMed  Google Scholar 

  122. Nikiforova, M. N. et al. Proximity of chromosomal loci that participate in radiation-induced rearrangements in human cells. Science 290, 138–141 (2000).

    Article  CAS  PubMed  Google Scholar 

  123. Roix, J. J., McQueen, P. G., Munson, P. J., Parada, L. A. & Misteli, T. Spatial proximity of translocation-prone gene loci in human lymphomas. Nature Genet. 34, 287–291 (2003).

    Article  CAS  PubMed  Google Scholar 

  124. Raghavan, S. C. & Lieber, M. R. DNA structures at chromosomal translocation sites. BioEssays 28, 480–494 (2006).

    Article  CAS  PubMed  Google Scholar 

  125. Greaves, M. F. & Wiemels, J. Origins of chromosome translocations in childhood leukaemia. Nature Rev. Cancer 3, 639–649 (2003). Discusses the prenatal origin of gene fusions and the latency period in the development of leukaemia.

    Article  CAS  Google Scholar 

  126. Huntly, B. J. P. & Gilliland, D. G. Leukaemia stem cells and the evolution of cancer-stem-cell research. Nature Rev. Cancer 5, 311–321 (2005).

    Article  CAS  Google Scholar 

  127. Wang, J. C. Y. & Dick, J. E. Cancer stem cells: lessons from leukemia. Trends Cell Biol. 15, 494–501 (2005). References 126–127 provide comprehensive reviews of the role of stem cells in oncogenesis.

  128. Al-Hajj, M., Wicha, M. S., Benito-Hernandez, A., Morrison, S. J. & Clarke, M. F. Prospective identification of tumorigenic breast cancer cells. Proc. Natl Acad. Sci. USA 100, 3983–3988 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Singh, S. K. et al. Identification of human brain tumour initiating cells. Nature 432, 396–401 (2004).

    Article  CAS  PubMed  Google Scholar 

  130. Bender Kim, C. F. et al. Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 121, 823–835 (2005).

    Article  CAS  Google Scholar 

  131. O'Brien, C. A., Pollett, A., Gallinger, S. & Dick, J. E. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445, 106–110 (2007).

    Article  CAS  PubMed  Google Scholar 

  132. Ricci-Vitiani, L. et al. Identification and expansion of human colon-cancer-initiating cells. Nature 445, 111–115 (2007).

    Article  CAS  PubMed  Google Scholar 

  133. Johansson, B., Fioretos, T. & Mitelman, F. Cytogenetic and molecular genetic evolution of chronic myeloid leukemia. Acta Haematol. 107, 76–94 (2002).

    Article  CAS  PubMed  Google Scholar 

  134. Turhan, A. G. et al. Highly purified primitive hematopoietic stem cells are PML-RARA negative and generate nonclonal progenitors in acute promyelocytic leukemia. Blood 85, 2154–2161 (1995).

    Article  CAS  PubMed  Google Scholar 

  135. Castor, A. et al. Distinct patterns of hematopoietic stem cell involvement in acute lymphoblastic leukemia. Nature Med. 11, 630–637 (2005).

    Article  CAS  PubMed  Google Scholar 

  136. Hotfilder, M. et al. Leukemic stem cells in childhood high-risk ALL/t(9;22) and t(4;11) are present in primitive lymphoid-restricted CD34+CD19- cells. Cancer Res. 65, 1442–1449 (2005).

    Article  CAS  PubMed  Google Scholar 

  137. Riggi, N. et al. Development of Ewing's sarcoma from primary bone marrow-derived mesenchymal progenitor cells. Cancer Res. 65, 11459–11468 (2005).

    Article  CAS  PubMed  Google Scholar 

  138. Riggi, N. et al. Expression of the FUS-CHOP fusion protein in primary mesenchymal progenitor cells gives rise to a model of myxoid liposarcoma. Cancer Res. 66, 7016–7023 (2006).

    Article  CAS  PubMed  Google Scholar 

  139. Janz, S., Potter, M. & Rabkin, C. S. Lymphoma- and leukemia-associated chromosomal translocations in healthy individuals. Genes Chromosomes Cancer 36, 211–223 (2003).

    Article  CAS  PubMed  Google Scholar 

  140. Nucifora, G., Larson, R. A. & Rowley, J. D. Persistence of the 8;21 translocation in patients with acute myeloid leukemia type M2 in long-term remission. Blood 82, 712–715 (1993).

    Article  CAS  PubMed  Google Scholar 

  141. Jurlander, J. et al. Persistence of the AML1/ETO fusion transcript in patients treated with allogeneic bone marrow transplantation for t(8;21) leukemia. Blood 88, 2183–2191 (1996).

    Article  CAS  PubMed  Google Scholar 

  142. Castilla, L. H. et al. The fusion gene Cbfb-MYH11 blocks myeloid differentiation and predisposes mice to acute myelomonocytic leukaemia. Nature Genet. 23, 144–146 (1999).

    Article  CAS  PubMed  Google Scholar 

  143. Higuchi, M. et al. Expression of a conditional AML1-ETO oncogene bypasses embryonic lethality and establishes a murine model of human t(8;21) acute myeloid leukemia. Cancer Cell 1, 63–74 (2002).

    Article  CAS  PubMed  Google Scholar 

  144. Kelly, L. M., Gilliland, D. G. Genetics of myeloid leukemias. Annu. Rev. Genomics Hum. Genet. 3, 179–198 (2002).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank A. Frigyesi for valuable help in constructing figure 4. Financial support from the Swedish Cancer Society and the Swedish Children's Cancer Foundation is gratefully acknowledged

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Correspondence to Felix Mitelman.

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The Cancer Genome Atlas

The Mitelman Database of Chromosome Aberrations in Cancer

Glossary

Pathognomonic

A sign or symptom that is so characteristic of a disease that it is sufficient for diagnosis.

Balanced rearrangements

Chromosome abnormalities that give rise to structurally altered chromosomes without the gain or loss of genetic material. Such changes comprise reciprocal translocations, inversions and insertions.

Dermatofibrosarcoma protuberans

A low-grade malignant skin tumour composed of fibroblast-like cells.

Pericytoma

A mesenchymal tumour composed of cells that resemble pericytic cells.

Episomes

Submicroscopic extra-chromosomal circular DNA structures.

Hypereosinophilic syndrome

A haematological disease defined as persistent eosinophilia associated with signs of organ involvement and dysfunction.

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Mitelman, F., Johansson, B. & Mertens, F. The impact of translocations and gene fusions on cancer causation. Nat Rev Cancer 7, 233–245 (2007). https://doi.org/10.1038/nrc2091

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