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tumoral translocations

Saturday 14 January 2006

Non-random chromosomal translocations are frequently associated with a variety of cancers, particularly hematologic malignancies and childhood sarcomas.

Chromosome aberrations, in particular translocations and their corresponding gene fusions, have an important role in the initial steps of tumorigenesis.

- List of tumoral translocations

Physiopathology

- The mechanisms that cause these translocations remain poorly understood. Illegitimate V(D)J recombination, class switch recombination, homologous recombination, non-homologous end-joining and genome fragile sites all have potential roles in the production of non-random chromosomal translocations.

- Mutations in DNA-repair pathways have been implicated in the production of chromosomal translocations in humans, mice and yeast.

- The identification of these same oncogenic chromosomal translocations in peripheral blood from healthy individuals strongly suggests that the translocation is not sufficient to induce malignant transformation, and that complementary mutations are required to produce a frank malignancy.

- Oncogenic chromosomal translocation partners can be identified by proteomic methods (16651537)

Gene fusions

In most tumors with acquired chromosomal translocations, a new fusion oncogene or promoter-oncogene fusion is created and drives tumor growth. In 2007, 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.

Gene deletions

Some translocations drive tumorigenesis via deletion of a tumor suppressor, as t(X;18) in Wilms tumor (17620295)

See also

- amplification of fusion genes
- fusion transcripts
- fusion proteins
- tumoral translocations

- translocation-associated proliferations

  • translocation-associated leukemias
  • translocation-associated tumors
    • translocation-associated Lymphomas
    • translocation-associated sarcomas
    • translocation-associated carcinomas

- chromosomal translocations
- Oncobase

Reviews

- Rabbitts TH. Chromosomal translocations in human cancer. Nature 1994;372:143-149. PMID: 7969446

- Rowley JD. The critical role of chromosome translocations in human leukemias. Annu Rev Genet 1998;32:495-519. PMID: 9928489

- Meyerson M. Cancer: broken genes in solid tumours. Nature 2007;448:545-546. PMID: 17671492

- Shaffer DR, Pandolfi PP. Breaking the rules of cancer. Nat Med 2006;12:14-15. PMID: 16397543

- Greaves MF, Wiemels J. Origins of chromosome translocations in childhood leukaemia. Nat Rev Cancer 2003;3:639-649. PMID: 12951583

- Mitelman F, Johansson B, Mertens F. The impact of translocations and gene fusions on cancer causation. Nat Rev Cancer. 2007 Apr;7(4):233-45. PMID: 17361217

- Novo FJ, Vizmanos JL. Chromosome translocations in cancer: computational evidence for the random generation of double-strand breaks. Trends Genet. 2006 Apr;22(4):193-6. PMID: 16499992

- Elenitoba-Johnson KS, Crockett DK, Schumacher JA, Jenson SD, Coffin CM, Rockwood AL, Lim MS. Proteomic identification of oncogenic chromosomal translocation partners encoding chimeric anaplastic lymphoma kinase fusion proteins. Proc Natl Acad Sci U S A. 2006 May 9;103(19):7402-7. PMID: 16651537

- Rabbitts TH, Stocks MR. Chromosomal translocation products engender new intracellular therapeutic technologies. Nat Med. 2003 Apr;9(4):383-6. PMID: 12669051

- Aplan PD. Causes of oncogenic chromosomal translocation. Trends Genet. 2006 Jan;22(1):46-55. PMID: 16257470

- Greaves MF, Wiemels J. Origins of chromosome translocations in childhood leukaemia. Nat Rev Cancer. 2003 Sep;3(9):639-49. PMID: 12951583

- Rego EM, Pandolfi PP. Reciprocal products of chromosomal translocations in human cancer pathogenesis: key players or innocent bystanders? Trends Mol Med. 2002 Aug;8(8):396-405. PMID: 12127726

- Tomescu O, Barr FG. Chromosomal translocations in sarcomas: prospects for therapy. Trends Mol Med. 2001 Dec;7(12):554-9. PMID: 11733218

- Rabbitts TH. Chromosomal translocations in human cancer. Nature 1994;372:143-149. PMID: 7969446

Translocations in leukemias

- Gilliland DG, Jordan CT, Felix CA. The molecular basis of leukemia. Hematology (Am Soc Hematol Educ Program). 2004;:80-97. PMID: 15561678

- Greaves MF, Wiemels J. Origins of chromosome translocations in childhood leukaemia. Nat Rev Cancer. 2003 Sep;3(9):639-49. PMID: 12951583

- Staudt LM. Molecular diagnosis of the hematologic cancers.
N Engl J Med. 2003 May 1;348(18):1777-85. PMID: 12724484

- Bohlander SK. Fusion genes in leukemia: an emerging network. Cytogenet Cell Genet. 2000;91(1-4):52-6. PMID: 11173830

- Rowley JD. The critical role of chromosome translocations in human leukemias. Annu Rev Genet 1998;32:495-519. PMID: 9928489

References

- Han M, Rivera MN, Batten JM, Haber DA, Cin PD, Iafrate AJ. Wilms’ tumor with an apparently balanced translocation t(X;18) resulting in deletion of the WTX gene. Genes Chromosomes Cancer. 2007 Oct;46(10):909-13. PMID: 17620295

History

- Groffen J, Stephenson JR, Heisterkamp N, de Klein A, Bartram CR, Grosveld G. Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22. Cell 1984;36:93-99. PMID: 6319012

- Heisterkamp N, Stephenson JR, Groffen J, et al. Localization of the c-ab1 oncogene adjacent to a translocation break point in chronic myelocytic leukaemia. Nature 1983;306:239-242. PMID: 6316147

- de Klein A, van Kessel AG, Grosveld G, et al. A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukaemia. Nature 1982;300:765-767. PMID: 6960256

- Rowley JD. A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 1973;243:290-293. PMID: 4126434

- Nowell PC, Hungerford DA. Chromosome studies on normal and leukemic human leukocytes. J Natl Cancer Inst 1960;25:85-109. PMID: 14427847

Portfolio

  • Consequences of tumoral chromosomal rearrangements