Translocation Breakpoints in Cancer

Andre Mascarenhas Oliveira, Brigham and Women's Hospital, Boston, Massachusetts, USA
Jonathan Alfred Fletcher, Brigham and Women's Hospital, Boston, Massachusetts, USA

Published online: January 2006

DOI: 10.1038/npg.els.0006066

Chromosomal translocations are structural abnormalities generated by double-strand DNA breakages in two or more chromosomes, followed by reciprocal exchange of the segments between the chromosomes. In cancer cells, these translocations often juxtapose regulatory or coding sequences from two different genes, resulting in highly activated oncogenes that regulate proliferation, apoptosis and other aspects of the neoplastic phenotype. Many such translocation-associated oncogenes have been described in human cancers.

Keywords: cytogenetic abnormality; chromosomal aberration; oncogene; translocation; cancer

Figure 1. Runx1–CBFB transcription factor complex. Runx1 binds to the consensus DNA enhancer sequence TG(T/C)GGT and activates the transcription of several genes involved in hematopoiesis (right). Runx1 also cooperates with other transcription factors, such as Myb, ETS and C/EBP (bottom). Interactions with CBFB increase the DNA-binding activity of Runx1, and several other coactivators and corepressors further regulate the Runx1–CBFB transcription machinery.
Figure 2. Fusion protein Runx1–CBFA2T1. Runx1–CBFA2T1 retains the Runx1 Runt domain and almost the entire CBFA2T1 sequence. The CBFA2T1 component recruits a transcriptional repressor complex, including the NcoR and mSin3A proteins and several histone deacetylases, which collectively create a myeloid differentiation block.
Figure 3. Fusion protein PML–RARA. PML–RARA proteins retain the RARA DNA-binding domain (region C) and the ligand-binding domain (region E). Most PML–RARA fusions retain the PML proline-rich region (Pro), the zinc-finger motif RING, the cysteine-rich B1 and B2 boxes and the -helical coiled-coil domain.
Figure 4. Fusion protein EWSR1–FLI1. The EWSR1–FLI1 fusion protein invariably retains the ETS DNA-binding domain of FLI1 at the C-terminal region.
Figure 5. PAX8–PPARG fusion protein. PAX8 paired and partial homeobox DNA-binding domains are represented by PD and HD respectively; PPARG DNA-binding, ligand-binding, RXR dimerization and transactivation nuclear receptor domains are represented by A/B, C, D and E/F respectively.
Figure 6. BCR–ABL1 fusion gene. The overall structures of the BCR and ABL1 genes are shown in (a). The arrows indicate the location of the breakpoints in the ABL1 gene on chromosome 9. In the BCR gene on chromosome 22, the breakpoints localize to three areas: m-bcr, M-bcr and -bcr. In most patients with CML, the BCR–ABL fusion oncoprotein is 210 kDa and includes the BCR oligomerization (oligo) and serine threonine kinase (S/TKinase) domains and the ABL tyrosine kinase domain.
Figure 7. (a) Follicular lymphoma showing the characteristic balanced translocation t(14;18) (q32;q21). Arrows indicate the translocation breakpoints on the rearranged copies of chromosomes 14 and 18. (b) Fluorescence in situ hybridization (FISH) image showing the same t(14;18)(q32;q21) translocation using probes that span the two loci involved (IgH@ and BCL2). The translocation produces two red–green (yellow) fusion FISH signals, one each on the translocated copies of chromosomes 14 and 18.
close
 References
    Alcalay M, Orleth A, Sebastiani C, et al. (2001) Common themes in the pathogenesis of acute myeloid leukemia. Oncogene 20: 5680–5694.
    Arvant A and Denny C (2001) Biology of EWS/ETS fusions in Ewing's family of tumors. Oncogene 20: 5747–5754.
    Barr F (1999) Translocations, cancer and the puzzle of specificity. Nature Genetics 19: 121–124.
    Boxer L and Dang C (2001) Translocations involving c-myc and c-myc function. Oncogene 20: 5595–5610.
    Daley G, McLaughlin J, Witte O and Baltimore D (1987) The CML-specific P210 bcr/abl protein, unlike v-abl, does not transform NIH/3T3 fibroblasts. Science 237: 532–535.
    Deininger MW, Goldman JM and Melo JV (2000) The molecular biology of chronic myeloid leukemia. Blood 96 (10): 3343–3356.
    Eguchi M, Eguchi-Ishimae M, Tojo A, et al. (1999) Fusion of ETV6 to neurotrophin-3 receptor TRKC in acute myeloid leukemia with t(12;15)(p13;q25). Blood 93 (4): 1355–1363.
    Falini B (2001) Anaplastic large cell lymphoma: pathological, molecular and clinical features. British Journal of Haematology 114: 741–760.
    French C, Miyoshi I, Aster J, et al. (2001) BRD4 bromodomain gene rearrangements in aggressive carcinoma with translocation t(15;19). American Journal of Pathology 159: 1987–1992.
    Gerald W, Rosai J and Ladanyi M (1995) Characterization of the genomic breakpoint and chimeric transcripts in the EWS-WT1 gene fusion in desmoplastic small round cell tumor. Proceedings of the National Academy of Sciences of the United States of America 92: 1028–1032.
    Hibbard M, Kozakewich H, Dal Cin P, et al. (2000) PLAG1 fusion oncogene in lipoblastoma. Cancer Research 60: 4869–4872.
    Knezevich SR, McFadden DE, Tao W, Lim JF and Sorensen PH (1998) A novel ETV6–NTRK3 gene fusion in congenital fibrosarcoma. Nature Genetics 18 (2): 184–187.
    Kroll TG, Sarraf P, Pecciarini L, et al. (2000) PAX8-PPAR gamma1 fusion oncogene in human thyroid carcinoma [corrected]. Science 289 (5483): 1357–1360.
    Kuppers R and Dalla-Favera R (2001) Mechanisms of chromosomal translocations in B-cell lymphomas. Oncogene 20: 5580–5594.
    Lawrence B, Perez-Atayde A, Hibbard M, et al. (2000) TPM3-ALK and TPM4-ALK oncogenes in inflammatory myofibroblastic tumors. American Journal of Pathology 157 (2): 377–384.
    Lock A (1997) Oncogenic transcription factors in the human acute leukemias. Science 278: 1059–1064.
    Pierotti MA, Vigneri P and Bongarzone I (1998) Rearrangements of RET and NTRK1 tyrosine kinase receptors in papillary thyroid carcinomas. Recent Results in Cancer Research 154: 237–247.
    Rowley J (1998) The critical role of chromosome translocations in human leukemias. Annual Review of Genetics 32: 495–519.
    Rubin BP, Chen CJ, Morgan TW, et al. (1998) Congenital mesoblastic nephroma t(12;15) is associated with ETV6–NTRK3 gene fusion: cytogenetic and molecular relationship to congenital (infantile) fibrosarcoma. American Journal of Pathology 153 (5): 1451–1458.
    Savage DG and Antman KH (2002) Imatinib mesylate – a new oral targeted therapy. New England Journal of Medicine 346 (9): 683–693.
    Simon MP, Pedeutour F, Sirvent N, et al. (1997) Deregulation of the platelet-derived growth factor B-chain gene via fusion with collagen gene COL1A1 in dermatofibrosarcoma protuberans and giant-cell fibroblastoma. Nature Genetics 15 (1): 95–98.
    Zelent A, Guidez F, Melnick A, Waxman S and Licht J (2001) Translocations of the RAR alpha gene in acute promyelocytic leukemia. Oncogene 20: 7186–7203.
 Web Links
    ePath Ataxia telangiectasia mutated (includes complementation groups A, C and D) (ATM); Locus ID: 472. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=472
    ePath Breakpoint cluster region (BCR); Locus ID: 613. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=613
    ePath ets variant gene 6 (TEL oncogene) (ETV6); Locus ID: 2120. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=2120
    ePath Runt-related transcription factor 1 (acute myeloid leukemia 1; aml1 oncogene) (RUNX1); Locus ID: 861. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=861
    ePath v-abl Abelson murine leukemia viral oncogene homolog 1 (ABL1); Locus ID: 25. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=25
    ePath Ataxia telangiectasia mutated (includes complementation groups A, C and D) (ATM); MIM number: 208900. OMIM: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?208900
    ePath Breakpoint cluster region (BCR); MIM number: 151410. OMIM: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?151410
    ePath ets variant gene 6 (TEL oncogene) (ETV6); MIM number: 600618. OMIM: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?600618
    ePath Runt-related transcription factor 1 (acute myeloid leukemia 1; aml1 oncogene) (RUNX1); MIM number: 151385. OMIM: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?151385
    ePath v-abl Abelson murine leukemia viral oncogene homolog 1 (ABL1); MIM number: 189980. OMIM: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?189980
    ePath Atlas of Genetics and Cytogenetics in Oncology and Hematology http://wwww.infobiogen.fr/services/chromcancer

Related Sub-Topics:

Cancer Genetics | Gene and Genome Structure and Organisation | Chromosomal Disorders | Genomic Disorders | Transcriptional Regulation | Chromosomes and Chromatin Modifications | Mechanisms of Cell Death, Senescence and Metabolism
Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Translocation Breakpoints in Cancer
 
How to Cite close
Oliveira, Andre Mascarenhas, and Fletcher, Jonathan Alfred(Jan 2006) Translocation Breakpoints in Cancer. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0006066]