Translocation Breakpoints in Cancer


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 PMLRARA. PMLRARA proteins retain the RARA DNA‐binding domain (region C) and the ligand‐binding domain (region E). Most PMLRARA fusions retain the PML proline‐rich region (Pro), the zinc‐finger motif RING, the cysteine‐rich B1 and B2 boxes and the α‐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.

PAX8PPARG 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 μ‐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.



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Web Links

Ataxia telangiectasia mutated (includes complementation groups A, C and D) (ATM); Locus ID: 472. LocusLink:

Breakpoint cluster region (BCR); Locus ID: 613. LocusLink:

ets variant gene 6 (TEL oncogene) (ETV6); Locus ID: 2120. LocusLink:

Runt‐related transcription factor 1 (acute myeloid leukemia 1; aml1 oncogene) (RUNX1); Locus ID: 861. LocusLink:

v‐abl Abelson murine leukemia viral oncogene homolog 1 (ABL1); Locus ID: 25. LocusLink:

Ataxia telangiectasia mutated (includes complementation groups A, C and D) (ATM); MIM number: 208900. OMIM:‐post/Omim/dispmim?208900

Breakpoint cluster region (BCR); MIM number: 151410. OMIM:‐post/Omim/dispmim?151410

ets variant gene 6 (TEL oncogene) (ETV6); MIM number: 600618. OMIM:‐post/Omim/dispmim?600618

Runt‐related transcription factor 1 (acute myeloid leukemia 1; aml1 oncogene) (RUNX1); MIM number: 151385. OMIM:‐post/Omim/dispmim?151385

v‐abl Abelson murine leukemia viral oncogene homolog 1 (ABL1); MIM number: 189980. OMIM:‐post/Omim/dispmim?189980

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Oliveira, Andre Mascarenhas, and Fletcher, Jonathan Alfred(Jan 2006) Translocation Breakpoints in Cancer. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1038/npg.els.0006066]