deregulated expression of structurally normal oncogenes by translocation
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Chromosomal rearrangements that juxtapose tissue-specific regulatory elements, such as gene promoters or enhancer sequences, to the coding sequence of a proto-oncogene deregulate expression of the proto-oncogene.
This abnormality is exemplified by the reciprocal translocations associated with Burkitt’s lymphoma, in which the enhancer of an immunoglobulin gene (IGHG1, band 14q32.33; IGKC, 2p12; and IGLC1, 22q11.2) drives the constitutive expression of the gene encoding the MYC transcription factor on band 8q24.21.
Chromosomal changes that cause overexpression of structurally normal genes occur in other cancers of B-cell or T-cell origin but were believed to be very rare in nonlymphoid cancers.
This view has changed since the recent discovery that prostate cancer (prostatic adenocarcinomas) is associated with chromosomal rearrangements that bring about overexpression of members of the ETSs family of transcription factors.
The most common of these rearrangements fuses all coding exons of the ERG gene to androgen-regulated sequences in the promoter of the prostate-specific TMPRSS2 gene; these sequences mediate the aberrant expression of ERG in prostate tissue.
Both genes are located on band 21q22.3, approximately 3 Mb apart, and multiple genomic alterations, such as heterozygous and homozygous deletions or insertions, contribute to the formation of various TMPRSS2-ERG fusion transcripts.
In addition, fusions between other ETS family members and TMPRSS2 and ETS rearrangements involving alternative fusion partners (including androgen-repressed and androgen-insensitive genes) occur.
It will be of prime importance to evaluate the use of these new genetic biomarkers for early detection and outcome prediction in prostate cancer.
Examples
| t(8;14)(q24;q32) | MYC-IGHG1 | Burkitt lymphoma |
| t(11;14)(q13;q32) | CCND1-IGHG1 | mantle cell lymphoma |
| t(12;13)(p13;q12) | ETV6-CDX2 | acute myeloid leukemia |
| t(14;18)(q32;q21) | IGHG1-BCL2 | follicular lymphoma |
| del(21)(q22.3q22.3) | TMPRSS2-ERG | prostatic adenocarcinomas |
See also
tumoral translocations
References
Fröhling S, Döhner H. Chromosomal abnormalities in cancer. N Engl J Med. 2008 Aug 14;359(7):722-34. PMID: #18703475#