Defining chromosomal translocation risks in cancer

Chromosomal translocations are a hallmark of cancer. Unraveling the molecular mechanism of these rare genetic events requires a clear distinction between correlative and causative risk-determinants, where technical and analytical issues can be excluded. To meet this goal, we performed in-depth analy...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2016-06, Vol.113 (26), p.E3649-E3656
Main Authors: Hogenbirk, Marc A., Heideman, Marinus R., de Rink, Iris, Velds, Arno, Kerkhoven, Ron M., Wessels, Lodewyk F. A., Jacobs, Heinz
Format: Article
Language:English
Subjects:
Animals
Biological Sciences
Cancer
Chromatin
Chromatin - genetics
Chromosomes
Genome
Genomes
Humans
Mice
Neoplasms - genetics
Neoplasms - metabolism
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
PNAS Plus
Promoter Regions, Genetic
Risk factors
Rodents
Transcription, Genetic
Transcriptional Elongation Factors - genetics
Transcriptional Elongation Factors - metabolism
Translocation, Genetic
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Summary:Chromosomal translocations are a hallmark of cancer. Unraveling the molecular mechanism of these rare genetic events requires a clear distinction between correlative and causative risk-determinants, where technical and analytical issues can be excluded. To meet this goal, we performed in-depth analyses of publicly available genome-wide datasets. In contrast to several recent reports, we demonstrate that chromosomal translocation risk is causally unrelated to promoter stalling (Spt5), transcriptional activity, or off-targeting activity of the activation-induced cytidine deaminase. Rather, an open chromatin configuration, which is not promoter-specific, explained the elevated translocation risk of promoter regions. Furthermore, the fact that gene size directly correlates with the translocation risk in mice and human cancers further demonstrated the general irrelevance of promoter-specific activities. Interestingly, a subset of translocations observed in cancer patients likely initiates from double-strand breaks induced by an access-independent process. Together, these unexpected and novel insights are fundamental in understanding the origin of chromosome translocations and, consequently, cancer.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1602025113