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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Vydané v:Proceedings of the National Academy of Sciences - PNAS Ročník 113; číslo 26; s. E3649 - E3656
Hlavní autori: Hogenbirk, Marc A, Heideman, Marinus R, de Rink, Iris, Velds, Arno, Kerkhoven, Ron M, Wessels, Lodewyk F A, Jacobs, Heinz
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: United States 28.06.2016
Predmet:
Animals
Chromatin - genetics
Genome
Humans
Mice
Neoplasms - genetics
Neoplasms - metabolism
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
Promoter Regions, Genetic
Transcription, Genetic
Transcriptional Elongation Factors - genetics
Transcriptional Elongation Factors - metabolism
Translocation, Genetic
cancer
multiomics
activation-induced cytidine deaminase
chromosomal translocation
paired integrative analysis
ISSN:1091-6490
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Popis
Shrnutí: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.
Bibliografia:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:1091-6490
DOI:10.1073/pnas.1602025113