期刊
CELL REPORTS
卷 17, 期 10, 页码 2620-2631出版社
CELL PRESS
DOI: 10.1016/j.celrep.2016.11.019
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资金
- NIH Pathway to Independence (PI) Award [R00CA160640]
- UT Southwestern
- ACS-IRG New Investigator Award in Cancer Research [IRG-02-196]
- Stewart Rahr-Prostate Cancer Foundation Young Investigator Award
- NIH Prostate SPORE [P50CA186786]
- Early Detection Research Network [U01CA111275, R01CA132874]
- Prostate Cancer Foundation
Approximately 50% of prostate cancers are associated with gene fusions of the androgen-regulated gene TMPRSS2 to the oncogenic erythroblast transformation- specific (ETS) transcription factor ERG. The three-dimensional proximity of TMPRSS2 and ERG genes, in combination with DNA breaks, facilitates the formation of TMPRSS2-ERG gene fusions. However, the origins of DNA breaks that underlie gene fusion formation in prostate cancers are far from clear. We demonstrate a role for inflammation-induced oxidative stress in the formation of DNA breaks leading to recurrent TMPRSS2-ERG gene fusions. The transcriptional status and epigenetic features of the target genes influence this effect. Importantly, inflammation-induced de novo genomic rearrangements are blocked by homologous recombination (HR) and promoted by nonhomologous end-joining (NHEJ) pathways. In conjunction with the association of proliferative inflammatory atrophy (PIA) with human prostate cancer, our results support a working model in which recurrent genomic rearrangements induced by inflammatory stimuli lead to the development of prostate cancer.
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