Journal Article Inflammation-Induced Oxidative Stress Mediates Gene Fusion Formation in Prostate Cancer

Mani, Ram S.  ,  Amin, Mohammad A.  ,  Li, Xiangyi  ,  Kalyana-Sundaram, Shanker  ,  Veeneman, Brendan A.  ,  Wang, Lei  ,  Ghosh, Aparna  ,  Aslam, Adam  ,  Ramanand, Susmita G.  ,  Rabquer, Bradley J.  ,  Kimura, Wataru  ,  Tran, Maxwell  ,  Cao, Xuhong  ,  Roychowdhury, Sameek  ,  Dhanasekaran, Saravana M.  ,  Palanisamy, Nallasivam  ,  Sadek, Hesham A.  ,  Kapur, Payal  ,  Koch, Alisa E.  ,  Chinnaiyan, Arul M.

17 ( 10 )  , pp.2620 - 2631 , 2016-12 , Elsevier (Cell Press)
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 non-homologous 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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