Inflammation induced oxidative stress mediates gene fusion formation in prostate cancer

While inflammation is strongly associated with cancer development, the underlying mechanisms are not clear. In terms of recurrent driver mutations, approximately 50% of prostate cancers are associated with gene fusions of the androgen regulated gene, TMPRSS2 to the oncogenic ETS transcription factor, ERG. Three-dimensional spatial proximity of TMPRSS2 and ERG genes in combination with DNA breaks facilitate the formation of TMPRSS2-ERG gene fusions. While androgen signaling induces the proximity of TMPRSS2 and ERG gene loci, the mechanisms contributing to DNA breaks that underlie the formation of TMPRSS2-ERG 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 strong 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 leads to the development of prostate cancer.