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


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.

  • Amin MA
  • Aslam A
  • Cao X
  • Chinnaiyan AM
  • Dhanasekaran SM
  • Ghosh A
  • Kalyana-Sundaram S
  • Kapur P
  • Kimura W
  • Koch AE
  • Li X
  • Mani RS
  • Palanisamy N
  • Rabquer BJ
  • Ramanand SG
  • Roychowdhury S
  • Sadek HA
  • Tran M
  • Veeneman BA
  • Wang L
PubMed ID
Appears In
Cell Rep, 2016, 17 (10)