Inflammation-Induced Oxidative Stress Mediates Gene Fusion Formation in Prostate Cancer
Ram S Mani1, Mohammad A Amin2, Xiangyi Li3
1Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75235, USA; Department of Urology, UT Southwestern Medical Center, Dallas, TX 75235, USA; Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75235, USA.
Abstract:
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.
Related Concept Videos
Cancer-Critical Genes I: Proto-oncogenes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
Exon Recombination
Exon shuffling follows “splice frame rules.” Each exon...
Induced Pluripotent Stem Cells
Somatic...
Abnormal Proliferation
Cancer Prevention
Some...
Cancers Originate from Somatic Mutations in a Single Cell


