title: Inflammation-Induced Oxidative Stress Mediates Gene Fusion Formation in Prostate Cancer.
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.
authors.affiliation: Department 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. Electronic address: ram.mani@utsouthwestern.edu.
authors.forename: Ram S
authors.initials: RS
authors.lastname: Mani
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Amin
authors.affiliation: Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75235, USA.
authors.forename: Xiangyi
authors.initials: X
authors.lastname: Li
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Shanker
authors.initials: S
authors.lastname: Kalyana-Sundaram
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Brendan A
authors.initials: BA
authors.lastname: Veeneman
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Aparna
authors.initials: A
authors.lastname: Ghosh
authors.affiliation: Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75235, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Aslam
authors.affiliation: Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75235, USA.
authors.forename: Susmita G
authors.initials: SG
authors.lastname: Ramanand
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Rabquer
authors.affiliation: Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75235, USA; Life Science Center, Tsukuba Advanced Research Alliance, University of Tsukuba, Ibaraki 305-8577, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Kimura
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Maxwell
authors.initials: M
authors.lastname: Tran
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Xuhong
authors.initials: X
authors.lastname: Cao
authors.affiliation: Department of Internal Medicine, The James Cancer Center, Ohio State University, Columbus, OH 43210, USA.
authors.forename: Sameek
authors.initials: S
authors.lastname: Roychowdhury
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Saravana M
authors.initials: SM
authors.lastname: Dhanasekaran
authors.affiliation: Department of Urology, Henry Ford Health System, Detroit, MI 48202, USA.
authors.forename: Nallasivam
authors.initials: N
authors.lastname: Palanisamy
authors.affiliation: Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75235, USA.
authors.forename: Hesham A
authors.initials: HA
authors.lastname: Sadek
authors.affiliation: Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75235, USA; Department of Urology, UT Southwestern Medical Center, Dallas, TX 75235, USA.
authors.forename: Payal
authors.initials: P
authors.lastname: Kapur
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA; VA Ann Arbor, Ann Arbor, MI 48105, USA.
authors.forename: Alisa E
authors.initials: AE
authors.lastname: Koch
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA; Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address: arul@umich.edu.
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
mesh_terms: D000728:Androgens / Q000235:genetics; D045744:Cell Line, Tumor; D053960:DNA Breaks; D059766:DNA End-Joining Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000235:genetics* / Q000473:pathology; D008297:Male; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D018384:Oxidative Stress / Q000235:genetics; D011471:Prostatic Neoplasms / Q000150:complications / Q000235:genetics* / Q000473:pathology; D012697:Serine Endopeptidases / Q000235:genetics*; D000071230:Transcriptional Regulator ERG / Q000235:genetics
chemical_list: D000728:Androgens; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D015514:Oncogene Proteins, Fusion; D000071230:Transcriptional Regulator ERG; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human
keywords: DNA breaks; NHEJ; ROS; TMPRSS2-ERG; TNF; gene fusion; inflammation; microhomology; oxidative stress; prostate cancer