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

Autor:	Mani RS; 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., Amin MA; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA., Li X; Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75235, USA., Kalyana-Sundaram S; 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., Veeneman BA; 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., Wang L; 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., Ghosh A; 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., Aslam A; Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75235, USA., Ramanand SG; Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75235, USA., Rabquer BJ; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA., Kimura W; 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., Tran M; 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., Cao X; 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., Roychowdhury S; Department of Internal Medicine, The James Cancer Center, Ohio State University, Columbus, OH 43210, USA., Dhanasekaran SM; 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., Palanisamy N; Department of Urology, Henry Ford Health System, Detroit, MI 48202, USA., Sadek HA; Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75235, USA., Kapur P; Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75235, USA; Department of Urology, UT Southwestern Medical Center, Dallas, TX 75235, USA., Koch AE; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA; VA Ann Arbor, Ann Arbor, MI 48105, USA., Chinnaiyan AM; 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.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2016 Dec 06; Vol. 17 (10), pp. 2620-2631.
DOI:	10.1016/j.celrep.2016.11.019
Abstrakt:	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. Competing Interests: of Potential Conflicts of Interest: A.M.C. is a co-inventor on a patent filed by the University of Michigan covering the diagnostic and therapeutic field of use for ETS fusions in prostate cancer. The diagnostic field of use has been licensed to Hologic. Hologic did not play a role in the design and conduct of this study, in the collection, analysis, or interpretation of the data, or in the preparation, review, or approval of the article. (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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