Document Type

Article

Publication Date

12-6-2016

Publication Title

Cell Rep

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.

Medical Subject Headings

Androgens; Cell Line, Tumor; DNA Breaks; DNA End-Joining Repair; DNA-Binding Proteins; Humans; Inflammation; Male; Oncogene Proteins, Fusion; Oxidative Stress; Prostatic Neoplasms; Serine Endopeptidases; Transcriptional Regulator ERG

PubMed ID

27926866

Volume

17

Issue

10

First Page

2620

Last Page

2631

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