Abstract IA25: Inflammation as the trigger of somatic epigenome defects in prostate cancer

Abstract

Abstract Prostate cancer has achieved epidemic proportions among men in the United States (US) and developed world; inflammation of the peripheral zone of the prostate, where the cancers arise, is just as ubiquitous (1). Accumulating insights from studies of prostatic carcinogenesis, using either human biospecimens or rodent models, indicate that stressors which cause prostate inflammation, including infections, estrogens, and the diet, also cause prostate cancer (1). Chronic inflammation in the prostate peripheral zone leads to the appearance of focal atrophy lesions of the prostate epithelium, replete with corpora amylacea, cellular and nuclear atypia, and a prostate stroma infiltrated by inflammatory cells (2). These proliferative inflammatory atrophy (PIA) lesions serve as the earliest precursors to prostate cancers, where epigenetic gene silencing, telomere shortening, and activation of c-Myc expression drive neoplastic transformation (3). Gene translocations/deletions that generate fusion transcripts between androgen-regulated genes (such as TMPRSS2) and genes encoding ETS family transcription factors (such as ERG1), typically arise later, during progression to invasive prostate cancer (4). The end consequence of these acquired defects in genes and in gene function is life-threatening prostate cancer, which when lethal exhibits widespread genome and epigenome corruption. Epigenetic silencing of GSTP1, encoding an oxidant and carcinogen detoxifying enzyme, is emblematic of the earliest steps in prostatic carcinogenesis, triggered in some way by prostate hypermethylation of the GSTP1 CpG island. This acquired epigenome alteration is present in nearly all prostate cancer cases, appearing at the very initiation of transformation, with some 5–10% of proliferative inflammatory atrophy (PIA) lesions and > 70% of prostatic intraepithelial neoplasia (PIN) lesions affected, and persisting throughout prostate cancer progression (3). In mouse models of prostate cancer, the mouse homologs of GSTP1, Gstp1 and Gstp2, serve as tumor suppressors, limiting progression of PIN to prostate cancer. Hopefully, such models can be used to ascertain how de novo GSTP1 methylation occurs during the pathogenesis of prostate cancer. Chronic or recurrent inflammatory processes leading to PIA appear to be the major driver of the prostate cancer epidemic in the developed world, raising the possibility that attenuation or prevention of inflammation, or of inflammatory damage to the prostate, might serve to prevent disease morbidity and mortality. Citation Format: William G. Nelson. Inflammation as the trigger of somatic epigenome defects in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr IA25.