TMPRS2型
前列腺癌
Erg公司
生物
前列腺
癌症
癌症研究
原位杂交
病理
基因
医学
遗传学
基因表达
视网膜
2019年冠状病毒病(COVID-19)
疾病
传染病(医学专业)
神经科学
作者
Eva Shrestha,Jonathan B. Coulter,William Guzman,Büşra Ozbek,Megan M. Hess,Luke Mummert,Sarah E. Ernst,Janielle P. Maynard,Alan K. Meeker,Christopher M. Heaphy,Michael C. Haffner,Angelo M. De Marzo,Karen S. Sfanos
标识
DOI:10.1073/pnas.2018976118
摘要
Prostate adenocarcinoma is the second most commonly diagnosed cancer in men worldwide, and the initiating factors are unknown. Oncogenic TMPRSS2:ERG (ERG+) gene fusions are facilitated by DNA breaks and occur in up to 50% of prostate cancers. Infection-driven inflammation is implicated in the formation of ERG+ fusions, and we hypothesized that these fusions initiate in early inflammation-associated prostate cancer precursor lesions, such as proliferative inflammatory atrophy (PIA), prior to cancer development. We investigated whether bacterial prostatitis is associated with ERG+ precancerous lesions in unique cases with active bacterial infections at the time of radical prostatectomy. We identified a high frequency of ERG+ non-neoplastic-appearing glands in these cases, including ERG+ PIA transitioning to early invasive cancer. These lesions were positive for ERG protein by immunohistochemistry and ERG messenger RNA by in situ hybridization. We additionally verified TMPRSS2:ERG genomic rearrangements in precursor lesions using tricolor fluorescence in situ hybridization. Identification of rearrangement patterns combined with whole-prostate mapping in three dimensions confirmed multiple (up to eight) distinct ERG+ precancerous lesions in infected cases. We further identified the pathogen-derived genotoxin colibactin as a potential source of DNA breaks in clinical cases as well as cultured prostate cells. Overall, we provide evidence that bacterial infections can initiate driver gene alterations in prostate cancer. In addition, our observations indicate that infection-induced ERG+ fusions are an early alteration in the carcinogenic process and that PIA may serve as a direct precursor to prostate cancer.
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