Oncogenic gene fusions in nonneoplastic precursors as evidence that bacterial infection can initiate prostate cancer.

Autor:	Shrestha E; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287., Coulter JB; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287.; Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287., Guzman W; Department of Art as Applied to Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287., Ozbek B; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287., Hess MM; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287., Mummert L; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287., Ernst SE; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287., Maynard JP; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287., Meeker AK; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287.; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287.; Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287., Heaphy CM; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287.; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287., Haffner MC; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287., De Marzo AM; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287.; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287.; Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287., Sfanos KS; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287; ksfanos@jhmi.edu.; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287.; Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 Aug 10; Vol. 118 (32).
DOI:	10.1073/pnas.2018976118
Abstrakt:	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. Competing Interests: The authors declare no competing interest.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu