Oncogenic gene fusions in nonneoplastic precursors as evidence that bacterial infection can initiate prostate cancer
Eva Shrestha, Jonathan B. Coulter, William Guzman, Büşra Özbek, 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
Abstract
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.