RT Journal Article
SR Electronic
T1 Oncogenic Gene Fusions in Non-Neoplastic Precursors as Evidence that Bacterial Infection Initiates Prostate Cancer
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.07.27.224154
DO 10.1101/2020.07.27.224154
A1 Eva Shrestha
A1 Jonathan B. Coulter
A1 William Guzman
A1 Busra Ozbek
A1 Luke Mummert
A1 Sarah E. Ernst
A1 Janielle P. Maynard
A1 Alan K. Meeker
A1 Christopher M. Heaphy
A1 Michael C. Haffner
A1 Angelo M. De Marzo
A1 Karen S. Sfanos
YR 2020
UL http://biorxiv.org/content/early/2020/07/28/2020.07.27.224154.abstract
AB 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 cancers1,2. Infection-driven inflammation is implicated in the formation of ERG+ fusions3, 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 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. We verified TMPRSS2:ERG genomic rearrangements in precursor lesions using tri-color fluorescence in situ hybridization. Identification of rearrangement patterns combined with whole prostate mapping in 3 dimensions confirmed multiple (up to 8) distinct ERG+ precancerous lesions in infected cases. Finally, we 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 initiate driver gene alterations in prostate cancer. Furthermore, infection-induced ERG+ fusions are an early alteration in the carcinogenic process and PIA may serve as a direct precursor to prostate cancer.Competing Interest StatementThe authors have declared no competing interest.