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

Menée in vitro, cette étude met en évidence une association entre la présence d'une infection bactérienne au niveau de la prostate, la présence du gène de fusion TMPRSS2:ERG dans des cellules prostatiques précancéreuses et le développement d'une tumeur invasive

Résumé en anglais

Prostate infections and inflammation are potential initiating factors in prostate cancer development. Here, we investigated whether bacterial infections are associated with the presence of the most common prostate cancer oncogenic gene fusion, TMPRSS2:ERG, in early precursor lesions. We provide evidence that TMPRSS2:ERG (ERG+) gene fusions can initiate in early prostate cancer risk factor lesions, including proliferative inflammatory atrophy in the setting of prostate infection. We further demonstrate that these infection-associated ERG+ precursor lesions are transitioning to early invasive cancer. Overall, we provide evidence that, in at least a subset of cases, infection-induced TMPRSS2:ERG gene fusions are an early alteration in the carcinogenic process.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.All study data are included in the article and/or supporting information.