Oncogenic gene fusions in nonneoplastic precursors as evidence that bacterial infection can initiate prostate cancer
Oncogenic gene fusions in nonneoplastic precursors as evidence that bacterial infection can initiate prostate cancer
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DOI：
10.1073/pnas.2018976118
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发表时间：
2021-08-10
影响因子：
11.1
通讯作者：
Sfanos, Karen S.
中科院分区：
文献类型：
--
作者：
Shrestha, Eva;Coulter, Jonathan B.;Sfanos, Karen S.
前列腺癌是世界范围内男性第二大常见癌症，其发病因素尚不清楚。致癌TMPRSS2:ERG （ERG+）基因融合通过DNA断裂促进，并在高达50%的前列腺癌中发生。感染驱动的炎症与ERG+融合的形成有关，我们假设这些融合始于早期炎症相关的前列腺癌前体病变，如增生性炎症性萎缩（PIA），在癌症发展之前。我们研究了在根治性前列腺切除术时活动性细菌感染的独特病例中，细菌性前列腺炎是否与ERG+癌前病变相关。我们发现，在这些病例中，ERG+非肿瘤性腺体出现的频率很高，包括ERG+ PIA向早期侵袭性癌症的转变。免疫组化检测ERG蛋白阳性，原位杂交检测ERG信使RNA阳性。我们还使用三色荧光原位杂交技术验证了TMPRSS2:ERG基因组重排在前体病变中。重排模式的识别结合全前列腺三维制图证实了感染病例中多个（多达八个）不同的ERG+癌前病变。我们进一步确定了病原体衍生的基因毒素大肠杆菌素作为临床病例和培养的前列腺细胞DNA断裂的潜在来源。总之，我们提供的证据表明，细菌感染可以启动前列腺癌的驱动基因改变。此外，我们的观察结果表明，感染诱导的ERG+融合是致癌过程的早期改变，PIA可能是前列腺癌的直接前兆。
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-neoplasticappearing 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 wholeprostate 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.