前列腺癌是最常见的恶性肿瘤之一，也是癌症死亡的第三大原因。基因组关联研究已经鉴定了与前列腺癌易感性相关的变异体，但这些突变的机制和功能验证尚不足。我们采用CRISPR-Cas9基因组编辑技术，在小鼠的Elac2基因中引入一个ELAC2基因中鉴定出的错义突变，并生成一个前列腺特异性的Elac2基因敲除。这些突变导致前列腺增大、炎症和结节形成。在转基因小鼠前列腺腺癌(TRAMP)模型中，Elac2突变与次生基因损伤结合会加速前列腺癌的起始和进展。多组学分析揭示了能量代谢缺陷，激活了炎症和肿瘤生成通路，因为非编码RNA处理受损和蛋白质合成减少。我们的生理相关模型表明，ELAC2变异是前列腺癌的易感因素，并确定了这种癌症发病机制的变化。© 2023作者。根据CC BY 4.0许可条款发布。

Prostate cancer is the most commonly diagnosed malignancy and the third leading cause of cancer deaths. GWAS have identified variants associated with prostate cancer susceptibility; however, mechanistic and functional validation of these mutations is lacking. We used CRISPR-Cas9 genome editing to introduce a missense variant identified in the ELAC2 gene, which encodes a dually localised nuclear and mitochondrial RNA processing enzyme, into the mouse Elac2 gene as well as to generate a prostate-specific knockout of Elac2. These mutations caused enlargement and inflammation of the prostate and nodule formation. The Elac2 variant or knockout mice on the background of the transgenic adenocarcinoma of the mouse prostate (TRAMP) model show that Elac2 mutation with a secondary genetic insult exacerbated the onset and progression of prostate cancer. Multiomic profiling revealed defects in energy metabolism that activated proinflammatory and tumorigenic pathways as a consequence of impaired noncoding RNA processing and reduced protein synthesis. Our physiologically relevant models show that the ELAC2 variant is a predisposing factor for prostate cancer and identify changes that underlie the pathogenesis of this cancer.© 2023 The Authors. Published under the terms of the CC BY 4.0 license.