Jiang Chenye, Hong Zhe, Liu Shiwei, Hong Zongyuan, Dai Bo
Department of Urology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Genitourinary Cancer Institute, Shanghai 200032, China.
Department of Urology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Genitourinary Cancer Institute, Shanghai 200032, China.
Biochim Biophys Acta Rev Cancer. 2025 Feb;1880(1):189247. doi: 10.1016/j.bbcan.2024.189247. Epub 2024 Dec 15.
Prostate cancer (PCa) is one of the most common cancers in men, and cyclin-dependent kinase 12 (CDK12) is emerging as a novel star player in the PCa tumorigenesis and progression to castration-resistant prostate cancer (CRPC). In PCa, CDK12 alterations are mostly loss-of-function mutations featuring intronic polyadenylation (IPA), focal tandem duplications (FTDs), and R-loops formation and transcription-replication conflicts (TRCs). The occurrence of IPA can result in homologous recombination deficiency (HRD) and androgen receptor (AR) variation. FTDs induce neoantigens and increase the expression of the AR, MYC, and other hotspot- associated genes. R-loops lead to TRCs and influence various cellular processes, including gene expression and genome stability. Due to the poor prognosis of CDK12-mutant PCa patients and the mediocre response to classic standard therapies, HRD and increased neoantigen levels have provided clinicians with new insights into alternative systematic treatments for this novel PCa phenotype. In this review, we summarize the roles of CDK12 mutations in PCa and discuss their clinical value, suggesting that CDK12 potentially represents a target for further research and the development of clinical strategies for PCa.
前列腺癌（PCa）是男性最常见的癌症之一，细胞周期蛋白依赖性激酶12（CDK12）正成为前列腺癌发生发展以及进展为去势抵抗性前列腺癌（CRPC）过程中的一个新的关键因素。在前列腺癌中，CDK12改变大多是功能丧失性突变，其特征为内含子聚腺苷酸化（IPA）、局灶性串联重复（FTDs）以及R环形成和转录-复制冲突（TRCs）。IPA的发生可导致同源重组缺陷（HRD）和雄激素受体（AR）变异。FTDs诱导新抗原并增加AR、MYC和其他热点相关基因的表达。R环导致TRCs并影响包括基因表达和基因组稳定性在内的各种细胞过程。由于CDK12突变型前列腺癌患者预后较差且对经典标准疗法反应平平，HRD和新抗原水平升高为临床医生针对这种新型前列腺癌表型的替代系统治疗提供了新的思路。在本综述中，我们总结了CDK12突变在前列腺癌中的作用并讨论了其临床价值，表明CDK12可能是前列腺癌进一步研究和临床策略开发的一个靶点。
