Ma Wenming, Ge Qintao, Guan Yu, Zhang Li, Huang Liqun, Chen Lei, Xu Wenlong, Meng Jialin, Yang Guosheng, Liang Chaozhao
Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, PR China; Institute of Urology, Anhui Medical University, Hefei, 230022, PR China; Anhui Province Key Laboratory of Urological and Andrological Diseases Research and Medical Transformation, Hefei, 230022, PR China.
Department of Urology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, PR China.
Transl Oncol. 2024 Sep;47:102042. doi: 10.1016/j.tranon.2024.102042. Epub 2024 Jun 25.
Clear cell renal cell carcinoma (ccRCC) is a common urological malignancy that is involved in tumor genesis and development. However, few studies have focused on the predictive role of the global histone modification status in ccRCC. A total of 621 patients with complete transcript information and corresponding clinical profiles were obtained from TCGA-KIRC, GSE22541, and EMTAB3267 cohorts. A total of 122 histone modification relevant pathways were derived from MSigDB, and their activation status was quantified using GSVA. Differentially expressed genes (DEGs) were identified and filtrated using univariate Cox regression analysis. The signature was built relied on the least absolute shrinkage and selection operator (LASSO) regression analysis, and evaluated from survival difference, chemotherapy response, and activated pathways. A novel nomogram was established to quantify the probability of death in different patients. Seven risky and fifty-eight protective genes were used in LASSO analysis, and six genes were used to build the histone modification gene (HiMG) signature, which showed significant independent prognostic potential in all three cohorts. The nomogram showed acceptable incremental predictions. CKS2 (p = 0.004) and PD1 (p = 0.002) expression were significantly higher in grade 3 ccRCC than in grades 1-2. CKS2 siRNA in renal cancer cells caused reductions in cellular proliferation, migration, and invasion. Patients with low HiMG may be potential responders to rapamycin, erlotinib and FH535, while AZD6482 and CHIR-99,021 may be more suitable for patients with high HiMG levels. ccRCC histone modification distribution and a clinical signature for prognosis prediction, clinical decision making, and molecular mechanism exploration, were established for risk stratification and personalized treatments.
透明细胞肾细胞癌（ccRCC）是一种常见的泌尿系统恶性肿瘤，参与肿瘤的发生和发展。然而，很少有研究关注整体组蛋白修饰状态在ccRCC中的预测作用。从TCGA-KIRC、GSE22541和EMTAB3267队列中获取了总共621例具有完整转录信息和相应临床资料的患者。从MSigDB中获得了总共122条与组蛋白修饰相关的通路，并使用GSVA对其激活状态进行了量化。使用单变量Cox回归分析鉴定并筛选差异表达基因（DEG）。基于最小绝对收缩和选择算子（LASSO）回归分析构建特征，并从生存差异、化疗反应和激活通路方面进行评估。建立了一种新的列线图来量化不同患者的死亡概率。在LASSO分析中使用了7个风险基因和58个保护基因，并用6个基因构建了组蛋白修饰基因（HiMG）特征，该特征在所有三个队列中均显示出显著的独立预后潜力。列线图显示出可接受的增量预测。CKS2（p = 0.004）和PD1（p = 0.002）在3级ccRCC中的表达明显高于1-2级。肾癌细胞中的CKS2 siRNA导致细胞增殖、迁移和侵袭减少。HiMG水平低的患者可能是雷帕霉素、厄洛替尼和FH535的潜在反应者，而AZD6482和CHIR-99,021可能更适合HiMG水平高的患者。建立了ccRCC组蛋白修饰分布以及用于预后预测、临床决策和分子机制探索的临床特征，以进行风险分层和个性化治疗。
