Data_Sheet_3_A novel thinking: DDR axis refines the classification of ccRCC with distinctive prognosis, multi omics landscape and management strategy.CSV

BackgroundDNA damage response and repair (DDR) related signatures play an important role in maintaining genome stability and other biological processes. It also affects the occurrence, development, and treatment of cancer. However, in renal cell carcinoma (RCC), especially clear cell renal carcinoma (ccRCC), the potential association between DDR-related signatures and tumor heterogeneity and tumor microenvironment (TME) remains unclear.
MethodsUtilizing unsupervised clustering algorithm, we divided RCC into two subgroups, DCS1 and DCS2, according to the differences in DDR gene expression, and compared the characteristics of the two subgroups through multiple dimensions.
ResultsCompared with DCS1, DCS2 patients have higher clinical stage/grade and worse prognosis, which may be related to active metabolic status and immunosuppression status. At the same time, the high mutation rate in DCS2 may also be an important reason for the prognosis. We also analyzed the sensitivity of the two subgroups to different therapeutic agents and established a subtypes' biomarkers-based prognostic system with good validation results to provide ideas for clinical diagnosis and treatment. Finally, we identified a pivotal role for DDX1 in the DDR gene set, which may serve as a future therapeutic target.
ConclusionThis study showed that DDR has an important impact on the development and treatment of RCC. DCS2 subtypes have a poor prognosis, and more personalized treatment and follow-up programs may be needed. The assessment of DDR gene mutations in patients may be helpful for clinical decision-making. DDX1 may be one of the effective targets for RCC treatment in the future.

背景：DNA损伤应答与修复（DNA damage response and repair, DDR）相关特征在维持基因组稳定性及其他生物学过程中发挥关键作用，同时亦可影响癌症的发生、发展与治疗。然而，在肾细胞癌（renal cell carcinoma, RCC），尤其是透明细胞肾细胞癌（clear cell renal carcinoma, ccRCC）中，DDR相关特征与肿瘤异质性、肿瘤微环境（tumor microenvironment, TME）之间的潜在关联仍未明确。
方法：本研究基于DDR基因表达差异，采用无监督聚类算法将肾细胞癌样本分为DCS1与DCS2两个亚型，并从多维度对两个亚型的特征进行比较分析。
结果：与DCS1亚型相比，DCS2亚型患者的临床分期/分级更高，预后更差，这可能与活跃的代谢状态及免疫抑制状态相关。同时，DCS2亚型较高的突变率或许亦是影响预后的重要因素。本研究还分析了两个亚型对不同治疗药物的敏感性，构建了基于亚型生物标志物的预后系统，该系统验证效果良好，可为临床诊疗提供思路。最后，本研究明确了DDX1在DDR基因集当中的关键作用，其有望成为未来的治疗靶点。
结论：本研究证实DDR对肾细胞癌的发生发展与治疗具有重要影响。DCS2亚型预后较差，或许需要更为个体化的治疗及随访方案。对患者DDR基因突变状态进行评估，可为临床决策提供参考。DDX1有望成为未来肾细胞癌治疗的有效靶点之一。