The emerging evidence suggested that senescence regulator genes were involved in multi cancers, which may be utilized as new targets for cancers. However, the dysregulation and clinical impact of senescence regulator genes in clear cell renal cell cancer (ccRCC) were still in foggy. Using multiomics data from TCGA-KIRC and other datasets, we comprehensively investigated the function of senescence regulator genes in ccRCC. ccRCC patients could be remodeled into 2 significant different groups basing on senescence regulators expression: senescence-pattern cancer subtype1 (SPCS1) and subtype2 (SPCS2). We further explored clinical characteristics, functional analysis, tumor immune microenvironment, immunotherapy response, genomic mutation and drug sensitivity between the 2 subtypes. Besides, senescence-pattern related risk model was established to determine the patient's prognosis of ccRCC. Finally, the overview of MECP2 function was investigated in multi cancers. ccRCC patients could be divided into SPCS1 (normal aging group) and SPCS2 (Aging disorder group). The 2 subtypes showed significant different clinical characteristics and biological process in ccRCC. SPCS2, an aggressive subtype, comprised higher clinical stage and worse prognosis of ccRCC patients. SPCS2 subtype indicated activated oncogenic signaling pathway and metabolic signatures to prompt cancer expansion. SPCS2 subgroup owned immunocompromised status, which induced immune dysfunction and low ICI therapy response. The genome-copy numbers of SPCS2, including arm-gain and arm-loss was significantly more frequent than SPCS1. In addition, the 2 subtypes argue contrasting drug sensitivity profiles in clinical specimens and matched cell lines. Finally, we constructed a prognostic risk model consisted of each subtype's leading biomarkers, which exerted a satisfied performance for ccRCC patients. Senescence regulator-related signature could modify functional pathways and tumor immune microenvironment by genome mutation and pathway interaction. Senescence regulator-related molecular subtype strengthen the understanding of ccRCC’ characterization and guide clinical treatment. Targeting senescence regulators may be regard as a proper way in ccRCC.

中文翻译：

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SPCS是一种基于衰老轴调节器的新型分类器系统，揭示肿瘤微环境异质性并指导透明细胞肾癌的一线治疗

新的证据表明衰老调节基因与多种癌症有关，这可能成为癌症的新靶点。然而，透明细胞肾细胞癌（ccRCC）中衰老调节基因的失调和临床影响仍不清楚。利用 TCGA-KIRC 和其他数据集的多组学数据，我们全面研究了 ccRCC 中衰老调节基因的功能。根据衰老调节因子的表达，ccRCC 患者可分为 2 个显着不同的组：衰老模式癌症亚型 1 (SPCS1) 和亚型 2 (SPCS2)。我们进一步探讨了两种亚型之间的临床特征、功能分析、肿瘤免疫微环境、免疫治疗反应、基因组突变和药物敏感性。此外，还建立了衰老模式相关风险模型来确定ccRCC患者的预后。最后，对 MECP2 在多种癌症中的功能进行了概述。 ccRCC患者可分为SPCS1（正常衰老组）和SPCS2（衰老障碍组）。 2种亚型在ccRCC中表现出显着不同的临床特征和生物学过程。 SPCS2是一种侵袭性亚型，ccRCC患者的临床分期较高，预后较差。 SPCS2 亚型表明激活的致癌信号通路和代谢特征可促进癌症扩散。 SPCS2亚组具有免疫功能低下状态，导致免疫功能障碍和ICI治疗反应低。 SPCS2 的基因组拷贝数（包括臂增加和臂丢失）明显高于 SPCS1。此外，这两种亚型在临床标本和匹配的细胞系中具有对比的药物敏感性特征。最后，我们构建了一个由每个亚型的主要生物标志物组成的预后风险模型，该模型对 ccRCC 患者发挥了令人满意的性能。衰老调节因子相关的特征可以通过基因组突变和途径相互作用来改变功能途径和肿瘤免疫微环境。衰老调节因子相关的分子亚型加强了对 ccRCC 特征的理解并指导临床治疗。针对衰老调节因子可能被视为ccRCC的正确途径。