Feulner Lara, Najafabadi Hamed S, Tanguay Simon, Rak Janusz, Riazalhosseini Yasser
Department of Human Genetics, McGill University, McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
Department of Surgery, Division of Urology, McGill University Health Center, McGill University, Montreal, Quebec, Canada.
Urol Oncol. 2019 Feb;37(2):166-175. doi: 10.1016/j.urolonc.2018.11.006. Epub 2018 Nov 23.
Clear cell renal cell carcinoma (ccRCC) is known to occur across the adult lifetime traversing the spectrum of age-related organismal changes. Little is known as to how the aging process may affect the course of renal cell carcinoma (RCC) and the repertoire of genes involved.
Using The Cancer Genome Atlas (n = 436) and Cancer Genomics of the Kidney (n = 89) datasets, we applied regression analysis to examine associations between patient age and gene expression profiles in ccRCC tumors and normal kidney tissues. Pathway enrichment analysis was performed to identify cellular process that is affected by aging in ccRCC. Moreover, connectivity mapping analysis was used to predict age-dependent response to drug treatments.
Our analysis revealed different age-dependent gene expression spectra in ccRCC and normal kidney tissues. These findings were significant and independently reproducible in both datasets examined. Age up-regulated genes, showing higher expression in older patients, were significantly enriched (false discovery rate <0.05) in normal tissues for pathways associated with immune response and extracellular matrix organization, whereas age up-regulated genes in tumors were enriched for metabolism and oxidation pathways. Strikingly, age down-regulated genes in normal cells were also enriched for metabolism and oxidation, while those in tumors were enriched for extracellular matrix organization. Further in silico analysis of potential drug targets predicted preferential efficacy of Phosphoinositide 3-kinase inhibitor or immunotherapy in association with age.
We report on previously unrecognized associations between age and molecular underpinnings of RCC, including age-associated expression of genes implicated in RCC development or treatment.
已知透明细胞肾细胞癌（ccRCC）在成年人一生中均可发生，贯穿与年龄相关的机体变化范围。关于衰老过程如何影响肾细胞癌（RCC）病程以及相关基因谱，目前知之甚少。
利用癌症基因组图谱（n = 436）和肾脏癌症基因组学（n = 89）数据集，我们应用回归分析来研究ccRCC肿瘤和正常肾组织中患者年龄与基因表达谱之间的关联。进行通路富集分析以确定ccRCC中受衰老影响的细胞过程。此外，利用连通性图谱分析来预测年龄依赖性药物治疗反应。
我们的分析揭示了ccRCC和正常肾组织中不同的年龄依赖性基因表达谱。这些发现在所研究的两个数据集中均具有显著性且可独立重复。年龄上调基因在老年患者中表达较高，在正常组织中与免疫反应和细胞外基质组织相关的通路中显著富集（错误发现率<0.05），而肿瘤中的年龄上调基因在代谢和氧化通路中富集。引人注目的是，正常细胞中的年龄下调基因在代谢和氧化方面也有富集，而肿瘤中的则在细胞外基质组织方面富集。对潜在药物靶点的进一步计算机分析预测了磷脂酰肌醇3-激酶抑制剂或免疫疗法与年龄相关的优先疗效。
我们报告了年龄与RCC分子基础之间以前未被认识的关联，包括与RCC发生或治疗相关基因的年龄相关表达。
