背景:肾细胞癌(RCC)是一种可以在成年期的任何时候发展的癌症,跨越身体中发生的与年龄相关的变化的范围。然而,RCC中年龄与基因突变之间联系的具体分子机制尚未得到广泛研究.
方法:从中国两个著名的医疗中心以及TCGA数据集中收集诊断为RCC患者的临床和遗传数据。根据预测的年龄将患者分为两组:年轻人(YAs)和老年人(OAs)。采用单变量和多变量分析来评估年龄与基因突变之间的关系。此外,进行了中介分析,以评估年龄和总生存率之间的关系,遗传差异作为中介。
结果:我们的分析显示,患有RCC的YAs和OAs之间的临床表现存在显着差异,包括组织病理学类型,肿瘤组织病理学分期,和肉瘤样分化。发现YAs具有较低的RCC突变负担和显著突变的基因(SMG)。然而,在10个典型致癌信号通路相关基因突变方面,我们没有观察到两组之间的任何显着差异,端粒酶相关基因(TRGs)突变,拷贝数更改,以及与临床上可行的靶向药物相关的基因突变。重要的是,我们在YAs中展示了优越的生存结果,我们证实了遗传差异对YAs和OAs之间这些生存结果差异的中介作用。
结论:我们的发现揭示了以前未认识到的年龄与RCC分子基础之间的关联。这些关联可以作为指导RCC精确诊断和治疗的有价值的见解。
BACKGROUND: Renal cell carcinoma (RCC) is a type of cancer that can develop at any point in adulthood, spanning the range of age-related changes that occur in the body. However, the specific molecular mechanisms underlying the connections between age and genetic mutations in RCC have not been extensively investigated.
METHODS: Clinical and genetic data from patients diagnosed with RCC were collected from two prominent medical centers in China as well as the TCGA dataset. The patients were categorized into two groups based on their prognosticated age: young adults (YAs) and older adults (OAs). Univariate and multivariate analysis were employed to evaluate the relationships between age and genetic mutations. Furthermore, a mediation analysis was conducted to assess the association between age and overall survival, with genetic disparities serving as a mediator.
RESULTS: Our analysis revealed significant differences in clinical presentation between YAs and OAs with RCC, including histopathological types, histopathological tumor stage, and sarcomatoid differentiation. YAs were found to have lower mutation burden and significantly mutated genes (SMGs) of RCC. However, we did not observe any significant differences between the two groups in terms of 10 canonical oncogenic signaling pathways-related genes mutation, telomerase-related genes (TRGs) mutation, copy number changes, and genetic mutations associated with clinically actionable targeted drugs. Importantly, we demonstrate superior survival outcomes in YAs, and we confirmed the mediating effect of genetic disparities on these survival outcome differences between YAs and OAs.
CONCLUSIONS: Our findings reveal previously unrecognized associations between age and the molecular underpinnings of RCC. These associations may serve as valuable insights to guide precision diagnostics and treatments for RCC.