The pan-cancer mutational landscape of the PPAR pathway reveals universal patterns of dysregulated metabolism and interactions with tumor immunity and hypoxia
The pan-cancer mutational landscape of the PPAR pathway reveals universal patterns of dysregulated metabolism and interactions with tumor immunity and hypoxia
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DOI：
10.1111/nyas.14170
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发表时间：
2019-07-01
影响因子：
5.2
通讯作者：
Lai, Alvina G.
中科院分区：
文献类型：
--
作者：
Chang, Wai Hoong;Lai, Alvina G.
过氧化物酶体增殖物激活受体（PPARs）是调节生命系统内的脂质代谢和生物能量需求的核受体家族。因此，PPAR基因的异常表达可能使个体易患疾病，包括癌症。PPAR信号在癌症中发挥多效性功能，但对泛癌症背景下通路基因的遗传和转录事件之间的相互作用知之甚少。采用涉及21种癌症的18，000多名患者的多维数据集，我们对74个PPAR途径基因的拷贝数改变和差异转录表达进行了系统表征。我们确定了18个基因表现出相互排斥的模式的损失和获得的功能表型。这些基因成功预测了膀胱癌、肾癌、神经胶质瘤、肝癌和胃癌/食管癌患者的生存率。这些癌症中的异常调节的PPAR信号传导聚集在与多种代谢过程相关的共同下游途径上。此外，观察到PPARs和缺氧之间的临床相关关系，其中缺氧进一步加剧了具有异常PPARs信号传导的肿瘤亚型中的疾病表型。在神经胶质瘤样本中，包括星形细胞瘤和寡星形细胞瘤，通过增加调节性T细胞表达，过氧化物酶体增殖物激活受体过度活化与免疫抑制相关。我们的分析揭示了PPAR基因的多样性和保守性水平被低估，这可能为针对肿瘤代谢，免疫和缺氧的治疗策略奠定基础。
Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors that regulate lipid metabolism and bioenergetic demands within living systems. Consequently, aberrant expression of PPAR genes could predispose individuals to diseases, including cancer. PPAR signaling exerts pleiotropic functions in cancer, yet little is known about the interactions between genetic and transcriptional events of pathway genes in a pan-cancer context. Employing multidimensional datasets of over 18,000 patients involving 21 cancers, we performed systematic characterization on copy number alteration and differential transcript expression of 74 PPAR pathway genes. We identified 18 genes demonstrating mutually exclusive patterns of loss- and gain-of-function phenotypes. These genes successfully predicted patient survival rates in bladder, renal, glioma, liver, and stomach/esophageal cancers. Dysregulated PPAR signaling in these cancers converged on common downstream pathways associated with multiple metabolic processes. Moreover, clinically relevant relationships between PPARs and hypoxia were observed, where hypoxia further aggravates disease phenotypes in tumor subtypes with aberrant PPAR signaling. In glioma samples, including astrocytoma and oligoastrocytoma, PPAR hyperactivation is associated with immunosuppression through increased regulatory T cell expression. Our analysis reveals underappreciated levels of diversity and conservation in PPAR genes that could lay the groundwork for therapeutic strategies targeting tumor metabolism, immunity, and hypoxia.