The pan‐cancer mutational landscape of the PPAR pathway reveals universal patterns of dysregulated metabolism and interactions with tumor immunity and hypoxia

Abstract 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.