Gene expression and coexpression alterations marking evolution of bladder cancer

Despite advancements in therapeutics, Bladder Cancer (BLCA) constitutes a major clinical burden, with locally advanced and metastatic cases facing poor survival rates. Aiming at expanding our knowledge of BLCA molecular pathophysiology, we integrated 1,508 publicly available, primary, well-characterized BLCA transcriptomes and investigated alterations in gene expression with stage (T0-Ta-T1-T2-T3-T4). We identified 157 genes and several pathways related prominently with cell cycle, showing a monotonically up- or down-regulated trend with higher disease stage. Genome wide coexpression across stages further revealed intrinsic and microenvironmental gene rewiring programs that shape BLCA evolution. Novel associations between epigenetic factors (CBX7, ZFP2) and BLCA survival were validated in external data. T0 together with advanced stages were heavily infiltrated with immune cells, but of distinct populations. We found AIF1 to be a novel driver of macrophage-based immunosuppression in T4 tumors. Our results suggest a continuum of alterations with increasing malignancy.