Conserved patterns of transcriptional dysregulation, heterogeneity and cell states in clear cell kidney cancer [Bulk RNA-seq]

Clear cell kidney cancers (ccRCC) stem from proximal tubule cells in which the VHL gene has been disrupted, causing activation of HIF transcription factors. Although this is essential for cancer initiation, it not sufficient for development of aggressive tumors. To better understand transcriptional programs underpinning ccRCC progression, we perform single cell transcriptomics on 75 kidney tumor and patient-matched normal kidney biopsies. We describe tumor dysregulated transcriptional programs that are conserved across patients, deconvoluted by cell type. Leveraging recurrent intratumor heterogeneity in chromosome 14q loss, a metastasis-associated copy number alteration, we describe the ensuing transcriptional programs to reveal potential mechanisms priming cells for metastasis. Lastly, we describe co-existing cancer cell states consistently found in all patients, underpinned by distinct transcriptional regulators and whose transcriptional signatures are prognostic. These cancer cell states reflect heterogeneity found in the normal proximal tubule epithelium, strongly indicating that they arise from lineage plasticity.