Non-coding DNA constitutes over 98% of the human genome and harbors numerous functional elements essential for regulating gene expression and maintaining chromosomal architecture1. Mutations at non-coding regions may drive cancer by dysregulating proto-oncogenes and tumor suppressor genes, as exemplified by recent studies demonstrating recurrent point mutations at the TERT promoter in multiple cancer types2,3 and TAL1 enhancer insertions in T-cell acute lymphoblastic leukemia4. While previous pan-cancer analyses of tumor genomes have nominated regulatory driver mutations5,6, these studies have typically not been sufficiently powered to identify tissue-specific non-coding driver mutations, as hundreds of samples are usually needed to reliably identify driver mutations in individual cancer types7. Recently, the whole-genome mutational landscapes of breast8, liver9, and pancreatic10 cancer tumors have been studied to identify cancer-specific non-coding drivers. However, the prevalence and impact of non-coding driver mutations is still unknown for most cancer types.