A Pan-cancer Transcriptome Analysis Reveals Pervasive Regulation through Alternative Promoters

Summary Most human protein-coding genes are regulated by multiple, distinct promoters, suggesting that the choice of promoteris as important as its level of transcriptional activity. However, while a global changein transcription is recognized as a defining feature of cancer, the contribution of alternative promotersstill remains largely unexplored. Here, we infer active promotersusing RNA-seqdata from 18,468 cancer and normal samples, demonstrating that alternative promotersare a major contributor to context-specific regulation of transcription. We find that promotersare deregulated across tissues, cancer types, and patients, affecting known cancer genes and novel candidates. For genes with independently regulated promoters, we demonstrate that promoteractivity provides a more accurate predictor of patient survival than gene expression. Our study suggests that a dynamic landscape of active promotersshapes the cancer transcriptome, opening new diagnostic avenues and opportunities to further explore the interplay of regulatory mechanisms with transcriptional aberrations in cancer.