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

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

Cell

10.1016/j.cell.2019.08.018

https://doi.org/10.1016/j.cell.2019.08.018

Deniz Demircioğlu, Engin Cukuroglu, Martin Kindermans, Tannistha Nandi, Claudia Calabrese, Nuno A. Fonseca, André Kahles, Kjong-Van Lehmann, Oliver Stegle, Alvis Brazma, Angela N. Brooks, Gunnar Rätsch, Patrick Tan, Jonathan Göke

cancer

05 September 2019

Demircioğlu, Deniz, et al. "A Pan-cancer Transcriptome Analysis Reveals Pervasive Regulation through Alternative Promoters." Cell 178.6 (2019): 1465-1477.

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

http://creativecommons.org/licenses/by-nc-nd/4.0/

This work is funded by the Agency for Science, Technology and Research (A∗STAR), Singapore, and supported by the Singapore Ministry of Health’s National Medical Research Council under its Individual Research Grant funding scheme ( OFIRG16nov019 ). A portion of this research is supported by the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative. P.T. is supported by National Medical Research Council grants TCR/009-NUHS/2013 and NMRC/STaR/0026/2015 . The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The GTEx data used for the analyses described in this manuscript were obtained from the dbGaP accession number phs000424.v6.p1 on September 4, 2015. The TCGA data used in this manuscript were obtained from the dbGaP accession number phs000178.v10.p8. The results published here are in whole or part based upon data generated by TCGA managed by the NCI and NHGRI. Information about TCGA can be found at http://cancergenome.nih.gov. We acknowledge the ENCODE Consortium and the ENCODE production laboratories for generating the datasets used in this study.

https://oar.a-star.edu.sg/communities-collections/articles/15594

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Genome Institute of Singapore