Analysis Of Global Cancer Data Shines Light On Alternative Gene “Switches” In Tumours

Novel genomics and computational methods reveal how gene “switches” impact survival rates of cancer patients, paving the way to targeted cancer treatments

The image illustrates the human genome (blue), and 3 alternative promoters (indicated by arrows) that activate and transcribe 3 different RNAs from the same gene. (Copyright: A*STAR’s Genome Institute of Singapore. Illustration by sci-illustrate (Radhika Patnala), featured on the cover of Cell, DOI: 10.1016/j.cell.2019.08.018)SINGAPORE – Scientists from the Agency for Science, Technology and Research (A*STAR)’s Genome Institute of Singapore (GIS) have discovered that many human cancers exhibit widespread alterations in gene activation, where the same gene uses different start positions to generate alternate gene products. These alterations, previously undetected by earlier methods of analysis, may identify novel biomarkers for predicting cancer patient survival and new targets for therapies. The study was published in Cell on 5 September 2019 and featured on the journal’s cover.

The human genome contains all our genes. The region which controls where a gene starts is called the promoter, or a ‘switch’ that turn on genes in the genome. Many genes have multiple promoters, and this can lead to different functions even from the same gene.

Prior to this study, cancer researchers lacked a comprehensive survey of alternative promoters in cancer genes, and whether different promoters leads to differences in clinical behaviour of cancer patients.

To fill the gap, the team designed a specialised software called proActiv to detect activated promoters on a genome-wide scale. The underlying algorithm in proActiv is applicable to RNA[1][1]-profiling data, which is routinely produced by hundreds of laboratories worldwide to study cancer. The team applied proActiv to a large collection of publicly-available data from over 18,000 cancer samples, and discovered that promoters in cancer genes are frequently different from their cancer-free counterparts. They also uncovered specific activated promoters that are linked to the survival rate of cancer patients, representing a new class of biomarkers.

Dr Jonathan Göke, Computational Biologist at the GIS and co-senior author of the study, explained, “We designed proActiv to work on RNA-profiling and it enables us to use the largest collection of data possible. At first that was very challenging. It was akin to solving a puzzle with thousands of pieces, where many of the pieces are almost identical. However, proActiv zooms in specifically on the unique puzzle pieces for each promoter, allowing detection of different promoters with high accuracy. The amazing part is that through this simple idea, we suddenly could analyse terabytes of data that was available to the public. The data was out there, but the information about promoters was hidden. With the new method, we managed to uncover this hidden information”.

Commenting on the study, Dr Andrew Futreal, Department Chair of Genomic Medicine at MD Anderson Cancer Center said, “The scale of this global study is impressive. It reveals that the usage of alternate promoters is a common feature of many cancer types. These findings will inspire more research into what controls this switching, and how we can use this information to improve outcomes for cancer patients.”

Prof Patrick Tan, co-senior author, Executive Director of the GIS, and a faculty member of Duke-NUS and Cancer Science Institute Singapore (CSI), said, “RNA-profiling is very frequently used in medical research. By using proActiv, scientists will be able to identify promoters without any additional experimental cost, which makes this very interesting to many research groups worldwide and opens the possibilities to explore alternative promoters in other diseases.” With the aim of advancing research in the wider scientific community, the team has deposited proActiv into the public domain, where it is free to use for other academic researchers.

The findings highlight that a promoter is a biomarker for cancer, but this does not imply that promoters cause a more severe form of cancer. “We have yet to determine if these promoters act like an emergency sign that is turned on because of a fire, or if these promoters are the fire itself,” added Dr Göke. For the GIS team in Singapore, the study is the first step towards many new possibilities to explore these questions, and to better understand the role of our genes in cancer.
Notes to Editor:

The research findings described in this media release can be found in the scientific journal Cell (DOI: 10.1016/j.cell.2019.08.018), under the title, “A Pan-Cancer Transcriptome Analysis Reveals Pervasive Regulation through Alternative Promoters” by Deniz Demircioğlu^1,2, Engin Cukuroglu¹, Martin Kindermans¹, Tannistha Nandi¹, Claudia Calabrese^3,4,20, Nuno A. Fonseca^3,5,20, André Kahles^{6,7,8,9,10,20}, Kjong-Van Lehmann^6,8,9,10,20, Oliver Stegle^3,4,11, Alvis Brazma^3,21, Angela N. Brooks^12,21, Gunnar Rätsch^{6,7,8,9,10,13,21}, Patrick Tan^{14,15,16,17,18,19,22}, Jonathan Göke^1,18,22,23.

1. Computational and Systems Biology, Genome Institute of Singapore, Singapore 138672, Singapore
2. School of Computing, National University of Singapore, Singapore 117417, Singapore
3. European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
4. Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, 69117, Germany
5. CIBIO/InBIO - Research Center in Biodiversity and Genetic Resources, Universidade do Porto, Vairão 4485-601, Portugal
6. Department of Computer Science, ETH Zurich, Zurich, 8092 Switzerland
7. Department of Biology, ETH Zurich, Zurich 8093, Switzerland
8. Computational Biology Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
9. SIB Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland
10. Biomedical Informatics Research, University Hospital Zurich, Zurich 8091, Switzerland
11. Division of Computational Genomics and Systems Genetics, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
12. Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, CA 95064, USA
13. Weill Cornell Medical College, New York, NY 10065, USA
14. Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore 169857, Singapore
15. Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore
16. Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore 138672, Singapore
17. SingHealth/Duke-NUS Institute of Precision Medicine, National Heart Centre Singapore, Singapore 169856, Singapore
18. Cellular and Molecular Research, National Cancer Centre, Singapore 169610, Singapore
19. Singapore Gastric Cancer Consortium, Singapore 119074, Singapore
20. 21. Alphabetical order
1. Senior authors
2. Lead contact.

* Correspondence: Jonathan Göke (gokej@gis.a-star.edu.sg)

For media queries and clarifications, please contact:

Lyn Lai

Officer, Office of Corporate Communications

Genome Institute of Singapore, A*STAR

Tel: +65 6808 8258

Email: laiy@gis.a-star.edu.sg

About A*STAR’s Genome Institute of Singapore (GIS)

The Genome Institute of Singapore (GIS) is an institute of the Agency for Science, Technology and Research (A*STAR). It has a global vision that seeks to use genomic sciences to achieve extraordinary improvements in human health and public prosperity. Established in 2000 as a centre for genomic discovery, the GIS will pursue the integration of technology, genetics and biology towards academic, economic and societal impact.

The key research areas at the GIS include Human Genetics, Infectious Diseases, Cancer Therapeutics and Stratified Oncology, Stem Cell and Regenerative Biology, Cancer Stem Cell Biology, Computational and Systems Biology, and Translational Research.

The genomics infrastructure at the GIS is utilised to train new scientific talent, to function as a bridge for academic and industrial research, and to explore scientific questions of high impact.

For more information about GIS, please visit www.a-star.edu.sg/gis.

About the Agency for Science, Technology and Research (A*STAR)

The Agency for Science, Technology and Research (A*STAR) is Singapore’s lead public sector agency that spearheads economic oriented research to advance scientific discovery and develop innovative technology. Through open innovation, we collaborate with our partners in both the public and private sectors to benefit society.

As a Science and Technology Organisation, A*STAR bridges the gap between academia and industry. Our research creates economic growth and jobs for Singapore, and enhances lives by contributing to societal benefits such as improving outcomes in healthcare, urban living, and sustainability.

We play a key role in nurturing and developing a diversity of talent and leaders in our Agency and research entities, the wider research community and industry. A*STAR’s R&D activities span biomedical sciences and physical sciences and engineering, with research entities primarily located in Biopolis and Fusionopolis. For ongoing news, visit www.a-star.edu.sg/.

[1][1] RNA is a nucleic acid present in all living cells, and carries genetic information of many viruses