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 todetect activated promoters on a genome-wide scale. The underlying algorithmin proActiv is applicable to RNA1-profiling data- which is routinely produced byhundreds of laboratories worldwide to study cancer. The team appliedproActiv to a large collection of publicly-available data from over 18-000cancer samples- and discovered that promoters in cancer genes arefrequently different from their cancer-free counterparts. They also uncoveredspecific 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 ofthe study- explained- "We designed proActiv to work on RNA-profiling and itenables 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- wheremany of the pieces are almost identical. However- proActiv zooms inspecifically on the unique puzzle pieces for each promoter- allowing detection
of different promoters with high accuracy. The amazing part is that throughthis simple idea- we suddenly could analyse terabytes of data that wasavailable to the public. The data was out there- but the information about
promoters was hidden. With the new method- we managed to uncover thishidden information".

Commenting on the study- Dr Andrew Futreal- Department Chair of GenomicMedicine at MD Anderson Cancer Center said- "The scale of this global studyis impressive. It reveals that the usage of alternate promoters is a commonfeature of many cancer types. These findings will inspire more research intowhat controls this switching- and how we can use this information to improveoutcomes for cancer patients."

Prof Patrick Tan- co-senior author- Executive Director of the GIS- and afaculty member of Duke-NUS and Cancer Science Institute Singapore (CSI)-said- "RNA-profiling is very frequently used in medical research. By usingproActiv- scientists will be able to identify promoters without any additionalexperimental cost- which makes this very interesting to many research groupsworldwide and opens the possibilities to explore alternative promoters in otherdiseases." With the aim of advancing research in the wider scientificcommunity- the team has deposited proActiv into the public domain- where itis free to use for other academic researchers.

The findings highlight that a promoter is a biomarker for cancer- but this doesnot imply that promoters cause a more severe form of cancer. "We have yet todetermine if these promoters act like an emergency sign that is turned onbecause of a fire- or if these promoters are the fire itself-" added Dr Göke. Forthe GIS team in Singapore- the study is the first step towards many newpossibilities to explore these questions- and to better understand the role ofour 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

22. Senior authors

23. Lead contact.

* Correspondence: Jonathan Göke (gokej@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/.