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EXPERT REACTION: Genetic 'fingerprints' behind cancer drivers revealed

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Many known causes of cancer, such as UV light and tobacco smoking, leave a specific fingerprint of damage in the DNA. International researchers have revealed the most detailed list of these genetic fingerprints to date, providing clues as to how each cancer developed. These fingerprints will allow scientists to search for previously unknown chemicals, biological pathways, and environmental agents responsible for causing cancer. This research is part of the global 'Pan-Cancer Project', which included Australian and international researchers and analysed more than 2,600 genomes of 38 different tumour types.

Journal/conference: Nature

DOI: 10.1038/s41586-020-1943-3

Organisation/s: The University of Melbourne, The University of Queensland, Peter MacCallum Cancer Centre, Garvan Institute of Medical Research, Walter and Eliza Hall Institute of Medical Research (WEHI), The University of New South Wales, Murdoch Children's Research Institute, Australian National University, Wellcome Sanger Institute, UK

Funder: This work was supported by Wellcome, the Singapore National Medical Research Council, NIH, ERC, Cancer Research UK and other funders. Please see the papers for the full lists of funding.

Media Release

From: Nature

Causes of cancer are being catalogued by a huge international study revealing the genetic fingerprints of DNA-damaging processes that drive cancer development. Researchers from the Wellcome Sanger Institute, Duke-NUS Medical School Singapore, University of California San Diego School of Medicine, the Broad Institute of MIT and Harvard and their collaborators around the world have achieved the most detailed list of these genetic fingerprints to date, providing clues as to how each cancer developed.

These fingerprints will allow scientists to search for previously unknown chemicals, biological pathways and environmental agents responsible for causing cancer.

The research, published in Nature today (5th February) as part of a global Pan-Cancer Project, will help understand the causes of cancer, informing prevention strategies, and help signpost new directions for cancer diagnosis and treatments.

Also published today in Nature and related journals, are 22 further studies from the Pan-Cancer Project. The collaboration involving more than 1,300 scientists and clinicians from 37 countries, analysed more than 2,600 genomes of 38 different tumour types. The project represents an unprecedented international exploration of cancer genomes, which significantly improves our fundamental understanding of cancer and zeros-in on mechanisms of cancer development.

In the UK, someone is diagnosed with cancer every two minutes, with 363,000 new cancer cases every year. The disease causes around 165,000 deaths in the UK annually*.

Cancer is caused by genetic changes - mutations - in the DNA of a cell, allowing the cell to divide uncontrollably. Many known causes of cancer, such as UV light and tobacco smoking, leave a specific fingerprint of damage in the DNA, known as a mutational signature. These fingerprints can help understand how cancers develop, and potentially, how they can be prevented. However, past studies have not been large enough to identify all potential mutational signatures.

The fingerprint study identified new mutational signatures that had not been seen before, from single letter ‘typo’ mutations, to slightly larger insertions and deletions of genetic code. The result is the largest database of reference mutational signatures ever. Only about half of all the mutational signatures have known causes, however this resource can now be used to help find more of these causes and better understand cancer development.


Professor Mike Stratton, a senior author of the study, and Director of the Wellcome Sanger Institute, said: “Using our detailed catalogue of the range of mutational signatures in cancer DNA, researchers worldwide will now be able to investigate which chemicals or processes are linked to these signatures. This will increase our understanding of how cancer develops, and discover new causes of cancer, helping to inform public health strategies to prevent cancer.”

Dr Ludmil Alexandrov, a first author of the study from the University of California San Diego, said: “We identified almost every publically available cancer genome at the start of this project and analysed their whole genome sequences. The data from these thousands of cancers allowed us to describe mutational signatures in much more detail than ever before, and we are confident that we now know most of the signatures that exist.”

Professor Steven Rozen, a senior author from Duke-NUS Medical School, Singapore, said: “Some types of these DNA fingerprints, or mutational signatures, reflect how the cancer could respond to drugs. Further research into this could help to diagnose some cancers and what drugs they might respond to.”

Professor Gad Getz, a senior author from the Broad Institute of MIT and Harvard, and Massachusetts General Hospital, said, “The availability of a large number of whole genomes enabled us to apply more advanced analytical methods to discover and refine mutational signatures and expand our study into additional types of mutations. Our new collection of signatures provides a more complete picture of biological and chemical processes that damage or repair DNA and will enable researchers to decipher the mutational processes that affect the genomes of newly sequenced cancers.”

Another study in the Pan-Cancer Project, published in Nature** today, discovered that larger, more complex genetic changes that rearrange the DNA could also act as mutational signatures, and point towards causes of cancer. Researchers from the Wellcome Sanger Institute and the Broad Institute of MIT and Harvard and their collaborators found 16 of these signatures that spanned from rearrangements of single genes to entire chromosomes.

The global Pan-Cancer Project is the largest and most comprehensive study of whole cancer genomes yet. The collaboration has created a huge resource of primary cancer genomes, available to researchers worldwide to advance cancer research.

Dr Peter Campbell, member of the Pan-Cancer steering committee and Head of Cancer, Ageing and Somatic Mutation at the Wellcome Sanger Institute, said: “The entire Pan-Cancer work is helping to answer a long-standing medical difficulty: why two patients with what appears to be the same cancer can respond differently to the same drug. We show that the reasons for these different effects of treatment are written in the DNA. The genome of each patient’s cancer is unique, but there are a finite set of recurring patterns in the DNA, so with large enough studies we can identify all these patterns to optimise cancer diagnosis and treatment.”

**Please note that a telephone press briefing will take place UNDER STRICT EMBARGO on Tuesday 4th February at 1500 London time (GMT) / 1000 US Eastern Time**

Authors Peter Campbell and Lincoln Stein will discuss the research. This will be followed by a Q&A session.

To attend this briefing you will need to pre-register by following the link here. Once you are registered, you will receive an email containing the dial-in details for the conference. You will also be provided with the option to save the details of the briefing to your calendar.

Attachments:

  • Wellcome Sanger Institute, UK
    Web page
  • Springer Nature
    Web page
    Dropbox with all 22 papers and releases

Expert Reaction

These comments have been collated by the Science Media Centre to provide a variety of expert perspectives on this issue. Feel free to use these quotes in your stories. Views expressed are the personal opinions of the experts named. They do not represent the views of the SMC or any other organisation unless specifically stated.

Professor Sean Grimmond holds the Bertalli Chair in Cancer Medicine at the University of Melbourne and led the Australian efforts, contributing around 10 per cent of samples for the study

This research will help identify what types of genetic test are needed for each cancer type – filling in potential existing gaps that we did not even know were there.

It demonstrates better than ever before how similar damage can cause cancer in different tissues – implications mean that, for example, a breast cancer drug could be effectively used to treat an oesophageal cancer. 

If we don’t understand where a cancer comes from, we can’t even rely on traditional clinical approaches to treatment.

Last updated: 05 Feb 2020 2:27pm
Declared conflicts of interest:
None declared.

Dr Tom Hudson is Chief Scientific Officer at AbbVie and a founder of the International Cancer Genome Consortium, USA

The completion of this project represents the culmination of more than a decade of ground-breaking work in studying the cancer genome. When we launched ICGC in 2007, an initiative of this magnitude was unprecedented.

I am thrilled that the scientific community has come together to produce this comprehensive study, which enhances our understanding of cancer and fosters the development of new medicines for cancer patients.

Last updated: 05 Feb 2020 2:25pm
Declared conflicts of interest:
Tom is an author on the paper.
Dr Peter Campbell, member of the Pan-Cancer Project steering committee and Head of Cancer, Ageing and Somatic Mutation at the Wellcome Sanger Institute in the UK

This work is helping to answer a long-standing medical difficulty: why two patients with what appear to be the same cancer can have very different outcomes to the same drug treatment. We show that the reasons for these different behaviours are written in the DNA.  

The genome of each patient’s cancer is unique, but there are a finite set of recurring patterns, so with large enough studies we can identify all these patterns to optimise diagnosis and treatment.

Last updated: 05 Feb 2020 2:25pm
Declared conflicts of interest:
Peter is an author on the paper.
Associate Professor Jyotsna Batra is NHMRC RD Wright Fellow and Group Leader of the Molecular Genetics Lab at QUT

This is the world’s largest study in which more than 2,600 DNA samples from 38 different tumour types have been fully sequenced.  

DNA is the basic unit of life, which transcribes to a messenger (mRNA). mRNA is further decoded to make proteins (using only using 2 per cent of the genome) which are the building blocks of the cell. DNA also codes for the long non-coding RNAs (lncRNAs), the molecules of emerging importance in cancer. 

Unlike previous studies, which were focussed only on the protein-coding regions of the genome, the Pan-Cancer Project identified cancer driver point mutations and/or structural rearrangements in ncRNA regions, with most still reported to be present in the protein-coding part of the genome. 

A major effort was put together to distinguish cancer-driver mutations from the passenger mutations and to decipher the mechanisms by which these mutations alter the DNA structure, their potential to transcribe mRNA, make new genes by fusion and even the order of key events during a cancer’s life history.

In addition to developing advanced methodology using cloud computing, the Pan-Cancer Project has generated an ocean of valuable data for scientists and clinicians to analyse, and help further understand the mechanism of cancer development and evolution and developing new markers for early cancer detection. In addition, several new genes and ncRNA have been identified, which can be targeted to develop personalised cancer therapies. We will be able to reap even richer dividend if the clinical data concerning patient outcomes and treatments can be linked to the generated genetic data through this project.

We are moving fast-forward in the direction of dealing with cancers not only on the basis of which organ did a cancer originate, but on the basis of what events at the DNA or RNA level are driving these tumours. 

These 22 studies represent a big move forward in genomics research, although are likely still far from complete. The common types of cancer such as liver, breast (most common female cancer in Australia), pancreas and prostate cancer (most common male cancer in Australia) have been thoroughly analysed; with fewer DNA from less common cancers. Interestingly, the analysis showed that average, cancer genomes contained 4–5 driver events; however, in around 5 per cent of cases, no causal changes leading to cancer development were identified, suggesting that additional efforts -  including an even higher number of patients, and also from multiple ethnic backgrounds such as unique population from Australian Aboriginal and Torres Strait patients - are required. 

A project called the International Cancer Genome Consortium–Accelerate Research in Genomic Oncology (ICGC–ARGO) is underway. This will create such a resource for more than 100,000 people with cancer and we look forward to its outcome building on the current Pan-Cancer project expertise.

Last updated: 05 Feb 2020 2:22pm
Declared conflicts of interest:
None declared.
Associate Professor Elizabeth D. Williams is Research Director at the Centre for the Personalised Analysis of Cancers, QUT

This set of papers describe a panel of comprehensive analyses of the largest publicly available multi-cancer dataset to date. The exciting results address many features of cancer, mainly focused on the complexity of alterations of the genetic material in tumour cells. It will be necessary to check whether the findings can be replicated in other collections of cancer samples. These papers identify potential new approaches to identify and control cancer cells, although these will require extensive further investigations to determine relevance.

Ultimately this research needs to be put into the clinical context, as limited information about the relationships between these genomic alterations and patient treatments and outcomes is currently available. These studies provide a terrific resource for cancer researchers around the world. The data will no doubt be very widely used to advance our understanding about what genetic changes are associated with different types of cancer, and how these can be targeted to identify cancer cells and improve cancer control.

Last updated: 05 Feb 2020 2:21pm
Declared conflicts of interest:
None declared.

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