Cancer-causing culprits will be caught by their DNA fingerprints

Study within Pan-Cancer Project will help research into cancer prevention, diagnosis and treatments

Cancer-causing culprits will be caught by their DNA fingerprints

Skin cancer cellsAnne Weston, Francis Crick Institute

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.

“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.”

Professor Mike Stratton, a senior author of the study, and Director of the Wellcome Sanger Institute

“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.”

Dr Ludmil Alexandrov, a first author of the study from the University of California San Diego

“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 Steven Rozen, a senior author from Duke-NUS Medical School, Singapore

“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.”

Professor Gad Getz, a senior author from the Broad Institute of MIT and Harvard, and Massachusetts General Hospital

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.

“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.”

Dr Peter Campbell, member of the Pan-Cancer steering committee and Head of Cancer, Ageing and Somatic Mutation at the Wellcome Sanger Institute 

Notes to Editors

*CRUK cancer statistics from 2016:  https://www.cancerresearchuk.org/health-professional/cancer-statistics-for-the-uk

Publications:

Ludmil Alexandrov, Jaegil Kim, Nicholas J Haradhvala, & Mi Ni Huang et al. (2020) The Repertoire of Mutational Signatures in Human Cancer. Nature. DOI: 10.1038/s41586-020-1943-3

**Yilong Li, Nicola D Roberts, Jeremiah A Wala & Ofer Shapira et al. (2020) Patterns of somatic structural variation in human cancer genomes. Nature. DOI: 10.1038/s41586-019-1913-9

The ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. (2020) Pan-cancer analysis of whole genomes. Nature. DOI 10.1038/s41586-020-1969-6

The Nature collection landing page with all PanCancer publications: https://www.nature.com/collections/pcawg/

§Further information on the Pan-Cancer Project:

The ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG), known as the Pan-Cancer Project, is the largest and most comprehensive study of whole cancer genomes yet. The collaboration involving more than 1,300 scientists and clinicians from 37 countries, analysed more than 2,600 genomes of 38 different tumour types, and has created a huge resource of primary cancer genomes, available to researchers worldwide to advance cancer research. https://dcc.icgc.org/pcawg

Main findings from the Pan-Cancer project include:

  • The cancer genome is finite and knowable, but enormously complicated. By combining sequencing of the whole cancer genome with a suite of analysis tools, we can characterise every genetic change found in a cancer, all the processes that have generated those mutations, and even the order of key events during a cancer’s life history.
  • Researchers are close to cataloguing all of the biological pathways involved in cancer and having a fuller picture of their actions in the genome. At least one causal mutation was found in virtually all of the cancers analysed and the processes that generate mutations were found to be hugely diverse -- from changes in single DNA letters to the reorganisation of whole chromosomes. Multiple novel regions of the genome controlling how genes switch on and off were identified as targets of cancer-causing mutations.
  • Through a new method of “carbon dating”, Pan-Cancer researchers discovered that it is possible to identify mutations which occurred years, sometimes even decades, before the tumour appears. This opens, theoretically, a window of opportunity for early cancer detection.
  • Tumour types can be identified accurately according to the patterns of genetic changes seen throughout the genome, potentially aiding the diagnosis of a patient’s cancer where conventional clinical tests could not identify its type. Knowledge of the exact tumour type could also help tailor treatments. 

Data access:

For access to all the open tier data in the Pan-Cancer project, go to https://dcc.icgc.org/

The reference mutational signatures and analysis are stored in COSMIC: Catalogue Of Somatic Mutations In Cancer - the world's largest and most comprehensive resource for exploring the impact of somatic mutations in human cancer.  https://cancer.sanger.ac.uk/cosmic

Funding:

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.

Selected Websites
Genomics in the cloudSanger ScienceGenomics in the cloud
The huge, international Pan-Cancer project is the first large-scale use of distributed cloud computing in genomics. As genomics becomes a big data science, it is likely to be the first of many

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