Finding cancer culprits' fingerprints
Researchers from the Wellcome Trust Sanger Institute’s cancer genome project have developed a computer model to identify the fingerprints of DNA-damaging processes that drive cancer development. Armed with these signatures, scientists will be able to search for the chemicals, biological pathways and environmental agents responsible.
The computer model will help to overcome a fundamental problem in studying cancer genomes: that the DNA contains not only the mutations that have contributed to cancer development, but also an entire lifetime’s worth of other mutations that have also been acquired. These mutations are layered on top of each other and trying to unpick the individual mutations, when they appeared, and the processes that caused them is a daunting task.
“The problem we have solved can be compared to the well-known cocktail party problem. At a party there are lots of people talking simultaneously and, if you place microphones all over the room, each one will record a mixture of all the conversations. To understand what is going on you need to be able to separate out the individual discussions. The same is true in cancer genomics. We have catalogues of mutations from cancer genomes and each catalogue contains the signatures of all the mutational processes that have acted on that patient’s genome since birth. Our model allows us to identify the signatures produced by different mutation-causing processes within these catalogues.”
Ludmil Alexandrov First author of the paper from Sanger Institute
To identify individual sets of mutations produced by a particular DNA-damaging agent, the cancer genome project at the Sanger Institute simulated cancer genomes and developed a technique to search for these mutational signatures. This approach proved to be very successful. The research team then explored the genomes of 21 breast cancer patients and identified five mutational signatures of cancer-causing processes in the real world.
“For a long time we have known that mutational signatures exist in cancer. For example UV light and tobacco smoke both produce very specific signatures in a person’s genome. Using our computational framework, we expect to uncover and identify further mutational signatures that are diagnostic for specific DNA-damaging processes, shedding greater light on how cancer develops.”
Dr Peter Campbell Head of the cancer genome project and co-senior author of the paper
The computer model offers great potential for future study: not only can the approach be applied to all forms of cancer, it can also be used to search for almost all forms of DNA damage. Depending on the type of changes the researchers want to study, the model can include single base substitutions, double nucleotide substitutions, indels, geographically localised forms of mutation such as kataegis and mutation features such as transcriptional strand bias. It is also possible that rearrangements and copy number changes (and potentially even epigenetic changes) could be incorporated into the model, providing a comprehensive overview of all the mutational processes at work.
“This new approach provides us with a valuable tool for exploring cancer genomes with a clarity and understanding that we haven’t had before. It will enable us to create a compendium of the mutational signatures of the many different DNA-damaging processes that operate during cancer development. This will help us understand why we get cancer by pointing to the underlying biological processes that mutate cells and cause them to become cancers, allowing us to estimate when each process took place and how much it contributed to each case.”
Professor Mike Stratton Director of the Sanger Institute and co-senior author of the paper
The team is now applying the model to several hundred whole genome cancer genomes and several thousand whole-exome (protein-coding regions of the genome) cancer samples to search for more mutational signatures. These signatures will enable the team to hypothesise what the causative agents could be, enabling testing in model systems (such as yeast) to reveal the biological, chemical or environmental culprits.
More information
Funding
This project was funded by the Wellcome Trust.
Participating Centres
- Cancer genome project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
- Department of Haematology, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
- Department of Haematology, University of Cambridge, Cambridge CB2 2XY, UK
Publications:
Selected websites
The Wellcome Trust Sanger Institute
The Wellcome Trust Sanger Institute is one of the world’s leading genome centres. Through its ability to conduct research at scale, it is able to engage in bold and long-term exploratory projects that are designed to influence and empower medical science globally. Institute research findings, generated through its own research programmes and through its leading role in international consortia, are being used to develop new diagnostics and treatments for human disease.
The Wellcome Trust
The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. We support the brightest minds in biomedical research and the medical humanities. Our breadth of support includes public engagement, education and the application of research to improve health. We are independent of both political and commercial interests.
Cancer Genome Project
Cancer is caused by the genetic changes acquired by our cells as we go through life. We use cutting-edge DNA sequencing methods to identify these genetic changes, known as mutations, from human cancer samples. Our aim is to discover the genes that are frequently mutated in tumours, since these provide important insights into the biology of cancer. We also study the patterns of mutations we see in cancer cells. These patterns represent a record of the cancer’s life history, and can illustrate the damaging factors the genome has been exposed to as the cancer has evolved from a normal cell.
Dr Peter Campbell
Peter Campbell’s research programme focuses on the genetic changes our cells acquire as we go through life, and how these mutations are related to ageing, cancer and other disease processes.
Professor Sir Mike Stratton
Mike’s primary research interests have been in the genetics of cancer. His early research focused on inherited susceptibility. Mike mapped and identified the major high-risk breast cancer susceptibility gene BRCA2 and subsequently a series of moderate-risk breast cancer and other cancer susceptibility genes.
Dr Serena Nik-Zainal
Serena explores patterns of mutations or "signatures" that arise in human cells to understand how DNA damage and DNA repair processes contribute towards aging and cancer.
