Revolutionising the understanding of how cancer develops

Dangerous levels of exposure to a carcinogen can elicit specific patterns of DNA damage called mutational signatures. If a tumour eventually develops, these mutational signatures can be used to ‘work backwards’ to identify exposure to both known and previously unknown carcinogenic agents. Understanding the mechanisms that lead from an initial exposure to mutation might hold promise in uncovering new preventive targets to stop, delay or weaken carcinogenic effects. 

This was the vision for the unusual mutations patterns challenge set by Cancer Grand Challenges in 2015 and, in 2017, the Mutographs team, led by Mike Stratton of the Wellcome Sanger Institute, UK, was awarded funding to take on this challenge. Over its funding period, the team has shifted the consensus around how mutations cause cancer and revolutionised the field of cancer epidemiology. They have discovered multiple widespread human mutagenic exposures, with both known and unknown causes, and highlighted the roles of non-mutagenic carcinogens in human cancer.  

Two known types of carcinogens exist: mutagenic and non-mutagenic. Mutagenic carcinogens, such as tobacco smoke and ultraviolet light, increase the chances of cancer ‘driver’ mutations occurring. 

Non-mutagenic, or ‘promotional’, carcinogens increase the chance that normal cells with pre-existing driver mutations will become cancer cells. This concept is supported by a long history of experimental rodent research, and recent studies, including those by the Mutographs team, have helped bring this promotion hypothesis to the fore again, by showing that normal, healthy tissues indeed carry many cell clones with cancer driver mutations.  

Mutographs has been tackling the challenge of unravelling these phenomena, by uniting global, interdisciplinary teams conducting work at the intersection of epidemiology and genomics. By studying the mutational signatures in the genomes of cancer cells versus normal cells in countries with high and low incidence of specific cancer types, the team has been working to catalogue the mutational processes that cause cancer in humans, understand their causes and apply this knowledge to cancer prevention.  

“From an epidemiological perspective, the team represents a significant advancement in our understanding of the environmental and lifestyle causes of cancer,” says Elisabete Weiderpass, director of the International Agency for Research on Cancer (IARC), France. 

One arm of Mutographs has used animal models to identify, characterise and understand the biological processes underlying mutational signatures. Findings from a 2020 Nature Genetics study, led by Mutographs co-investigator Allan Balmain of the University of California, San Francisco, US, and Mutographs collaborator David Adams of the Wellcome Sanger Institute, suggested an alternative view challenging the long-held notion that carcinogens directly cause mutations.  

In the study, the team conducted the first survey of a broad range of known or suspected environmental carcinogens in mouse models accurately representing exposure. Many of these potential carcinogens were expected mutagens, including trichloropropane (TCP), which is often present in the drinking water near toxic-waste sites. The team’s aim was to classify these chemicals either as mutagens or as non-mutagenic tumour promoters.  

To the researchers’ surprise, only three of the 20 tested compounds, including TCP, showed clear evidence of mutagenic activity.  

Allan says that mutations can be found in mice due to exposure to mutagens such as TCP, or because of simple mistakes that are made in cells replicating their DNA. The presence of these mutations ensures that cancer has the potential to develop during the entire lifetimes of exposed animals. In some cases, the mutations are essential but not sufficient for tumour development. The role of the non-mutagenic promoters is to awaken these dormant mutated cells so that they can grow and become cancerous.  

“Our study indicated that the vast majority of known or suspected human carcinogens are not in fact mutagens,” says Allan. “That was pretty dramatic, because many people suspected there were all these chemicals that in some way cause mutations that contribute to cancer. Our study showed, however, that many chemicals do not seem to do that.” 

Mutographs has shown that this research is relevant in human cancers. For example, the team looked at oesophageal squamous cell carcinoma (ESCC) cases from eight different countries with widely differing incidence rates, including Iran, Kenya and China. Surprisingly, they found no differences in mutational loads or mutational signatures in these tumours – nothing that indicated that a chemical or some other factor caused mutations that led to ESCC.  

This landmark study, published in Nature Genetics, as well as the seminal discoveries in mice, shifted thinking to reposition promotion as a key mechanism in cancer initiation. 

As in all Cancer Grand Challenges teams, patient advocacy is hugely important. For Mutographs, the patient advocates were given the task of helping to spread any public health messages that come from the research of the team. To do this effectively meant that they had to immerse themselves in the research unique to each country where the team had sourced patient samples. 

Mutographs patient advocate Mimi McCord participated in the study, travelling to Kenya and other countries. “My involvement helped me to have a perspective of how cancer is perceived and the stigma that it has, particularly in Kenya,” says Mimi. “The patient advocates put a human element into a very science-based project, which may ultimately benefit patients in the future.” 

These findings, which really have changed the consensus on the relationship between mutagenic and non-mutagenic carcinogens, as well as insights from normal tissues containing cell clones with cancer-driving mutations, prompted Cancer Grand Challenges to set the Normal Phenotypes challenge in 2020. The challenge called for teams to look beyond the accumulation of mutations and understand in molecular detail how a normal cell harbouring a cancer mutation is restrained from oncogenic progression and then identify the critical steps for progression at the earliest steps of tumour development.  

Building on findings from Mutographs, the PROMINENT team, led by Allan alongside Paul Brennan of IARC (who is also a co-investigator in Mutographs) and Núria López-Bigas of the Institute for Research in Biomedicine Barcelona, Spain, is tackling the Normal Phenotypes challenge by investigating the promoter hypothesis as an alternative theory about the very early stages of cancer development. 

Cancer promotion and its potential importance in public health was highlighted in a study published in Nature in 2023, led by Charles Swanton of The Francis Crick Institute, UK, and member of the Cancer Grand Challenges Scientific Committee. 

The researchers found that tiny particles in vehicle exhaust and smoke from fossil fuels are associated with non-small cell lung cancer. These particles promote lung cancer by acting on cells bearing pre-existing mutations in the EGFR and KRAS genes. EGFR mutations are present in approximately half of all people with lung cancer who have never smoked.  

The findings suggest that environmental triggers awaken normal cells that carry cancer-causing mutations. In combination with the findings from the Mutographs team, this work is revolutionising the field of cancer epidemiology and may lead to the development of new prevention strategies and therapies for lung cancer.  

Through a powerful alliance between the Wellcome Sanger Institute and IARC, Mutographs has driven a whole new approach to cancer epidemiology.  

In emerging research, Mutographs has examined the geographic variation of mutagenic exposures in kidney cancer. Researchers sequenced clear cell renal cell carcinomas, the most common type of kidney cancer, from 11 countries and found that somatic (acquired) mutation profiles differed among the countries. In Romania, Serbia and Thailand, for example, mutational signatures likely caused by acids of Aristolochia plants were present in most cases, but rare in other countries. In Japan, a distinctive mutational signature was linked to about 70% of kidney cancers, which the researchers did not find elsewhere. 

The results indicate the existence of multiple, widespread, geographically variable mutagenic exposures to known and unknown causes, which could contribute to the incidence of kidney cancer.  

“We see differences in mutation loads and mutation patterns in different parts of the world,” explains Mike. “We can’t be absolutely sure what is happening in the whole population, but tens of millions of people could be affected.” 

Underpinning the discoveries from the Mutographs team, Ludmil Alexandrov, Mutographs co-investigator of the University of California, San Diego, US, has developed a suite of AI-powered tools, called SigProfiler, to identify and analyse mutational signatures. These computational tools have become widely used by the scientific community. 

In a study published in Cell Reports, he and Burçak Otlu, a former postdoctoral researcher in Ludmil’s laboratory and now an assistant professor at Middle East Technical University, Turkey, used SigProfiler to show that mutations marked by mutational signatures are affected by the shape, structure and characteristics of the genome. The study integrated mutations from 5,120 whole-genome-sequenced tumours from 40 cancer types with 516 distinct topographical features.   

“Our findings suggest that certain mutagenic processes are breaking the rules in protected regions of the genome,” says Ludmil. “Rather than occurring randomly, as many people thought, these mutations accumulate in particular areas based on the architecture of the genome.” 

“Studying signatures through a topographical lens will allow us to identify key driver processes and mutations underlying cancer formation,” adds Burçak, “which will ultimately help us to create better diagnostic and prognostic tools.” 

The features that Ludmil and his team identified are now available to other researchers through the Catalogue of Somatic Mutations in Cancer (COSMIC), the world’s largest, most comprehensive resource for exploring the interaction between mutational signatures and topographic features within and across cancer types.  

Mutographs has transformed the field of cancer genomic epidemiology, and has advanced understanding of the lifestyle and environmental causes of cancer. The team has changed our scientific understanding of the mechanisms of carcinogenesis by discovering multiple, widespread human mutagenic exposures of known and unknown causes, and it has also changed how cancer biologists think about the mechanisms of carcinogenesis as well as the somatic mutation landscape of normal tissues in health and disease.  

“This research,” says Elisabete, “has the potential to improve our ability to reduce cancer risk, develop more effective prevention and treatment strategies and inform government policies to address specific cancer risks.” 

This article, written by Scott Edwards, was originally included in our annual progress magazine, Discover: a year of scientific creativity. 

Image: The Mutographs team at IARC, 2023. Credit: ©IARC/N O’Connor