Mutographs of Cancer - CRUK Grand Challenge Project
Mutographs of Cancer - CRUK Grand Challenge Project
This CRUK-funded Grand Challenge Project seeks to fill in the missing gaps to identify the unknown cancer-causing factors and reveal how they lead to cancer. To do this 5,000 pancreatic, kidney, oesophageal and bowel cancer patients, from five continents will be studied and compared.
About the Partnership
Human behaviours such as smoking and drinking alcohol, and enviromental factors such as UV light can cause cancer by damaging cells’ DNA. This damage occurs in distinctive patterns – known as ‘mutational signatures’ – that are unique to the factor that caused the damage. So far 50 cancer-associated mutational fingerprints have been identified, but only half of them have known cause.
To identify the unknown cancer-causing factors and reveal how they lead to cancer, the genomes of 5,000 pancreatic, kidney, oesophageal and bowel cancer patients from five continents will be studied and their mutational signatures compared. Information about the patients' about the habits, lifestyles and environments will be gathered to help elucidate causative agents. The researchers will also contine to search for other mutational signatures that haven't yet been found.
Over the past century, we have learnt much about the environmental, lifestyle, genetic and other factors that cause human cancer. This knowledge has provided the foundation for successful cancer prevention programmes including those aimed at:
reducing tobacco smoking
eradicating carcinogenic viruses
eliminating environmental and industrial exposures such as radiation and asbestos
reducing breast and ovarian cancer in women with high inherited risk.
However, many common cancers exhibit major differences in incidence between different geographical areas and trends over time for which we do not understand the reasons despite determined investigation. Therefore, important causes of cancer and opportunities for prevention remain to be identified.
All cancers are caused by changes in the DNA within cells in the body that occur over the course of an individual’s lifetime - somatic mutations. Different patterns of somatic mutation, known as “mutational signatures”, are generated by the different environmental, lifestyle and genetic factors that cause cancer.
For example, tobacco smoke and ultraviolet radiation in sunlight both cause cancer by producing somatic mutations; however, the particular mutational signature caused by tobacco smoke chemicals is found in lung cancers and the distinct mutational signature of ultraviolet light is found in skin cancers.
Recently, through analysis of the DNA sequences of many thousands of cancers of diverse types from across the world, approximately 40 different mutational signatures have been reported. However, the environmental, lifestyle, genetic or other potential causes of many of these mutational signatures are unknown.
The overall goal of this "Mutographs of Cancer" CRUK Grand Challenge Project is to advance understanding of the causes of cancer through studies of mutational signatures. This will be achieved by:
Investigating whether different mutational signatures in the DNA of cancers explain geographic differences in cancer incidence by collecting cancer samples and information about cancer-causing exposures from 5,000 patients with colorectal, oesophageal, pancreatic and kidney cancer living in regions of high or low cancer incidence in five continents, sequencing the DNA of these cancers and comparing the mutational signatures present.
Identifying specific causes of mutational signatures by sequencing the DNA of rodent cancers and cultured human cells experimentally exposed to 150 cancer-causing agents, thus assembling a compendium of mutational signatures associated with known causes of cancer.
Investigating whether mutational signatures in the DNA of normal cells can be used to understand and monitor cancer-causing exposures in healthy people by sequencing the DNA of normal lung, kidney, liver and blood from people who have been exposed to cancer-causing agents.
Understanding the causes of cancer, our work may lead to new approaches to prevent it and provide opportunities for more effective application of therapies.
Structure of the Research
Through studying the mutational signatures present in the genomes of cancer and normal cells we aim to comprehensively catalogue the mutational processes that cause human cancer, to understand their causes and to apply this knowledge to cancer prevention. To achieve this the research has been structure into work packages to deliver three Specific Aims:
To elucidate the causes of major global geographical and temporal differences in cancer incidence through mutational signatures.
To identify, characterise and understand the biological processes underlying mutational signatures.
To survey and monitor mutagenic exposures in normal cells in humans through mutational signatures.
Specific Aim 1: To elucidate the causes of major global geographical and temporal differences in cancer incidence through study of mutational signatures
Throughout life, the genome within cells of the human body is exposed to DNA damage and suffers mistakes in replication. These corrosive influences result in progressive, subtle divergence of the DNA sequence in each cell from that originally constituted in the fertilised egg. The Cancer Genome Project uses high-throughput genome sequencing to identify these somatically acquired mutations with the aim of characterising cancer genes, mutational processes and patterns of clonal evolution in human tumours.
Paul Brennan leads Work Package 1: Mutational signatures in five cancer types across five continents. This work supports Specific Aim 1: To elucidate the causes of major global geographical and temporal differences in cancer incidence through study of mutational signatures.
Ludmil Alexandrov leads Work Package 2: Development of computational approaches for mutational signature analysis. This work supports Specific Aim 1: To elucidate the causes of major global geographical and temporal differences in cancer incidence through study of mutational signatures.
Allan Balmain leads Work Package 3: Mutational signatures of cancer development in rodents exposed to known or suspected carcinogens. This work supports Specific Aim 2: To identify and characterise the biological processes underlying mutational signatures.
David Phillips leads Work Package 4: Establishing a compendium of mutational signatures through exposure of cells in culture to defined mutagens. This work supports Specific Aim 2: To identify and characterise the biological processes underlying mutational signatures.
Peter Campbell leads Work Package 5: Understanding mutation burdens and mutational signatures in non-cancer tissues. This work supports Specific Aim 3: To survey and monitor mutagenic exposures in normal cells in humans through mutational signature analysis.
Mike Stratton leads Work Package 6: Surveying mutagenic exposures and endogenous mutation rates in normal white blood cells. This work supports Specific Aim 3: To survey and monitor mutagenic exposures in normal cells in humans through mutational signature analysis.
A key data source will be rat and mouse tissue samples from the National Toxicology Program (NTP) Archives. The NTP Archives is a unique repository of rodent tumor tissues exposed to more than 590 chemical carcinogens. A thorough examination of these tissues will help scientists understand how various environmental exposures may play a role in cancer.
Contributor of sequenced data for colorectal, kidney, pancreatic, and oesophageal cancers, 700 sets in total, expanding the project’s coverage to East Asia. The NCC drives the nation’s research for personally optimized cancer treatments based on genomic information. With an edge in chemical carcinogenesis and cancer prevention, and the full spectrum of cancer research from prevention, diagnosis to treatment, the NCC brings insight to the project.
The Cancer, Ageing and Somatic Mutation Programme seeks to provide leadership in data aggregation and informatics innovation, developing high-throughput cellular models of cancer for genome-wide functional screens and drug testing, and exploring basic scientific questions about the role somatic mutation plays in clonal evolution, ageing and development.