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.
The Cancer, Ageing and Somatic Mutation Programme will:
conduct computational meta-analyses on large, aggregated cancer genome data sets to identify the long tail of infrequently mutated cancer genes, to characterise mutational signatures and to inform on the evolution of cancer cell clones.
take a lead in developing the next generation of cancer cell lines and use cell lines to systematically explore in vitro sensitivity to large numbers of anticancer drugs and drug combinations in order to inform choice of cancer types for early drug trials.
continue to develop and maintain the COSMIC database of somatic mutations.
use CRISPR-Cas technology to carry out genome-wide screens of gene-gene, gene-drug and cancer-microenvironment interactions in cells and mice in order to explore fundamental biology and to identify drug targets and drug resistance/sensitisation mechanisms.
seek to identify the mutational processes underlying mutational signatures found in cancers, characterise the mutational processes operating in normal cells, use phylogenetic analyses of somatic mutations in humans to explore cellular lineages during embryonic development
explore mutation accumulation during ageing and characterise its consequences for development of neoplastic clonal expansions in non-cancerous cell populations throughout life.
The Cancer, Ageing and Somatic Mutation Programme encompasses three Projects that respectively cover the genomics of human cancers; functional analysis of the cancer genome using a range of in vitro and in vivo model systems; and the characterisation of somatic mutations in development and adult homeostasis in health and disease.
A key challenge in cancer genomics is of heterogeneity. We see extensive variability in genomes among tumours of different tissue types, among different patients within a tissue type and among subclones within a given patient’s cancer. The rejoinder to the challenge of heterogeneity is scale.
For discovery of new cancer genes and mutational processes, aggregation of tens of thousands of cancer genomes is needed – we are establishing a virtual marketplace for exchange of genomes and informatics and develop increased functionality through the COSMIC portal.
For understanding the biology of gene-gene, gene-drug and gene-microenvironment interactions, a considerably broader range of in vitro and in vivo model systems is required – we are generating 1,000 organoid cultures from human cancers, characterising their genomes, functional dependencies and drug response, and we are expanding our in vivo models to study the interface between cancer and the immune system and microenvironment.
For setting cancer in the context of ageing tissue, study of normal adult homeostasis is important – we are studying mutational processes, clonal dynamics and cellular competition in thousands of non-cancerous cells and samples from a range of tissue types, in health and disease.
We are developing the concept of using somatic mutations present at adulthood to reconstruct the phylogeny of an individual’s development. The depth of insight is limited only by the numbers of cells sequenced and cheaper sequencing will enable us to see far back to the early stages of life, and study inter-individual variation in development. We also seek similar scaling up of the in vitro experiments, sampling deeper into the landscape of cancer genes, gene-gene interactions and combination drug responses.
We work closely with the Human Genetics and Cellular Genetics programmes.
This CRUK-funded Grand Challenge Project (Mutographs.org) 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.
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.
The group studies how normal cell behaviour is altered by mutation in the early stages of cancer evolution. We focus on squamous tissues, the skin epidermis and the lining of the oesophagus, using transgenic models, novel sequencing approaches, live imaging and single cell analysis to uncover key steps in cancer development, with aim of developing rational interventions to decrease cancer risk.
The Haematological Cancer Genetics team, led by George Vassiliou, studies the genes and genetic pathways involved in the development of blood cancers, with a particular emphasis on Acute Myeloid Leukaemia and related malignancies. The ultimate goal of the team is to develop methods for early detection of those at risk of blood cancers and new treatments that can improve the survival and quality of life of blood cancer sufferers.
Thierry Voet's group focuses on developing methods that characterise the DNA and RNA in a single cell to enable the exploration of DNA-mutation, the genetic differences between cells in a person's body and the relation of this diversity to disease.
Steve Jackson's research focuses on understanding how cells detect and repair DNA damage via the activities of the 'DNA-damage response' (DDR). The importance of the DDR for maintaining good health is shown by the diseases that are associated with the alteration or loss of these activities; including neurodegenerative disease, immunodeficiency, premature ageing, infertility and cancer.
Until they moved to the University of Cambridge in 2017, the Signatures of mutagenesis in somatic cells group explored patterns of mutations or signatures that arise in human cells to understand how DNA damage and DNA repair processes contribute towards aging and cancer.
The organoids developed by the Sanger Institute lead the UK effort as part of the international Human Cancer Model Initiative (HCMI) and will soon be available for researchers, together with their associated genomic data