Cancer genetics is based on the study of germline variation (inherited) and somatic variation (acquired by tumours as they grow). Our work is based on the discovery of genes that predispose to cancer (germline variation), accompanied by use of the genetic data to demonstrate new mechanisms of tumorigenesis, and to identify novel evolutionary principles underlying cancer growth.
Much of our work is historically derived from insights into tumorigenesis provided by rare inherited cancer syndromes. We are especially focussed on genetic variants that cause patients to develop bowel polyps and colorectal cancer (CRC), the latest such gene being the base excision repair enzyme MBD4. We continue to work on other genes in which we have found ermine mutations that predispose to cancer, including POLE and POLD1 mutations that inactivate the error-checking (proofreading) activity of the major DNA polymerases, causing a huge mutation burden in tumours, and GREM1 mutations that inactivate the bone morphogenetic protein (BMP) pathway, which normally maintains the balance between differentiated and stem cells in the gut. In these cases, the mechanisms of tumorigenesis remain incompletely understood and are being investigated in humans, cells and mouse models. All the seven high-risk cancer genes we have founded are now routinely tested in the clinical diagnostic laboratory.
We also study common polymorphisms that individually have modest effects on cancer risk, but that can have larger effects collectively. We have historically been at the vanguard of genome-wide association studies (GWAS) for colorectal, uterine and oesophageal cancers. These studies have moved from variant discovery to analyses of clinical utility, for example using risk scores to stratify bowel cancer screening using a so-called “precision prevention” strategy.
Another component of our work is the study of cancer evolution, especially the importance of selection and mutation in driving tumour growth. Much of our work focuses on a “just right” model of tumorigenesis, in which many of the functional derangements that cause tumorigenesis are not binary on:off changes, but instead lie within a window; hence, too small a change is insufficient for tumorigenesis and too much is excessive, for example by causing cell toxicity. Our original discovery of this model came from the colorectal cancer tumour suppressor gene APC, in which the two mutations needed to inactivate the gene are non-random with respect to each and cause an intermediate level of Wnt pathway activation. We have more recently extended it to other tumour suppressor genes and oncogenes. Two cancer driver genes with evidence of “just right” selective constraints are isocitrate dehydrogenases IDH1 and IDH2 in which the spectrum of mutations varies considerably among tumours of different sites, and cannot be explained by mutational processes. We are also interested in the broader concept of evolutionary pathways of tumorigenesis, including polyclonality in cancer precursor lesions and the “mini-driver” model of polygenic tumorigenesis, in which driver mutations do not all affect major driver genes or pathways, but instead have smaller effects, for example optimising existing defects or acting in concert with other mutations of modest effects.
Our work provides a route into cancer biology, and our focus is on genetic variation in the BMP pathway which is a striking determinant of colorectal cancer risk predisposition in the general population (in addition to its role in rare Mendelian syndromes shown above). We are performing functional analyses to explore the potential of BMP modulation in colorectal cancer prevention and is in progress. Thus, although the BMP pathway in the gut is incompletely understood, our data have indicated for the first time its central importance in CRC risk and its potential as a target for CRC prevention in high-risk groups, and the general population.
Emma Jaeger, Senior Postdoctoral Researcher
Stephen Thorn, Bioinformatician
Ignacio Soriano, Post-Doctoral Research Fellow in Cancer Genetics and Evolution
Juan Fernandez-Tajes, Bioinformatician / Biostatistician / Computer Scientist
Nagore de Leon Marcos, Senior Post-Doctoral Research Fellow in Cancer Genetics
Amjad Khan, Visiting Professor of Clinical Biochemistry and Experimental Medicine