Contact information
Annabelle Lewis
Dr, Group Head/PI
Many common genetic variants in the human genome have been associated with a small increase in the risk of cancer. However the majority of these variants lie in non-coding regions of DNA and their functions are currently unknown. It is likely that they affect gene regulatory elements such as promoters, enhancers and insulators, or epigenetic programmes, rather than altering the protein itself.
My group’s main interest lies in cancer gene regulation, with a particular focus on exploring the role of common genetic variants in cancer predisposition and progression. We are interested in identifying regulatory elements, particularly those that may be involved in colorectal cancer risk. We will investigate how they control the gene in normal and cancerous cells, the effect of SNP variants on their normal function and the role they play in cancer predisposition and progression.
A major focus of the lab is a cancer predisposition variant lying in the promoter of the mismatch repair pathway gene, MLH1. MLH1 is disrupted in about 15% of colorectal cancers, termed MSI+ cancers. These tumours generally show a good prognosis at early stages but have a differential response to chemotherapy. The common variant, rs1800734, near MLH1 is strongly linked to increased DNA methylation and MLH1 gene repression, but the mechanisms involved are poorly understood. Our aims are to investigate and correlate allele specific MLH1 expression, DNA methylation and protein binding in the region in patient samples. We will use cell lines and develop model systems to define the primary cause of repression (eg DNA methylation, transcription factor binding) and the critical effect that rs1800734 has in the pathway of cancer development.The knowledge from these studies will help us to understand the effects of MLH1 disruption on tumours and provide information to help with clinical diagnosis, prognosis and therapy.
We are also interested in SNP variants associated with colorectal cancer risk in the POLD3 locus. POLD3 is a component of the Pol δ polymerase which functions in both replication and repair. However, its role in colorectal cancer is largely unexplored. We are using in vitro and in vivo model systems to investigate the role of POLD3 in cancer pathways. In addition we are working to identify the causative SNP and regulatory element(s) and the mechanisms by which they influence cancer initiation or progression.