Cancer Gene Regulation
Many common genetic variants that are associated with increased risk of cancer have been found in recent years. However these variants, known as single nucleotide polymorphisms (SNPS), most commonly lie outside of coding regions and often some distance away from any gene.
The mechanisms by which these SNPs exert their effect on cancer initiation or progression are currently poorly understood, although it is likely that they modify the expression levels or pattern of specific genes. Translating this growing resource of genetic data into information that is clinically useful is both important and challenging.
Our lab focusses on finding out how non-coding SNPS associated with colorectal cancer (CRC) affect gene expression and cancer pathways. A major project within the lab involves a SNP 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 poor response to some common chemotherapy treatments. The SNP variant, rs1800734, near MLH1 is strongly associated with increased risk of MSI+ colorectal cancer and also linked with increased DNA methylation and MLH1 gene repression.
Our aims are to investigate and correlate allele specific MLH1 expression, DNA methylation and protein binding in the region. To do this we are developing isogenic colon cancer cell lines, and we will compare these with normal and cancer patient samples. In addition we plan to manipulate MLH1 expression and methylation independently in our cell line systems to investigate their reciprocal interactions and any allele specific effects of the SNP on this interplay. Finally we develop transgenic mouse models modifying the SNP and investigate its effect on mice with a CRC predisposition.
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 parallel we are working to identify the causative SNP and regulatory element(s) and the mechanisms by which they influence cancer initiation or progression.
MRC New Investigator Research Grant, CRUK Oxford Development Fund
Cancer gene regulation and epigenetics
Keywords: Gene expression, cancer genetics, colorectal cancer, transcription, single nucleotide polymorphism, DNA methylation, epigenetics, functional genomics.
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