Lewis Group

Cancer Gene Regulation

Research Overview

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.

 
prelim meth_edited-1
Bisulphite pyrosequencing of the MLH1 promoter from fresh-frozen normal colorectal epithelium. Samples carrying a risk allele show significantly higher methylation.

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.

Funding sources

MRC New Investigator Research Grant, CRUK Oxford Development Fund

Research area

Cancer gene regulation and epigenetics

Keywords

Keywords: Gene expression, cancer genetics, colorectal cancer, transcription, single nucleotide polymorphism, DNA methylation, epigenetics, functional genomics.

Selected Publications

Cheng, T. H. et al. Five endometrial cancer risk loci identified through genome-wide association analysis. Nat Genet 48, 667-674, doi:10.1038/ng.3562 (2016).

Davis, H. et al. Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche. Nat Med 21, 62-70, doi:10.1038/nm.3750 (2015).

Lewis, A. et al. A polymorphic enhancer near GREM1 influences bowel cancer risk through differential CDX2 and TCF7L2 binding. Cell Rep 8, 983-990, doi:10.1016/j.celrep.2014.07.020 (2014).

Lewis, A. & Tomlinson, I. Cancer. The utility of mouse models in post-GWAS research. Science 338, 1301-1302, doi:10.1126/science.1231733 (2012).

Lewis, A. et al. The C-terminus of Apc does not influence intestinal adenoma development or progression. J Pathol 226, 73-83, doi:10.1002/path.2972 (2012).

Jaeger, E. et al. Hereditary mixed polyposis syndrome is caused by a 40-kb upstream duplication that leads to increased and ectopic expression of the BMP antagonist GREM1. Nat Genet 44, 699-703, doi:10.1038/ng.2263 (2012).

Tomlinson, I. P. et al. Multiple common susceptibility variants near BMP pathway loci GREM1, BMP4, and BMP2 explain part of the missing heritability of colorectal cancer. PLoS Genet 7, e1002105, doi:10.1371/journal.pgen.1002105 (2011).

Lewis, A. et al. Severe polyposis in Apc(1322T) mice is associated with submaximal Wnt signalling and increased expression of the stem cell marker Lgr5. Gut 59, 1680-1686, doi:10.1136/gut.2009.193680 (2010).

Reik, W. & Lewis, A. Co-evolution of X-chromosome inactivation and imprinting in mammals. Nat Rev Genet 6, 403-410, doi:10.1038/nrg1602 (2005).

Lewis, A. et al. Imprinting on distal chromosome 7 in the placenta involves repressive histone methylation independent of DNA methylation. Nat Genet 36, 1291-1295, doi:10.1038/ng1468 (2004).