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Modelling the effects on tumour phenotype and mutational landscape of common genetic variance linked with colorectal cancer susceptibility


About This PhD Project

Project Description

This PhD studentship funded by CRUK and is available to start in November 2019 at the MRC Human Genetics Unit, which is part of the Institute of Genetics and Molecular Medicine (IGMM) at the University of Edinburgh. Applicants should hold at least an upper second-class degree in a relevant subject and comply with the University of Edinburgh’s English language requirements.

Project details

Cancer of the large intestine, or colorectal cancer (CRC), is one of the most common fatal malignancies in developed and developing countries. There are environmental and genetic contributions to disease aetiology, with common genetic variance explaining at least 20% of CRC risk. This means that modifying risk factor exposures, as well as modulating the disordered molecular pathways underlying genetic susceptibility could lead to novel approaches to cancer treatment and prevention. As an example, PD-1 inhibitors are now used in patients developing tumours exhibiting DNA mismatch repair gene deficiency resulting from germline inheritance of loss-of-function mutations in MLH1, MSH2 and MSH6. As an extension of this paradigm, this project will examine the role in cancer evolution and progression/metastasis of common genetic variation that is associated with CRC risk and which causes differential gene expression. Since 2007, we have identified over 701-6 common genetic variants associated with colorectal cancer risk at genomewide levels of statistical significance. Whilst the effect size (risk) associated with each of these variants is modest (typically around a 10% per-allele increase in risk), they are common in the general population and so make a substantial contribution to overall CRC incidence.

Many common genetic CRC risk variants exhibit genomic control effects on the expression of nearby, or even distant, genes. Thus, these variant sequences exert expression quantitative trait (eQTL) effects in cis or in trans respectively. Through extensive RNAseq and genotyping studies in human subjects, we have identified a large number of genomic control elements where the allele linked with CRC risk causes lower expression in the normal epithelium. These are akin to the loss-of-function mutations detectable in the mendelian dominant syndromes associated with APC (FAP), DNA mismatch repair (Lynch syndrome), MutYH (MAP), LKB1 (Peutz-Jeghers syndrome) and SMAD4 (juvenile polyposis). However, they are far more common and thus potentially have much greater impact on disease burden than the rare autosomal high-penetrance disorders.

Mouse models of CRC have been developed7 which facilitate the study of novel genes or agents in ameliorating, or abrogating, the tumorigenic effects of known somatic colorectal cancer gene aberrations, such as APC, p53 and Kras8,9. Indeed, one of us (R-F J) has developed a model of metastatic CRC that enables the development of novel approaches to preventing the tumour progression and spread outwith the primary organ8.

This exciting and innovative project will bring together mouse modelling of the somatic events leading to human CRC alongside novel understanding of the mechanisms of germline susceptibility to the disease. In the first instance, this project will focus on study of SHROOM2, an X-linked CRC susceptibility gene that we first identified in 20135 and which is subject to cis-eQTL effects from genetic variation in the promoter region of the gene. In unpublished work (MS in preparation), we have shown by transgenic approach and by CRISPR that depletion of SHROOM2 results in a a dramatic effect on tumour phenotype in male mice. Hence, in the first instance SHROOM2 will be targeted in tumour organoids from two of the mouse models of somatic mutation that have been developed by us (KPC and KPN initially), either by orthotopic implantation or in the germline. This will determine whether SHROOM2 induces a metastatic phenotype to non-metastatic tumour models and whether it causes an even more malignant phenotype in the KPN metastatic model. The ultimate aim is to rescue the effects of germline susceptibility by augmenting the respective pathways. Thus, genetic tools (including CRISPR) will be used to re-introduce human SHROOM2 into mouse tumour organoids and thereby replenish the downstream pathways that we have shown link directly and indirectly to wnt signalling. Small molecule approaches will also be used to recapitulate the downstream functions of SHROOM2. The project will also involve working with human samples and datasets to examine the relationship of genetic findings in mouse models to incidence, stage and progression as well as ultimately survival from this common cause of cancer death. The ultimate potential for this project is to develop new strategies aimed at cancer prevention and treatment.

References

1. Law PJ, Timofeeva M, et al and Dunlop MG. Association analyses identify 31 new risk loci for colorectal cancer susceptibility. Nat Commun. 2019 May 14;10(1):2154. doi: 10.1038/s41467-019-09775-w. PubMed PMID: 31089142; PubMed Central PMCID:PMC6517433.
2. Timofeeva MN, et al, Dunlop MG and Houlston RS. Recurrent Coding Sequence Variation Explains Only A Small Fraction of the Genetic Architecture of Colorectal Cancer. Sci Rep. 2015 Nov 10;5:16286. doi: 10.1038/srep16286. PubMed PMID: 26553438.
3. Al-Tassan NA, et al Dunlop MG, Tomlinson IP, Cheadle JP, Houlston RS. A new GWAS and meta-analysis with 1000Genomes imputation identifies novel risk variants for colorectal cancer. Sci Rep. 2015 May 20;5:10442. doi: 10.1038/srep10442.
4. Whiffin N, et al, and Dunlop MG. Identification of susceptibility loci for colorectal cancer in a genome-wide meta-analysis. Hum Mol Genet. 2014 Sep 1;23(17):4729-37. doi: 10.1093/hmg/ddu177.
5. Dunlop MG, et al . Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk. Nat Genet. 2012 May 27;44(7):770-6. doi: 10.1038/ng.2293. PubMed PMID: 22634755.
6. Dunlop MG, et al. Cumulative impact of common genetic variants and other risk factors on colorectal cancer risk in 42,103 individuals. Gut. 2013 Jun;62(6):871-81. doi:10.1136/gutjnl-2011-300537.
7. Jackstadt R and Sansom OJ. Mouse models of intestinal cancer. J Pathol. 2016 Jan;238(2):141-51. doi: 10.1002/path.4645. PMID:26414675.
8. Jackstadt R, et al and Sansom OJ. Epithelial NOTCH signalling rewires the tumor microenvironment of colorectal cancer to drive 2 poor-prognosis subtypes and metastasis. Cancer Cell 2019; In press.
9. Gay DM, Ridgway RA, Müller M, Hodder MC, Hedley A, Clark W, Leach JD, Jackstadt R, Nixon C, Huels DJ, Campbell AD, Bird TG, Sansom OJ. Loss of BCL9/9l suppresses Wnt driven tumourigenesis in models that recapitulate human cancer. Nat Commun. 2019; 13;10(1):723. doi: 10.1038/s41467-019-08586-3.

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