Identifying patients with germline mismatch repair gene variants, and understanding how aspirin prevents colorectal cancer in this high-risk population

At Newcastle University, Dr Richard Gallon is a Research Associate developing a novel microsatellite instability (MSI) assay, in continuation of work started during his PhD. The MSI assay is designed for high throughput testing of colorectal cancers (CRCs) to screen for Lynch Syndrome (LS), following the diagnostic guidelines (DG27) published in February 2017 by NICE.  LS is a cancer predisposition syndrome, with particularly high risk of endometrial cancer and CRC, caused by germline pathogenic variants affecting one allele of a mismatch repair (MMR) gene.  LS patients benefit from daily aspirin intake to reduce their CRC risk, as shown by CAPP2 randomised control trial. Richard is now working to commercialise the assay and deploy it into clinical practice.  

Aspirin: Understanding its anti-cancer properties and enhancing its utility

This PhD project based at Newcastle University will explore the molecular impact of aspirin upon cancer development, and aims to identify patient groups who will benefit most from its use.  This studentship will use tumours arising within an ongoing aspirin dose-finding clinical trial involving Lynch Syndrome patients to investigate the molecular basis of aspirin action. It will also use high thorughput sequence assays to attempt to identify further patient subgroups with increased cancer risk, or with increased risk of adverse effects of long term aspirin use. 

Does regulation of inflammatory cytokines play a role in the cancer-preventative actions of aspirin?

This PhD project at Queen Mary University of London will measure inflammatory cytokine levels in plasma and other body fluids pre-and post-aspirin dosing in trials involving both cancer patients and normal control individuals. A meta-analysis will also be conducted of the literature on plasma/serum cytokines and cancer susceptibility in population cohorts. Some inflammatory cytokines, especially IL-6, have predictive value in population-based cancer studies with cohort studies associating elevated blood levels of IL-6 with increased cancer risk. To further understand actions of aspirin in cancer-associated inflammation, we will also conduct experiments with novel 3D multi-cellular models of the tumour microenvironment looking at the effects of aspirin on inflammatory cytokine production and on the role of platelets in promoting malignant cell invasion. 

Platelet activation and inhibition in cancer

Platelets are activated in response to different agonists, thereby releasing several lipid mediators and including Thromboxane (TX) A2, the main product of arachidonic acid metabolism via cyclooxygenase (COX)-1. TXA2 biosynthesis and TXA2 dependent platelet activation can be suppressed by low-dose aspirin that irreversibly inactivates COX-1. This PhD project project based at the Universita Cattolica del Sacro Cuore in Rome will investigate platelet and inhibition in a subgroup of patients enrolled on the Add-Aspirin Trial.  Through measurements of urinary 11-dehydro-thromboxane B2 (a major enzymatic metabolite of TXA2/TXB2) as validated index of in vivo platelet activation.  The project will investigate the extent of TXA2-dependent platelet activation among patients with different locations of an early stage common solid tumour. It will also explore whether the degree of platelet activation is similar in patients allocated to 100mg or 300mg of aspirin and to correlate the level of baseline platelet activation with clinical outcomes.  

Epigenomic approach to predict beneficial and adverse effects of aspirin

The aim of this PhD project based at Queen Mary University of London is to investigate the mechanisms of action whereby aspirin prevents cancer and identify potential biomarkers for both positive anti-cancer effects and adverse effects. In order to achieve this we are analysing over 250 samples from patients that have been taking various doses of aspirin. These samples will be analysed by Reduced Representation Bisulfite Sequencing (RRBS). Using this technique we hope to identify differential methylation markers in participants DNA. These markers will then allow us to identify those who will get the most benefit from taking aspirin while avoiding people who are more likely to suffer adverse effects.  Deeper analysis into sets of genes that have their methylation levels altered by aspirin treatment will help us elucidate the mechanisms by which aspirin causes both its positive and negative effects. For future research we plan to investigate how aspirin treatment may also effect the methylation status of RNA.