Determining the relationship between inflammation, clonal hematopoiesis and cancer

Clonal haematopoiesis of indeterminate potential (CHIP) is defined as the presence of blood cancer-associated mutations without evidence of haematologic malignancy. While sensitive sequencing technologies can identify CHIP in all adults > 50y, we use the commonly accepted definition of clones contributing > 4% of blood cells or a variant allele frequency (VAF) of >2%. The prevalence of CHIP rapidly increases with age, affecting an estimated 1 million Australians 70y+. While CHIP carries an increased risk of haematologic malignancy (HR ~13), the absolute risk is small (0.5% per year) and cannot explain the 40% increased risk of death. Large observational studies have attributed the increased mortality to cardiovascular diseases driven by a pro-inflammatory state. However, these studies are based upon a single measurement of CHIP in cohorts with inherent selection biases, inconsistent data collection and confounding risk factors. Longitudinal studies of CHIP are needed to understand the value of detecting and monitoring CHIP in an aging population, its clinical consequences and identify effective intervention. Addressing these knowledge gaps is a matter of urgency because clinicians have already established multi-disciplinary ‘CHIP’ clinics and are contemplating changes to clinical care based upon a single finding of CHIP. Leveraging the landmark ASPirin in Reducing Events in the Elderly (ASPREE) study, we have established the largest, longitudinal cohort study of CHIP. ASPREE-CHIP is internationally unique, with serial bio-specimens linked to high quality longitudinal clinical data in the setting of a randomised trial of aspirin. Preliminary analyses have found increased all-cause mortality in individuals with large CHIP (VAF>10%) that can be explained by increased risk of solid cancers. Most remarkably, aspirin abrogated the increased risk of cancer in those with large CHIP. This project will use the Bio-Plex 200 system to measure 48 inflammatory cytokines in serum samples from 500 participants at baseline and year 3 of the study. Data from this assay will be used to identify inflammatory cytokines associated with CHIP, the impact of aspirin on growth of CHIP and the relationship between inflammation, CHIP and cancer development. This work will (1) generate new knowledge about the relationship between inflammation, CHIP and disease (2) identify serum biomarkers that predict development of CHIP and (3) identify inflammatory targets for suppressing the growth and disease outcomes of CHIP.