Background: Hematologic malignancies constitute a major cause of global morbidity and mortality. Clonal hematopoiesis of indeterminate potential (CHIP) is a key pre-malignant state, defined by the presence of somatic mutations (eg!in DNMT3A, TET2) at a variant allele frequency greater than or equal to 2%. While CHIP elevates the risk of subsequent cancer, the precise mechanistic links remain unclear. The rich resources of the UK Biobank-including exome sequencing, serial hematology and biochemistry measurements, Olink proteomics, and cancer registry linkages-provide a unique opportunity to causally dissect the role of CHIP-driven immune dysregulation in malignant transformation.
Research Questions: (1) Baseline biomarkers (biochemistry/hematology/proteomics) associating with incident malignancies overall/subtypes? (2) Can blood counts/biochemistry/proteomics/polygenic risk improve 3-5 year prediction? (3) How do CHIP burden/driver genes alter inflammatory proteins and hematopoietic parameters? (4) Are these biomarkers causal mediators via genetic approaches? (5) Do baseline multi-omics stratify survival in CHIP-positive malignancies?
Methods: CHIP defined by driver mutations from exome sequencing. Stepwise Mendelian randomization uses CHIP-associated SNPs as instruments. Time-to-event models apply multiple-testing control. Proteome-wide scans, polygenic risk scores, and cis-pQTL MR with colocalization prioritize causal targets. Predictive models (regularized/boosted) undergo cross-validation, calibration, decision-curve analysis, and subgroup evaluation. Dissemination follows UK Biobank policies.
Significance: First formal causal analysis of CHIP-immune-microenvironment-malignancy axis, informing early interception. UK Biobank’s prospective multi-omics data uniquely enables this, advancing biological understanding and clinical strategies. Open-access publications with reproducible code ensure transparency.
