Introduction: Although the proportion of T-cell lymphoma(TCL) patients originated from clonal hematopoiesis of indeterminate potential (CHIP) in hematopoietic stem cells, clinical and prognostic significance of CHIP in lymphoma is not systemically analyzed yet. This study aimed to evaluate the association of CHIP status with the incidence of lymphoma subtypes and all-cause mortality.
Methods: Using UK Biobank data, we assessed the link between CHIP status and the incidence of Classical Hodgkin Lymphoma (cHL), T-cell Lymphoma (TCL), B-cell Lymphoma (BCL), Diffuse Large B-cell Lymphoma (DLBCL), and all-cause mortality. Models adjusted for CHIP status, age, sex, and the first 10 genetic principal components. CHIP mutations were grouped by variant allele frequency (VAF) using a 10% threshold.
Results: CHIP mutation significantly elevates risk of lymphoma development with hazard ratio (HR) of 1.69 (p=0.006), 3.46 (p< 0.001), 1.40 (p< 0.001), 1.42 (p=0.001), in cHL, TCL, BCL, DLBCL, respectively. TET2high CHIP shows substantial increase of hazard for lymphoma incidence but not all-cause mortality. Especially, HR of incidence in TET2high CHIP was highest in TCL with HR of 13.17 (p< 0.001) (HR was 4.68 (p< 0.001), 2.40 (p< 0.001), and 3.38 (p< 0.001) for cHL, BCL, DLBCL, respectively). In addition, DNMT3AR882high also significantly increased TCL incidence risk (HR 9.48, p< 0.001). DNMT3AR882 was also associated with elevated HRs in both high-VAF (HR 4.42, p< 0.001) and low-VAF (HR 8.84, p=0.032) in TCL.
Conclusion
CHIP mutations, especially high-VAF TET2, significantly influence T-cell lymphoma (TCL) risk, suggesting clonal evolution. DNMT3AR882 further correlates with both increased incidence and mortality in TCL, potentially due to chemotherapy-induced HSC dysfunction.
