Abstract 7357: Mediators of inflammation modify the association between clonal hematopoiesis and incident hematologic malignancy in ARIC

Abstract Background: Clonal hematopoiesis (CH) is associated with a higher hematologic malignancy (HM) risk, and risk increases with variant allele frequency (VAF). We determined whether inflammatory factors modify the association between CH and HM. Methods: We conducted a prospective cohort analysis of 9, 978 participants (55.9% female, 29.5% Black) in the Atherosclerosis Risk in Communities (ARIC) study who were 44-80 years old and did not have a cancer history. Median follow up was 20.9 years. CH (VAF≥2%: 9.8%; VAF≥10% [large CH]: 4.7%) was identified from whole exome sequencing data constrained to 74 genes (Bick et al. Nature 2020). Incident HM (N=434) was ascertained mainly by cancer registry linkage. Aspirin was assessed at study visits by review of containers of prescribed and over the counter drugs used in the last 2 weeks. Plasma proteins were measured by SomaScan® 5K assay. We prespecified interleukin (IL)-6, interferon-gamma (IFN-gamma), IL-8, IL-1beta, and tumor necrosis factor (TNF)-alpha. We estimated the association between CH and HM stratified by aspirin use and plasma protein levels (median; 8, 693 participants) using Cox regression adjusting for age, sex, race, and risk factors for HM. Results: The association between large CH (vs no CH) and HM was weaker in aspirin users (HR=1.58, 95% CI 0.91-2.72, p-trend [across no, small, large CH]=0.26) than in non-users (HR=2.02, 95% CI 1.29-3.15, p-trend=0.008). The association between large CH and HM was stronger in participants with higher (HR=2.11, 95% CI 1.29-3.44, p-trend=0.10) than lower (HR=1.38, 95% CI 0.77-2.48, p-trend=0.56) plasma IL-6. Median VAF in those with large CH was comparable between higher (18%) and lower (16%) IL-6 strata, as was percentage of common genes mutated (DNMT3A: higher 48%, lower 48%; TET2: higher 21%, lower 23%). Patterns of association between CH and HM by strata of IFN-gamma (higher: p-trend=0.014; lower: p-trend=0.46) and IL-8 (higher: p-trend=0.01, lower: p-trend=0.46) were similar to IL-6. In contrast, for TNF-alpha strata, the association between large CH and HM was weaker in participants with higher (p-trend=0.20) than with lower (p-trend=0.06) levels, and the percentage with mutated DNMT3A appeared to differ by TNF-alpha level (higher 51%, lower 43%). Associations between large CH and HM were comparable in the higher (p-trend=0.05) and lower (p-trend=0.12) IL-1beta strata. Conclusions: Regular aspirin use may dampen CH-associated hematologic malignancy risk. Higher plasma levels of some pro-inflammatory cytokines, especially IL-6, may exacerbate CH-associated hematologic malignancy risk. While IL-6 is produced by immune cells with DMNT3A and/or TET2 mutations, the similar VAF and percentage of mutated gene by IL-6 level suggests that IL-6 is not simply marking CH extent. Laboratory experiments are needed to establish cause for these inflammation mediators. Support: NHLBI, NCI, NPCR Citation Format: Elizabeth A. Platz, Vernon A. Burk, Meng Ru, Sergiu Pasca, Lukasz P. Gondek, Katherine Y. King, Ajibike D. Lapite, Anna Prizment, Corinne E. Joshu, Pradeep Natarajan, Margaret A. Goodell, Christie M. Ballantyne, Koichi Takahashi. Mediators of inflammation modify the association between clonal hematopoiesis and incident hematologic malignancy in ARIC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7357.