Abstract 2205: Modifiable risk factors are associated with clonal hematopoiesis

Abstract Observational studies have implicated modifiable factors like smoking, alcohol intake, physical activity (PA), and sleep to cancer risk. Clonal hematopoiesis (CH), marked by clonal expansions of mutated hematopoietic progenitors with mosaic chromosomal alterations (mCAs) or clonal hematopoiesis of indeterminate potential (CHIP), has been associated with the risk of serval cancers and may shed light the interplay between these factors and early preneoplastic hematopoietic expansion. Leveraging genotyping array and whole-exome sequencing data of leukocyte-derived DNA from 485, 028 participants without hematologic malignancies in the UK Biobank (UKBB), we performed genome-wide characterization of two common forms of CH—mCAs and CHIP. To assess associations between social deprivation, self-reported modifiable risk factors, and CH risk, we employed multivariable logistic regression models adjusted for potential confounders including age, sex, smoking history, and genetic ancestry. We identified 11, 826 (2. 4%) individuals with autosomal mosaic chromosomal alterations (auto mCAs), 15, 499 (3. 2%) with loss of the X chromosome (mLOX), 43, 044 (8. 8%) with loss of the Y chromosome (mLOY) and 22, 508 (4. 6%) with CHIP. Individuals with any CH subtype were on average older than CH-free individuals (p 9. 11 × 10−52). Multivariable models identified a significant negative association between mLOY and social deprivation in England (1 SD change in score: OR = 0. 968 0. 956-0. 980, p = 4. 88 × 10−7), suggesting modifiable risk factors could influence risk of mLOY. We observed a positive association with ever smoking and CH, which decreased with increased years since smoking cessation. Current smokers were at higher risk for auto mCAs (Odds ratio (OR) = 1. 23, 95% Confidence Interval (CI): 1. 16-1. 31, P-value (p) = 2. 63 × 10−11), mLOY (OR = 2. 25, 95%CI: 2. 17-2. 33, p 9. 11 × 10−52), and CHIP (OR = 1. 40, , 95%CI: 1. 34-1. 47 p 9. 11 × 10−52) ; and former smokers also exhibited significant associations for mLOY (OR = 1. 16, 95%CI: 1. 13-1. 19, p = 2. 97 × 10−32) and CHIP (OR = 1. 11, 95%CI: 1. 08-1. 15, p = 2. 75 × 10−13). Alcohol consumption was associated with a significant increase in the risk of mLOX in heavy drinkers (2-3 drinks/day) compared to non-drinkers (OR = 1. 16, 95%CI: 1. 09-1. 24, p = 1. 21 × 10−5). Moderate and high PA levels (categorized as level 2 and 3 based on total activity), were positively associated with increased mLOY frequency (moderate: OR = 1. 05, 95%CI: 1. 02-1. 08, p = 8. 6 × 10−2, high: OR = 1. 06, 95%CI: 1. 03-1. 08, p = 1. 6 × 10−3). We observed no evidence for an association between sleep patterns and CH. Our investigation in a large cohort identified associations between CH and social deprivation, smoking, alcohol consumption and PA. As CH is an intermediate marker for hematologic cancer risk, our findings imply that modifiable exposures may contribute to hematologic cancer risk through clonal mechanisms. Citation Format: Corey D. Young, Aubrey K. Hubbard, Pedro Saint-Maurice, Irenaeus Chan, Kelly L. Bolton, Stephen J. Chanock, Charles Matthews, Steven C. Moore, Erikka Loftfield, Yin Cao, Mitchell J. Machiela, Duc Tran. Modifiable risk factors are associated with clonal hematopoiesis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 2205.