Title: clonal hematopoiesis of indeterminate potential and the risk of breast cancer a UK Biobank cohort study.

Objective: This study aims to investigate the association between clonal hematopoiesis of indeterminate potential (CHIP) and the risk of breast cancer.

Methods: We analyzed data from the UK Biobank, initially comprised 502,170 participants who met our inclusion criteria. Baseline data on age, body mass index (BMI), alcohol consumption, smoking habits, diet quality scores, physical activity levels, and health status. Whole-exome sequencing (WES) data was used to detect CHIP. Logistic regression and Cox proportional hazards (CoxPH) models were employed to assess the association between CHIP and breast cancer risk, adjusting for potential confounders. Additionally, we compared cumulative incident breast cancer cases between CHIP and non-CHIP groups.

Results: Univariable analysis showed that CHIP had a higher risk of developing breast cancer (OR [95% CI] = 1.200 [1.09-1.31], P = 8.94e-05). This association persisted after adjusting for potential confounders related to lifestyle, inflammation, health status and genetic factors (OR [95% CI] = 1.19 [1.09-1.31], P = 1.77e-04). The correlation remained consistent even after excluding participants with extreme BMI or those diagnosed with breast cancer within two-or five-years of follow-up (all OR = 1.18, P value < 0.01). Additionally, individuals with CHIP exhibited a significantly higher incidence of breast cancer compared to non-CHIP individuals (Log-Rank P = 5.19e-05). The risk of breast cancer associated with CHIP was predominantly driven by mutations in the gene ATM (OR [95% CI] = 3.97 [2.89, 5.36], P = 2.02e-18), and DNMT3A (OR [95% CI] = 1.33 [1.03, 1.66], P = 0.014).

Conclusions: CHIP is associated with an increased risk of breast cancer, particularly influenced by the ATM and DNMT3A genes.