Clonal hematopoiesis of indeterminate potential is a risk factor of gastric cancer: A Prospective Cohort in UK Biobank study.

Importance: Gastric cancer is often diagnosed at an advanced stage and at order age, identification of high-risk population is needed for detection of early-stage gastric cancer.

Objective: To examine whether clonal hematopoiesis of indeterminate potential (CHIP) is a risk factor of gastric cancer.

Design: This cohort study used data from the UK Biobank collected from baseline (2006-2010) to the end of follow-up in March 2024.

Setting: Data on age, sex, race, alcohol consumption, smoking status and type 2 diabetes were collected at baseline interview. Previous and diagnosed cancer or diseases were collected from self-reported and in-hospital records.

Participants: Participants with no previous cancer or hematologic disorders were selected. Participants with gastric cancer cases were aged 60.7 (S.D. 6.62), 71.8 % male; controls were aged 56.1 (S.D. 8.11), 47.4 % male.

Exposures: Whole-exome sequencing was performed on blood samples collected at baseline. A CHIP status was identified based on the mutations on 43 CHIP-related genes.

Main Outcomes And Measures: Odds ratio (OR) of CHIP with gastric cancer risk was estimated using multivariable logistic regression models. Participants were grouped based on age and CHIP status to examine if there are differences in the cumulative incidence of gastric cancer.

Results: Among 402,253 participants, 1,070 incident gastric cancer cases were identified (mean age, 60.7 ± 6.62 years). The prevalence of CHIP at baseline was associated with an increased risk of gastric cancer (cases: 6.54 % vs. controls 5.14 %; OR without adjustment, 1.29; 95 % CI, 1.004 to 1.63). The stratified OR (95 % CI) of individuals aged ≥ 57 was 1.33 (1.02 to 1.72) for overall CHIP, whereas the OR for younger individuals was 0.79 (0.37 to 1.44). CHIP involving DNMT3A (OR, 1.81; 95 % CI, 1.05 to 2.88; P = 0.0193) and ASXL1 (OR, 2.43; 95 % CI, 0.95 to 4.99; P = 0.032) was associated with an increased risk of gastric cancer. These positive associations remained significantly in sensitivity analyses adjusted by known risk factors. Compared to younger individuals and non-CHIP carriers, older participants with CHIP exhibited a significantly higher cumulative incidence of gastric cancer (P < 0.0001).

Conclusions And Relevance: CHIP is associated with gastric cancer in the elderly and contributes to the positive association between DNM3A and ASXL1 mutations and risk of gastric cancer.