Impact of clonal hematopoiesis on cardiovascular outcomes in cancer patients of the UK Biobank

Abstract

Background: Clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) have been linked to increased risks of cardiovascular disease (CVD) and mortality. CHIP and mCAs may also then contribute to CVD in cancer patients. Our objective was to investigate the prevalence of CHIP mutations and mCAs in cancer patients, their co-occurrence, and the associated CVD outcomes across different cancer types.

Patients and methods: We carried out a case-control analysis of CHIP and mCA on the risks of CVD-related outcomes using the UK Biobank. Somatic CHIP mutations were identified from whole-exome sequencing and mCAs from genotyping data among patients diagnosed with cancers. Logistic regression and Cox proportional hazards models were used to assess the associations between CHIP mutations, mCAs, and CVD outcomes, and overall mortality.

Results: Overall, 2701 patients (5.5%) harbored CHIP mutations. Increasing age, current smoking, and chemotherapy exposure were associated with higher odds of CHIP mutations and mCAs. Co-occurrence of CHIP and mCAs was observed in 695 patients (25.7% of those with CHIP mutations). Loss of the Y chromosome (LOY) was inversely correlated with CHIP mutations among men [odds ratio (OR) 0.65, 95% confidence interval (CI) 0.57-0.74, P < 0.001] whereas loss of the X chromosome (LOX) was positively correlated with CHIP mutations among women (OR 1.24, 95% CI 1.03-1.49, P = 0.03). CHIP mutations were associated with an increased risk of incident CVD [hazard ratio (HR) 1.07, 95% CI 1.02-1.13, P = 0.004] and overall mortality (HR 1.31, 95% CI 1.22-1.40, P < 0.001). Notably, there was no synergistic impact of CHIP mutations co-occurring with mCAs (LOY/LOX) on considered outcomes.

Conclusions: CHIP mutations and mCAs are prevalent in cancer patients and are associated with significant increases in cardiovascular risk and mortality, with variations across cancer types. These findings underscore the importance of considering clonal hematopoiesis in the clinical management of cancer patients to mitigate cardiovascular risks.

Keywords: CHIP; UK Biobank; cancer; cardiovascular mortality; clonal hematopoiesis; mosaic chromosomal alterations.

Figure 1

Prevalence of CHIP and mCA, and both by age in individuals diagnosed with cancer within the UK Biobank. Bar chart shows the full age distribution of all participants in this cohort at baseline (n = 49 519). CHIP, clonal hematopoiesis of indeterminate potential; mCA, mosaic chromosomal alterations.