Sun M, Busque L, Sandoval J, Lemieux Perreault L-P, Barhdadi A, Cyr M-C, Tardif J-C, Dubé M-P
Montreal Heart Institute, Montreal, Canada; Université de Montréal Beaulieu-Saucier Pharmacogenomics Centre, Montreal, Canada; Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Canada.
Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Canada; Hôpital Maisonneuve-Rosemont, Montreal, Canada.
ESMO Open. 2025 Aug 7;10(8):105539. doi: 10.1016/j.esmoop.2025.105539.
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.
背景：不确定潜能的克隆性造血（CHIP）和嵌合染色体改变（mCAs）与心血管疾病（CVD）风险及死亡率增加有关。CHIP和mCAs可能也会促使癌症患者发生CVD。我们的目的是调查癌症患者中CHIP突变和mCAs的患病率、它们的共现情况以及不同癌症类型中相关的CVD结局。 患者和方法：我们利用英国生物银行对CHIP和mCA与CVD相关结局风险进行了病例对照分析。从全外显子测序中识别出体细胞CHIP突变，从诊断为癌症的患者的基因分型数据中识别出mCAs。采用逻辑回归和Cox比例风险模型评估CHIP突变、mCAs与CVD结局及总死亡率之间的关联。 结果：总体而言，2701名患者（5.5%）携带CHIP突变。年龄增加、当前吸烟和化疗暴露与CHIP突变和mCAs的较高几率相关。在695名患者中观察到CHIP和mCAs的共现（占CHIP突变患者的25.7%）。男性中Y染色体丢失（LOY）与CHIP突变呈负相关[比值比（OR）0.65，95%置信区间（CI）0.57 - 0.74，P < 0.001]，而女性中X染色体丢失（LOX）与CHIP突变呈正相关（OR 1.24，95% CI 1.03 - 1.49，P = 0.03）。CHIP突变与CVD发病风险增加相关[风险比（HR）1.07，95% CI 1.02 - 1.13，P = 0.004]以及总死亡率增加相关（HR 1.31，95% CI 1.22 - 1.40，P < 0.001）。值得注意的是，CHIP突变与mCAs（LOY/LOX）共现对所考虑的结局没有协同影响。 结论：CHIP突变和mCAs在癌症患者中普遍存在，并且与心血管风险和死亡率显著增加相关，不同癌症类型存在差异。这些发现强调了在癌症患者的临床管理中考虑克隆性造血以降低心血管风险的重要性。
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