The JAK2V617F and CALR mutations and risk of cancer, cardiovascular diseases, and all‐cause mortality

Abstract Background Clonal hematopoiesis (CH) is associated with adverse outcomes. We hypothesized that CH ( JAK2V617F and CALR ) is associated with cancer, vascular disease, and all‐cause mortality, even at a variant allele frequency (VAF) <1%. Methods We screened 19,832 individuals from the Danish General Suburban Population Study for JAK2V617F and CALR mutations by digital‐droplet PCR. We used Cox regression with hazard ratio (HR) and 95% confidence interval (95%CI), stratified by CH ( JAK2V617F and CALR ), VAF (<1% vs. ≥1%), mutation type ( JAK2V617F or CALR ), and JAK2V617F VAF. Results The HR (95%CI) for any cancer was 1.71 (1.46–2.01) in CH, 1.28 (1.05–1.56) in VAF < 1%, 4.35 (3.34–5.66) in VAF ≥ 1%, and higher for JAK2V617F but not CALR . For hematological cancer, the HR (95%CI) was 8.41 (6.44–10.99) in CH, 3.53 (2.35–5.30) in VAF < 1%, and 40.01 (28.97–55.26) in VAF ≥ 1%, and also higher for JAK2V617F and CALR . For arterial diseases, the HR (95%CI) was 1.25 (1.03–1.52) in CH, 1.75 (1.18–2.59) in VAF ≥ 1%, and 1.28 (1.05–1.55) in JAK2V617F . The HR for venous disease was only higher in JAK2V617F VAF ≥ 1%. The HR (95%CI) for all‐cause mortality was 1.45 (1.19–1.75) in CH, 1.36 (1.10–1.69) in VAF < 1%, 1.91 (1.26–2.88) in VAF ≥ 1%, and also higher for JAK2V617F and CALR . The population‐attributable risk proportion (95%CI) for myeloproliferative neoplasms (MPNs) was 76.6% (66.8–86.4) in CH, 47.1% (29.6–64.6) in VAF < 1%, and 71.0% (59.4–82.6) in VAF ≥ 1%, with a nomogram generated. Conclusions CH—defined by the JAK2V617F and CALR mutations—was associated with cancer, MPN, all‐cause mortality—even with VAF < 1%—and vascular diseases at VAF ≥ 1%. These are novel findings, indicating that the JAK2V617F and CALR mutations confer an oncogenic potential with a VAF below the current CH of indeterminate potential definition.