The <i>JAK2V617F</i> and <i>CALR</i> mutations and risk of cancer, cardiovascular diseases, and all‐cause mortality

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.