The <i>JAK2V617F</i> and <i>CALR</i> mutations and risk of cancer, cardiovascular diseases, and all‐cause mortality
Morten Kranker Larsen, Vibe Skov, Lasse Kjær, Christina Schjellerup Eickhardt‐Dalbøge, Trine Alma Knudsen, Marie Hvelplund Kristiansen, Anders Lindholm Sørensen, Sabrina Cordua, Troels Wienecke, M. Hauer Jensen, Morten Andersen, Johnny T. Ottesen, Johanne Gudmand‐Hoeyer, Jordan Andrew Snyder, Henrik E. Poulsen, Thomas Stiehl, Christina Ellervik, Hans Carl Hasselbalch
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.