Prevalence and phenotypes of JAK2 V617F and calreticulin mutations in a Danish general population

Abstract

The JAK2 V617F and calreticulin mutations (CALR) are frequent within myeloproliferative neoplasms (MPNs). JAK2 V617F has been detected in the general population, but no studies have previously investigated the CALR prevalence. Thus, we aimed to determine the CALR and JAK2 V617F population prevalence and assess the biochemical profile and lifestyle factors in mutation-positive individuals with and without MPN. 19 958 eligible participants, enrolled from 2010-2013, from the Danish General Suburban Population Study were screened for JAK2 V617F and CALR by droplet digital polymerase chain reaction with (3.2%) mutation positives of which 16 (2.5%) had MPN at baseline. Of 645 participants, 613 were JAK2 V617F positive, and 32 were CALR positive, corresponding to a population prevalence of 3.1% (confidence interval [CI], 2.8-3.3) and 0.16% (CI, 0.11-0.23), respectively. Increasing age, smoking, and alcohol were risk factors for the mutations. JAK2 V617F positives with and without MPN presented elevated odds for prevalent venous thromboembolism. The odds ratio for a diagnosis of MPN per percentage allele burden was 1.14 (95% CI, 1.09-1.18; P = 1.6 × 10−10). Mutation positives displayed higher blood cell counts than nonmutated participants, and 42% of mutation positives without MPN presented elevation of ≥1 blood cell counts; 80 (13%) even presented blood cell counts in accordance with current MPN diagnostic criteria. In conclusion, we present a novel population prevalence of CALR and a JAK2 V617F prevalence that is 3 to 30 times higher compared with less sensitive methods. Mutation-positive non-MPNs with elevated blood cell counts raise concerns of MPN underdiagnosis in the population.

Reconstructing the lineage histories and differentiation trajectories of individual cancer cells inJAK2-mutant myeloproliferative neoplasms

“…using JAK2-V617F mutant-specific inhibitors. This rationale is further supported by the fact that JAK2-V617F clonal hematopoiesis is associated with an increased risk of cardiovascular disease 36 and venous thrombosis 45,46 and by the decades long time interval between JAK2-V617F acquisition and MPN development uncovered by our work.…”

Superiority of Droplet Digital PCR Over Real-Time Quantitative PCR for JAK2 V617F Allele Mutational Burden Assessment in Myeloproliferative Neoplasms: A Retrospective Study

“…Although the JAK2 V617F mutation is considered to be the major cause of MPN, it has been recently shown that JAK2 V617F positive neoplasms often develop in a background characterized by clonal hematopoiesis and other genetic alterations. Recently, different exome-analyses studies have identified the occurrence of age-related clonal hematopoiesis in healthy populations, to which the JAK2 V617F prevalence in the Danish population, close to 3%, could be ascribed [18]. By using highly sensitive methods, like ddPCR, we did not find a JAK2 V617F mutation in the control population, probably due to the low number of control samples used in our study.…”

Smoking, blood cells and myeloproliferative neoplasms: meta‐analysis and Mendelian randomization of 2·3 million people

“…The Danish General Suburban Population Study ( GESUS ) is a cross‐sectional general population study of 21 205 adults (participation rate 43%) from 2010 to 2013 (Bergholdt et al , ; Cordua et al , ). We included 11 083 healthy participants {mean age was 52 years [SD (s tandard deviation ): 12], 53·5% were women} with no cardiovascular disease or cancer.…”