The driver mutation JAK2 V617F and Calreticulin (CALR) mutations constitute major diagnostic criteria of myeloproliferative neoplasms (MPNs), and, while JAK2 V617F has been detected in healthy volunteers, few studies have assessed the frequency of CALR in general populations. In a cross-sectional study published in Blood, Sabrina Cordua, MD, from Zealand University Hospital in Denmark, and colleagues reviewed data from nearly 20,000 people in a general Danish population to determine the prevalence of these mutations and characterize their biochemical profiles and lifestyles in relation to their mutational status.
The authors found that CALR mutations are prevalent but less frequent compared with the estimated prevalence of JAK2 V617F mutations. The presence of these mutations also was linked to a distinct blood count profile, even in the absence of an MPN diagnosis.
“Our findings suggest that a higher percentage of the CALR positives in the general population evolves into MPNs, compared with JAK2 V617F positives,” study author Christina Ellervik, MD, from Boston Children’s Hospital, explained to ASH Clinical News. “This is supported by our MPN data, where approximately three times as many of the CALR positives have an MPN diagnosis compared with the frequency within JAK2 V617F positives.”
Dr. Ellervik and co-authors analyzed data from the Danish General Suburban Population Study (GESUS), which included a cohort of 19,958 Danish residents who had biobank-stored DNA available for research. Participants underwent health examinations, biochemical measurements, and responded to a questionnaire regarding health and lifestyle. Mutations were detected via a pooled multiplex droplet digital polymerase chain reaction assay.
Approximately 3.5% (n=645) of GESUS participants who underwent screening for JAK2 V617F and CALR were mutation-positive; 2.5% (n=16) of these participants had MPN at baseline assessment.
JAK2 V617F was found in 613 participants, corresponding to a population prevalence of 3.1%, while CALR was found in 32 participants, corresponding to a population prevalence of 0.16%. The type 1 mutation comprised 75% of CALR cases. Overall, the ratio of JAK2 V617F to CALR was 19 to 1.
Most mutation-positive participants had allele burdens <1%, and the researchers also observed an association between higher age and allele burden (beta coefficient = 1.01; 95% CI 1.00-1.03; p=0.02). There also was an association between higher age and the presence of mutation (odds ratio [OR] = 1.02; 95% CI 1.02-1.03; p<0.001).
“[These findings] are supportive of screening for JAK2 V617F more regularly in target populations at risk of MPN.”
—Christina Ellervik, MD
When compared with the nonmutated background population, mutation-positive status was associated with higher hematocrit, neutrophil, platelet, and leukocyte counts and lower cholesterol. This finding suggests that “presence of a driver mutation is associated with a distinct paraclinical profile that mimics the MPN phenotype, also present in individuals with allele burdens <1% and no MPN diagnosis registered,” they wrote.
In a subpopulation of participants without smoking-related diseases (acute myocardial infarction, ischemic heart disease, cancer, diabetes, etc.), mutations were associated with the following factors:
- smoking (23% in mutation-positive individuals vs. 19% in nonmutation individuals; p=0.04)
- alcohol use (8.8 units/week vs. 6.7 units/week; p=0.02)
Individuals positive for the JAK2 V617F mutation – both with and without MPNs – had increased odds for prevalent venous thromboembolism, compared with nonmutated individuals (OR with MPNs = 2.8; 95% CI 1.1-7.0; p=0.03 and OR without MPNs = 6.0; 95% CI 1.3-28; p=0.02).
“As 40% of mutation-positive [individuals without MPNs] have elevated blood cell counts, we have concerns that many of these have an undiagnosed MPN,” the authors wrote. “We therefore suggest that individuals with a driver mutation, even at a very low mutant allele burden, be considered [at higher risk for] MPNs.”
Dr. Ellervik said that the authors were surprised by several of their observations. “First, the JAK2 V617F prevalence was much higher in our population compared with others, likely due to higher sensitivity of the assay,” she noted. “Second, 80 (13%) of the mutation-positive participants with no previous diagnosis of MPN presented blood cell counts in accordance with the current World Health Organization diagnostic criteria of essential thrombocythemia, polycythemia vera, or primary myelofibrosis.”
Together, these findings “are supportive of screening for JAK2 V617F more regularly in target populations at risk of MPN.”
Smoking cessation and minimizing alcohol consumption should also be considered in mutation-positive individuals, the researchers added, “as change of these lifestyle factors might diminish further progression toward MPN by reduction of the driving inflammatory stimulus.”
The cross-sectional design of the analysis may have limited its ability to draw causality conclusions. “In regard to CALR,” the researchers added, “the fact that we have tested only for type 1 and 2 mutations implies that the true total CALR prevalence may be slighter higher assuming that type 1-like, type 2-like, and type 3 CALR are present in the background population, as well.”
The authors report relationships with Novartis, Qiagen, Roche, and Incyte.
Cordua S, Kjaer L, Skov V, et al. Prevalence and phenotypes of JAK2 V617F and Calreticulin mutations in a Danish general population. Blood. 2019 June 19. [Epub ahead of print]