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UNEXPECTED PREVALENCES OF THE JAK2V617F AND CALR MUTATIONS IN THE GENERAL POPULATION
Author(s): ,
Sabrina Cordua
Affiliations:
Department of Hematology,Zealand University Hospital,Roskilde,Denmark
,
Lasse Kjaer
Affiliations:
Department of Hematology,Zealand University Hospital,Roskilde,Denmark
,
Vibe Skov
Affiliations:
Department of Hematology,Zealand University Hospital,Roskilde,Denmark
,
Christina Ellervik
Affiliations:
Faculty of Health and Medical Sciences,University of Copenhagen,Copenhagen,Denmark;Department of Research, Production, Innovation,Zealand Region,Soroe,Denmark
,
Niels Pallisgaard
Affiliations:
Department of Pathology,Zealand University Hospital,Roskilde/Naestvaed,Denmark
Hans Carl Hasselbalch
Affiliations:
Department of Hematology,Zealand University Hospital,Roskilde,Denmark
(Abstract release date: 05/17/18) EHA Library. Cordua S. 06/16/18; 214616; S885
Sabrina Cordua
Sabrina Cordua
Contributions
Abstract

Abstract: S885

Type: Oral Presentation

Presentation during EHA23: On Saturday, June 16, 2018 from 17:00 - 17:15

Location: Room A8

Background
The JAK2V617F mutation (JAK2) and calreticulin mutations type 1 and 2 (CALR) are predominantly found within the chronic Philadelphia-negative myeloproliferative neoplasms (MPN). Few studies have assessed the JAK2 prevalence in the general population with very limited reports on the association with MPN over time. To our knowledge, no corresponding studies of CALR exist.

Aims
1) to determine the prevalence of JAK2 and CALR mutations in a Danish population study 2) to assess the kinetics of the allele burden and blood cell counts over time by inclusion of mutated citizens in a follow up program.

Methods
Inclusion of participants in the general population study in Region Zealand took place during 2010-2013 (N=20,000). When included, a broad range of blood samples were collected as well as DNA to be stored in a biobank, and all participants were asked for a written consent to allow the data and DNA to be used in future research. This DNA was in our study analyzed for JAK2 and CALR by digital droplet PCR. The assays used have high accuracy and sensitivity with a detection level of allele burden at 0.01%. Part of our ongoing follow up program during 2017-2018 on citizens with mutation includes blood samples and a current allele burden for JAK2/CALR, thereby obtaining a follow up time of 5-8 years.

Results
In a preliminary mutational analysis of 9,000 individuals, 285 (3.2%) were JAK2 positive and 18 (0.2%) were CALR positive corresponding to a JAK2:CALR ratio of 16. Among the citizens with mutation, median age was 63 years (range 23-93), and 82% presented low allele burden less than 1%. These proportions were similar when looking at the JAK2- and CALR-mutated groups separately. We noticed that 40% of the citizens concurrently with their mutation had an aberrant blood cell count – leukocytosis (defined as >8.8 x 10^9/L) being the most frequent and present in 54% of the cases.

Conclusion
To our knowledge, we are the first to determine the prevalence of JAK2 and CALR in the general population with such a sensitive method, and our preliminary results indicate that the true prevalence of JAK2 in the general population is much higher than previously reported with dominance of low allele burdens. On the contrary, we find the CALR prevalence low compared to JAK2. The difference cannot entirely be explained by the distribution of the mutations within the MPN diagnoses. The long-term perspective of this study is to reduce thrombotic and hemorrhagic events in today’s pre-MPN diagnosis phase by diagnosing MPN in earlier disease stages in the future. Thus, we find the high prevalence of low allele burden and mild cytosis intriguing, and we hope that the follow up program can elucidate whether we can discriminate between early signs of MPN and clonal hematopoiesis of indeterminate potential; though these two wordings in time might turn out to be two sides of the same coin.

Session topic: 16. Myeloproliferative neoplasms - Clinical

Keyword(s): Mutation, Myeloproliferative disorder, Prevalence, Screening

Abstract: S885

Type: Oral Presentation

Presentation during EHA23: On Saturday, June 16, 2018 from 17:00 - 17:15

Location: Room A8

Background
The JAK2V617F mutation (JAK2) and calreticulin mutations type 1 and 2 (CALR) are predominantly found within the chronic Philadelphia-negative myeloproliferative neoplasms (MPN). Few studies have assessed the JAK2 prevalence in the general population with very limited reports on the association with MPN over time. To our knowledge, no corresponding studies of CALR exist.

Aims
1) to determine the prevalence of JAK2 and CALR mutations in a Danish population study 2) to assess the kinetics of the allele burden and blood cell counts over time by inclusion of mutated citizens in a follow up program.

Methods
Inclusion of participants in the general population study in Region Zealand took place during 2010-2013 (N=20,000). When included, a broad range of blood samples were collected as well as DNA to be stored in a biobank, and all participants were asked for a written consent to allow the data and DNA to be used in future research. This DNA was in our study analyzed for JAK2 and CALR by digital droplet PCR. The assays used have high accuracy and sensitivity with a detection level of allele burden at 0.01%. Part of our ongoing follow up program during 2017-2018 on citizens with mutation includes blood samples and a current allele burden for JAK2/CALR, thereby obtaining a follow up time of 5-8 years.

Results
In a preliminary mutational analysis of 9,000 individuals, 285 (3.2%) were JAK2 positive and 18 (0.2%) were CALR positive corresponding to a JAK2:CALR ratio of 16. Among the citizens with mutation, median age was 63 years (range 23-93), and 82% presented low allele burden less than 1%. These proportions were similar when looking at the JAK2- and CALR-mutated groups separately. We noticed that 40% of the citizens concurrently with their mutation had an aberrant blood cell count – leukocytosis (defined as >8.8 x 10^9/L) being the most frequent and present in 54% of the cases.

Conclusion
To our knowledge, we are the first to determine the prevalence of JAK2 and CALR in the general population with such a sensitive method, and our preliminary results indicate that the true prevalence of JAK2 in the general population is much higher than previously reported with dominance of low allele burdens. On the contrary, we find the CALR prevalence low compared to JAK2. The difference cannot entirely be explained by the distribution of the mutations within the MPN diagnoses. The long-term perspective of this study is to reduce thrombotic and hemorrhagic events in today’s pre-MPN diagnosis phase by diagnosing MPN in earlier disease stages in the future. Thus, we find the high prevalence of low allele burden and mild cytosis intriguing, and we hope that the follow up program can elucidate whether we can discriminate between early signs of MPN and clonal hematopoiesis of indeterminate potential; though these two wordings in time might turn out to be two sides of the same coin.

Session topic: 16. Myeloproliferative neoplasms - Clinical

Keyword(s): Mutation, Myeloproliferative disorder, Prevalence, Screening

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