title: Distinct clinical characteristics of myeloproliferative neoplasms with calreticulin mutations.
abstract: Somatic insertions/deletions in the calreticulin gene have recently been discovered to be causative alterations in myeloproliferative neoplasms. A combination of qualitative and quantitative allele-specific polymerase chain reaction, fragment-sizing, high resolution melting and Sanger-sequencing was applied for the detection of three driver mutations (in Janus kinase 2, calreticulin and myeloproliferative leukemia virus oncogene genes) in 289 cases of essential thrombocythemia and 99 cases of primary myelofibrosis. In essential thrombocythemia, 154 (53%) Janus kinase 2 V617F, 96 (33%) calreticulin, 9 (3%) myeloproliferative leukemia virus oncogene gene mutation-positive and 30 triple-negative (11%) cases were identified, while in primary myelofibrosis 56 (57%) Janus kinase 2 V617F, 25 (25%) calreticulin, 7 (7%) myeloproliferative leukemia virus oncogene gene mutation-positive and 11 (11%) triple-negative cases were identified. Patients positive for the calreticulin mutation were younger and had higher platelet counts compared to Janus kinase 2 mutation-positive counterparts. Calreticulin mutation-positive patients with essential thrombocythemia showed a lower risk of developing venous thrombosis, but no difference in overall survival. Calreticulin mutation-positive patients with primary myelofibrosis had a better overall survival compared to that of the Janus kinase 2 mutation-positive (P=0.04) or triple-negative cases (P=0.01). Type 2 calreticulin mutation occurred more frequently in essential thrombocythemia than in primary myelofibrosis (P=0.049). In essential thrombocythemia, the calreticulin mutational load was higher than the Janus kinase 2 mutational load (P<0.001), and increased gradually in advanced stages. Calreticulin mutational load influenced blood counts even at the time point of diagnosis in essential thrombocythemia. We confirm that calreticulin mutation is associated with distinct clinical characteristics and explored relationships between mutation type, load and clinical outcome.
authors.affiliation: Laboratory of Molecular Diagnostics, Hungarian National Blood Transfusion Service, Budapest andrikovics.hajnalka@ovsz.hu.
authors.forename: Hajnalka
authors.initials: H
authors.lastname: Andrikovics
authors.affiliation: Laboratory of Molecular Diagnostics, Hungarian National Blood Transfusion Service, Budapest.
authors.forename: Tunde
authors.initials: T
authors.lastname: Krahling
authors.affiliation: Laboratory of Molecular Diagnostics, Hungarian National Blood Transfusion Service, Budapest.
authors.forename: Katalin
authors.initials: K
authors.lastname: Balassa
authors.affiliation: Department of Hematology and Stem Cell Transplantation, St. Istvan and St. Laszlo Hospital, Budapest.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Halm
authors.affiliation: Laboratory of Molecular Diagnostics, Hungarian National Blood Transfusion Service, Budapest.
authors.forename: Andras
authors.initials: A
authors.lastname: Bors
authors.affiliation: Laboratory of Molecular Diagnostics, Hungarian National Blood Transfusion Service, Budapest.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Koszarska
authors.affiliation: Department of Hematology and Stem Cell Transplantation, St. Istvan and St. Laszlo Hospital, Budapest.
authors.forename: Arpad
authors.initials: A
authors.lastname: Batai
authors.affiliation: Department of Hematology and Stem Cell Transplantation, St. Istvan and St. Laszlo Hospital, Budapest.
authors.forename: Janos
authors.initials: J
authors.lastname: Dolgos
authors.affiliation: Department of Pathology, St. István and St. Lászlo Hospital, Budapest.
authors.forename: Judit
authors.initials: J
authors.lastname: Csomor
authors.affiliation: Department of Haematology, Kaposi Mor Hospital, Kaposvar.
authors.forename: Miklos
authors.initials: M
authors.lastname: Egyed
authors.affiliation: Department of Hematology and Stem Cell Transplantation, St. Istvan and St. Laszlo Hospital, Budapest.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sipos
authors.affiliation: Department of Hematology and Stem Cell Transplantation, St. Istvan and St. Laszlo Hospital, Budapest.
authors.forename: Peter
authors.initials: P
authors.lastname: Remenyi
authors.affiliation: Laboratory of Molecular Diagnostics, Hungarian National Blood Transfusion Service, Budapest.
authors.forename: Attila
authors.initials: A
authors.lastname: Tordai
authors.affiliation: Department of Hematology and Stem Cell Transplantation, St. Istvan and St. Laszlo Hospital, Budapest 3 Department of Internal Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: Tamas
authors.initials: T
authors.lastname: Masszi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D037282:Calreticulin / Q000235:genetics*; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality; D011087:Polycythemia Vera / Q000175:diagnosis / Q000235:genetics / Q000401:mortality; D055728:Primary Myelofibrosis / Q000175:diagnosis / Q000235:genetics / Q000401:mortality; D013920:Thrombocythemia, Essential / Q000175:diagnosis / Q000235:genetics / Q000401:mortality; D055815:Young Adult
chemical_list: D037282:Calreticulin; D053614:Janus Kinase 2