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• W2059202491 abstract "Even after the discovery of the JAK2 V617F and MPL mutations, around 40% of patients with essential thrombocythaemia (ET) still lacked any relevant molecular markers. The ‘missing-puzzle’ piece was revealed in 2013, when two research groups, led by Robert Kralovics and Anthony Green, using an exome sequencing strategy, reported that most ET patients with non-mutated JAK2 and MPL harbour somatic mutations within the CALR gene, encoding calreticulin (Klampfl et al, 2013; Nangalia et al, 2013). Even though the two groups reported an abundance of different insertions and/or deletions (indels) in exon 9 of the CALR gene, two were predominantly detected (84·7–86% of all CALR mutations detected): a 52 bp deletion (L367 fs*46 or type 1 mutation), and a 5 bp insertion (K385 fs*47 or type 2 mutation). We hereby aimed to characterize CALR status in a cohort of ET patients. We also sought to compare the biological features of ET patients, according to the mutations displayed (JAK2 V617F, MPL, CALR or triple-negative). We included in our study 141 patients with ET, followed in three Romanian haematology units: Cluj-Napoca (‘Ion Chircuţă’ Cancer Institute), Tîrgu-Mureş (First Haematology Clinic) and Bucharest (Colentina Hospital), diagnosed between 1985 and 2014. We included only patients with full medical records who had samples available for molecular analysis. Th diagnosis was reviewed according to the 2008 WHO classification of myeloid neoplasms (Tefferi & Vardiman, 2008). The study was approved by the Ethics Committee of the ‘Iuliu Haţieganu’ University of Medicine and Pharmacy, Cluj-Napoca. Written consent regarding the genetic testing was also obtained from each patient. All the genotyping procedures were performed on DNA obtained from peripheral blood leucocytes, using commercially available kits [Wizard Genomic DNA Purification Kit (Promega, Madison, WI, USA) and Quick-gDNA MiniPrep Kit (ZymoResearch, Irvine, CA, USA)]. The JAK2 V617F mutation was assessed in all patients by a tetra-primer polymerase chain reaction (PCR) assay, as previously described (Jones et al, 2005). The MPL W515L/K/A and S505N mutations were genotyped by a multiplex allele-specific PCR assay, as previously described (Furtado et al, 2013). In order to analyse the common mutations within the exon 9 of the CALR gene (type 1 and type 2 mutations), which account for almost 90% of all CALR mutations, we developed a simplex PCR assay (conditions are available upon request). In order to validate our PCR assay, we randomly selected 24 samples and sequenced them bidirectionally. There was a 100% concordance between the results obtained by sequencing and those obtained by the PCR assay. The various CALR genotypes obtained using our PCR assay are presented in Fig 1. The distribution of qualitative variables between different groups was compared using the chi-square test or Fisher's exact test, when appropriate. The differences of quantitative variables between different groups were compared using the Mann–Whitney test. All the tests were performed using the SPSS version 21 software (Chicago, IL, USA). The level of statistical significance was set at 0·05. JAK2 V617F was the most common mutation, seen in 76 patients (53·9%), while CALR exon 9 mutations characterized 40 patients (28·4%). Type 1 mutation was more frequent than Type 2 (25 vs. 15 patients). Three patients (2·1%) harboured the MPL W515L mutation. The MPL group was excluded from the statistical analysis due to its small size. CALR mutations were mutually exclusive with both JAK2 and MPL mutations. Twenty-two patients (15·6%), were considered triple-negative, as they lacked JAK2 V617F, CALR or MPL mutations. Then, we analysed the biological features of the patients, according to the mutational status, with a special focus on the CALR-mutated versus JAK2-mutated subgroups, as these two types of mutations were predominant. Recent data indicated that CALR-mutated patients were younger than their JAK2 counterparts (Klampfl et al, 2013; Nangalia et al, 2013; Rotunno et al, 2014; Rumi et al, 2014; Tefferi et al, 2014). We observed the same trend in our cohort, although our observation did not attain statistical significance. Platelets counts were higher in CALR- than in JAK2-mutated patients (P = 0·005). The white blood cell (WBC) counts were significantly lower in CALR- than in JAK2-mutated patients (P = 0·03). The major thrombotic events, both arterial and venous (stroke/transient ischaemic attack, acute limb ischaemia, acute coronary disease, splenic infarction, lower limb deep venous thrombosis and splanchnic thrombosis) were seen more frequently in JAK2-mutated patients than in their CALR-mutated counterparts (P = 0·009). Splenomegaly was encountered more frequently in JAK2-mutated patients (P = 0·01), compared to CALR-mutated patients. Our results match recent data regarding the platelet and WBC counts in CALR-mutated patients (Klampfl et al, 2013; Rotunno et al, 2014; Rumi et al, 2014; Tefferi et al, 2014). We attempted to compare the biological features between the two types of CALR mutations in ET patients. Type 1 mutation tended to correlate with the male sex, and Type 2 mutation with the female sex and higher platelet counts. However, these observations did not reach statistical significance, probably due to the small size of each CALR subgroup. These data parallel the observations reported by Tefferi et al (2014). Table 1 shows in detail the comparisons performed between CALR- and JAK2-mutated patients. We also compared the parameters of the CALR- and JAK2-mutated patients to those who were triple-negative. JAK2-mutated patients tended to have higher haematocrit and haemoglobin levels (P = 0·06 and 0·05, respectively), while CALR-mutated patients tended to have lower WBC and higher platelet counts (P = 0·06 and 0·09, respectively) than those who were triple-negative. Even though our study enrolled a relatively limited number of patients, we found that CALR-mutated ET patients display a distinct phenotype compared to JAK2-mutated ET patients. This phenotype is characterized by higher platelet counts, lower WBC counts and a lower thrombotic risk. Interestingly, splenomegaly is less likely in CALR-mutated ET patients. Thus, CALR-mutated ET might represent a more benign entity than the JAK2-mutated one. This work was partially supported by the projects: POSDRU 107/1.5/S/78702 to APT and an Internal Research Grant from the University of Medicine and Pharmacy Tîrgu Mureş, România to CB (grant number 1/30.01.2013). APT designed research, performed genetic analysis, analysed data and wrote the manuscript; RAP and CB designed research, performed genetic analysis and revised the manuscript; AC designed research, collected samples and patients data and wrote the manuscript; MT, MM, DD and MC collected samples and patients data; BM and MSM performed genetic analysis; ȘCV analysed data; IVP designed research and revised the mansucript. The authors reported no potential conflicts of interest." @default.
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• W2059202491 title "<i>CALR versus JAK2</i>mutated essential thrombocythaemia - a report on 141 patients" @default.
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