Mutation Profile in BCR-ABL1-Negative Myeloproliferative Neoplasms

Abstract

Objective/Background: Recurrent somatic mutations in the JAK2, calreticulin (CALR), and the MPL genes are described as drivers of BCR-ABL1-negative myeloproliferative neoplasms (MPN) that includes polycythemia vera (PV), essential thrombocytosis (ET), primary myelofibrosis (PMF), and MPN unclassified (MPN-U). Methods: We describe the mutation profile and clinical features of MPN cases diagnosed at a tertiary care center. JAK2V617F and MPL (S505/W515) mutations were screened by allele-specific polymerase chain reaction, while CALR exon 9 and JAK2 exon 12 mutations were screened by fragment analysis/Sanger sequencing. Among the 1,570 patients tested for these mutations during the study period, 407 were classified as MPN with a diagnosis of PV, ET, PMF, and MPN-U seen in 30%, 17%, 36%, and 17%, respectively, screened. Results: Similar to previous reports from Asian countries, the incidence of PMF was the highest among the classic MPN. JAK2V617F mutation was detected in 90% of PV, 38% of ET, 48% of PMF, and 65% of MPN-U. JAK2 exon 12 mutations were seen in 5.7% of PV and 1.4% of PMF. CALR exon 9 mutations were seen in 33% of ET, 33% of PMF, and 12% of MPN-U. MPL mutations were detected in 2.8%, 2.7%, and 2.9% of ET, PMF, and MPN-U, respectively. Fifteen % of PMF, 26% of ET, and 22% of MPN-U were triple negative. Conclusion: There was a significantly higher incidence of CALR mutation in PMF and ET cases. Our study highlights the challenges in the diagnosis of JAK2-negative PV and the need for harmonization of criteria for the same.

The clinicopathological spectrum and driver mutation profile in classic BCR-ABL1 negative myeloproliferative neoplasms: a three-year study from a tertiary care center in Kerala, South India

“…We found that CALR positive cases present at a younger age with lower hemoglobin and higher platelet count in ET and PMF. These findings are in concordance with studies conducted by Maddali et al 9 In our study, MPL was found in 3.1% of patients with PMF and 4.4% patients with ET, similar to published data. 14 A comparison of driver mutation analysis with other studies is given in Table 2.…”

“…This frequency of JAK2 V617F was lower than 71% in a survey conducted by Dixith et al and 68% in a study conducted by Sazawal et al 7,8 The frequency of CALR and MPL was 13.9% and 2%, which correlates with the published data. In this study, JAK2 V617F mutation was noted in 29 patients (65.9%) with PV, which is lower than 90% in a study conducted by Maddali et al 74% in a study conducted by Singh et al and 85% in a study conducted by Yassin et al 3,9,10 A possible reason may be due to the overdiagnosis of JAK2 negative PV. 2016 WHO diagnostic PV criteria were less precise and lacked a separate criterion for labeling JAK2 negative PV.…”

“…In PMF, six patients (18.8%) were type 1 CALR, and four patients (12.5%) were type 2 CALR. The frequency of CALR in ET was lower than the findings of Singh et al, Maddali et al and Tefferi et al 9,10,12,13 Our study also compared the clinical phenotype of CALR positive and negative ET and PMF cases. We found that CALR positive cases present at a younger age with lower hemoglobin and higher platelet count in ET and PMF.…”

Approach to Diagnosis of BCR::ABL1-Negative Myeloproliferative Neoplasms

“…The risk of occurrence of complications such as thromboembolic phenomena or the progression to acute myeloid leukemia (AML) differs between these types of MPNs and hence, correct diagnosis is imperative for effective management and long-term follow-up. 6…”

“…The risk of occurrence of complications such as thromboembolic phenomena or the progression to acute myeloid leukemia (AML) differs between these types of MPNs and hence, correct diagnosis is imperative for effective management and long-term follow-up. 6 Classical MPNs include three entities, namely, ET, PV, and PMF. Although the clinical features of these entities are different in their typical forms, the majority of the cases have overlapping clinicopathologic and morphologic features; hence, accurate diagnosis is often challenging.…”