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Who to screen for calreticulin mutations? An audit of real-life practice and review of current evidence

Published:January 26, 2017DOI:https://doi.org/10.1016/j.ejim.2017.01.020
      The myeloproliferative neoplasms (MPN) are clonal, hematopoietic stem cell-derived diseases characterised by bone marrow proliferation of one or more of the myeloid cell lineages with the main subtypes being polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The diagnosis and classification of these diseases is dependent on clinical, hematological, histo-morphological and molecular genetic findings. The most commonly acquired mutation associated with MPN is the JAK2 V617F, occurring in approximately 95% of PV cases and in 50–60% of ET and PMF patients. Further mutations in MPL exon 10 are present in approximately 5% and 3% of PMF and ET patients respectively. In 2013, whole exome sequencing studies reported insertion and/or deletion (indel) mutations in exon 9 of CALR, the gene that encodes the endoplasmic reticulum-associated, calcium binding protein, calreticulin. These MPN disease driving mutations of CALR result in a frame shift of the coding sequence, altered amino acid composition of the translated protein and loss of the endoplasmic reticulum retention motif. CALR mutations appear not to occur in PV patients but are present in up to 80% of ET and PMF patients who are JAK2 V617F-and MPL-mutation negative [
      • Passamonti F.
      • Mora B.
      • Maffioli M.
      New molecular genetics in the diagnosis and treatment of myeloproliferative neoplasms.
      ]. Analysis of CALR mutations has rapidly been adopted into MPN molecular diagnostic algorithms with identification now a major diagnostic criterion for ET and PMF [
      • Arber D.A.
      • Orazi A.
      • Hasserjian R.
      • Thiele J.
      • Borowitz M.J.
      • Le Beau M.M.
      • et al.
      The 2016 revision of the World Health Organization classification of myeloid neoplasms and acute leukemia.
      ]. In addition to their diagnostic value, CALR mutations are associated with a higher platelet count, a reduced hemoglobin level and a reduced risk of thrombosis when compared to their JAK2 V617F-positive counterparts with patients responding to therapies such as interferon and JAK 1/2 inhibitors. While numerous studies have addressed the technical aspects of CALR mutation identification and mutant allele burden estimation and despite guidelines clearly indicating analysis for the diagnosis of ET and PMF, limited information exists on the criteria for requesting molecular testing of CALR mutations and the reproducibility of application of these criteria in a real world situation. Given the previously noted referral centre variation in JAK2 V617F requesting patterns in the Republic of Ireland [
      • Langabeer S.E.
      Referral centre variation in requesting JAK2 V617F mutation analysis for the investigation of a myeloproliferative neoplasm.
      ], an audit was performed on the CALR mutation requests in order to determine if requests were being made on appropriate patients and to refine the currently adopted molecular diagnostic algorithm for MPN.

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