Testing for activating mutations in the Calreticulin (CALR) gene
Improving diagnostic and prognostic classification in patients with myeloproliferative neoplasms.
- CALR is a novel biomarker for the detection of myeloproliferative neoplasms.
- Mutations in CALR are present in a significant proportion of patients with essential thrombocythemia, primary myelofibrosis and polycythemia vera.
- Frameshift mutations in CALR exon 9 result in constitutive pathway activation and are an early and disease-initiating event.
- Testing for CALR, along with JAK2 and MPL mutations is essential for accurate diagnostic and prognostic classification of myeloproliferative neoplasms.
Somatic mutations in the Janus kinase 2 gene (JAK2), or the thrombopoietin receptor gene (MPL) occur in many myeloproliferative neoplasms. Testing for these mutations improves diagnostic and prognostic classification in myeloproliferative neoplasms, by helping to differentiate between neoplastic and reactive processes. Recent independent landmark studies have additionally identified the endoplasmic reticulum chaperone CALR gene which is another important contributor to the molecular pathogenesis of these neoplasms. CALR mutations have been detected in up to 70% of patients with JAK2-negative essential thrombocythemia (ET) and 60-80% of patients with JAK2-negative primary myelofibrosis.
Calreticulin is a calcium-binding protein involved in expression regulation and signalling that is believed to be responsible for clearing mis-folded proteins. CALR insertion/deletion (indel) mutations reported in myeloproliferative neoplasms lead to translation frameshifts in exon 9, truncating the C-terminal calcium binding domain and creating a novel C-terminal peptide. This leads to constitutive activation of signal transduction and transcriptional activation.
Current evidence supports the role of CALR mutations as an early and disease-initiating event which favours expansion of the megakaryocytic lineage. CALR mutation testing also has prognostic value as patients with CALR mutations may have longer survival times, and fewer thrombotic events compared to patients with JAK2 mutations.
When to order
One of our specialist haematologists can assist you in ordering this test.
In myeloproliferative disorders:
Essential Thrombocythaemia (ET)
CALR mutations have been reported to occur in approximately 25% of ET overall. Patients with CALR-mutated ET tend to be younger and have higher platelet counts and lower haemoglobin than those with JAK2-mutated ET. Risk of thrombosis is lower in CALR-mutated ET patients than those with JAK2 or MPL mutations and compares with the risk of mutation-negative patients. Evidence for long term prognosis of CALR-mutated ET is unfolding.
CALR in Primary Myleofibrosis (PMF)
CALR mutations have been detected in 88% PMF patients without JAK2 and MPL mutations. PMF patients with CALR mutations are reported to have longer overall survival than those with JAK2 and MPL mutations.
CALR in Polycythemia Vera (PV)
CALR mutations are not reported in PV patients. Testing can therefore be used to distinguish PV patients from those with ET or PMF.
CALR and other haematologic disorders:
CALR mutations are reported in 8% of patients with MDS, are rarely found in CMML or atypical CML, and not reported in lymphoid leukemia or solid tumors.
Patients will incur an out-of-pocket cost of $85.00* at the time of collection. There is no Medicare rebate available.
The turnaround time is 7-10 business days.
All test enquiries should be directed to:
National Head of Genetics
Dr Kim Mina MBBS, PhD, FRCPA
Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med.2013;369(25):2391-405.
Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med.2013;369(25):2379-90.
Rumi E, Pietra D, Ferretti V, et al. JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes. Blood. 2014 Mar 6;123(10):1544-51
Rotunno G, Mannarelli C, Guglielmelli P, et al. Impact of calreticulin mutations on clinical and hematological phenotype and outcome in essential thrombocytopenia. Blood. 2014 Mar 6;123(10):1552-5
Lundberg P1, Karow A, Nienhold R, et al Clonal evolution and clinical correlates of somatic mutations in myeloproliferative neoplasms. Blood. 2014 Apr 3;123(14):2220-8
Harrison CN, Butt N, Campbell P, et al. Modification of British Committee for Standards in Haematology diagnostic criteria for essential thrombocythaemia. Br J Haematol. 2014 [Epub ahead of print].
* Prices are correct as of August 2015 and may be subject to change.