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Calreticulin (CALR) Mutation Analysis

Test code(s) 92074

Question 1. What are the clinical indications for calreticulin (CALR) mutation testing?

CALR mutation testing can be used in the diagnosis of myeloproliferative neoplasms (MPN), in particular essential thrombocythemia (ET) and primary myelofibrosis (PMF). Patients who are suspected of having an MPN and who have tested negative for BCR-ABL1 and JAK2 mutations are suitable for testing.

CALR mutations are absent in patients with BCR-ABL1, JAK2, and MPL mutations. Thus, they are absent in patients with chronic myelogenous leukemia or polycythemia vera. Approximately 70% of JAK2/MPL-negative patients with ET test positive for a CALR mutation.1-4 Similarly, 56% to 88% of JAK2/MPL-negative patients with PMF test positive for a CALR mutation.1,2,4,5

Initial studies suggest patients with CALR-positive MPN may have a more benign clinical course than those with a JAK2 or MPL mutation.1,3-7Given the diagnostic and prognostic correlates, inclusion of CALR mutation status as a distinct feature in the newest hematologic malignancy classification has been proposed.8

Question 2. How is CALR mutation testing performed?

PCR amplification of CALR exon 9 is followed by Sanger sequencing. The assay can detect mutant alleles that constitute more than 10% to 15% of alleles present in the sample.

Question 3. Which CALR mutations are detected?

The assay detects mutations in exon 9 which is the location of the clinically characterized CALR mutations in myeloid neoplasms. Nearly all of theseare deletions and/or insertions that shift the reading frame and result in a calreticulin protein with a novel C-terminus. The type and significance of any mutation detected will be reported in an interpretive comment.

Question 4. What types of specimens can be tested?

Peripheral blood, bone marrow aspirates, fixed cell pellets, and formalin-fixed paraffin-embedded tissue, including decalcified bone marrow cores, can all be tested.  For ease of collection, use of the Hematopathology Transport Kit is recommended (see Directory of Services or sales representativefor further information).

Question 5. What other testing can be performed to identify mutations in MPNs?

Testing can be performed for the following MPN-related mutations:

  • JAK2 V617F and JAK2 exons 12 and 13 mutations (test code 18950 or 16539)
  • MPL W515 and S505 mutations (test code 16184)
  • TET2, ASXL1, KRAS, NRAS, EZH2, IDH1 and IDH2 mutations (test code 91401)

The latter test code is suitable for patients with granulocytosis, erythrocytosis, or thrombocytosis, especially when they have tested negative for a BCR-ABL1 fusion transcript and for JAK2 and CALR mutations.

 

References

  1. Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369:2379-2390.
  2. Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013;369:2391-2405.
  3. 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. [published online ahead of print December 23, 2013]. Blood. doi:10.1182/blood-2013-11-539098.
  4. Lundberg P, Karow A, Nienhold R, et al. Clonal evolution and clinical correlates of somatic mutations in myeloproliferative neoplasms. [published online ahead of print January 29, 2014]. Blood. doi:10.1182/blood-2013-11-53716.
  5. Teferri A, Lasho TL, Finke CM, et al. CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons. [published online ahead of print January 9, 2014]. Leukemia. doi:10.1038/leu.2014.3.
  6. Rotunno G, Mannarelli C, Guglielmelli P, et al. Impact of calreticulin mutations on clinical and hematological phenotype and outcome in essential thrombocythemia. [published online ahead of print December 26, 2013]. Blood. doi:10.1182/blood-2013-11-538983.
  7. Panagiota V, Thol F, Markus B, et al. Prognostic effect of calreticulin mutations in patients with myelofibrosis after allogeneic hematopoietic stem cell transplantation. [published online ahead of print February 21, 2014]. Leukemia. doi: 10.1038/leu.2014.66.
  8. Tefferi A, Thiele J, Vannucchi AM, Barbui T. An overview on CALR and CSF3R mutations and a proposal for revision of WHO diagnostic criteria for myeloproliferative neoplasms. [published online ahead of print February 11, 2014]. Leukemia. doi: 10.1038/leu.2014.35.
This FAQ is provided for informational purposes only and is not intended as medical advice. A physician’s test selection and interpretation, diagnosis, and patient management decisions should be based on his/her education, clinical expertise, and assessment of the patient.
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