Cancer Treatment Today

The discovery of somatic mutations within the gene encoding calreticulin (CALR) in 2013 represented a major milestone in the molecular diagnosis of BCR-ABL negative myeloproliferative neoplasms (MPN). In fact, exome sequencing revealed that most patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF) lacking JAK2 or MPL mutations, harbor somatic insertion and/or deletion in exon 9 of CALR gene.

Alterations in exon 9 of CALR have been estimated to be present in approximately 20-35% of all individuals with ET and PMF (which accounts for approximately 60%-80% of individuals with JAK2/MPL-negative ET and MF). CALR-Type 1 mutations (52 base pair deletions) occur more frequently in individuals with MF while CALR-Type 2 mutations (5 base pair insertions) are preferentially associated with ET.

NCCN guidelines on Myeloproliferative Neoplasms V2.2019 include the following recommendations for CALR mutation testing:

Molecular testing for JAK2 V617F mutations is recommended as part of initial workup for all patients. If JAK2 V617F mutation testing is negative, molecular testing for MPL and CALR mutations should be performed for patients with MF and ET; molecular testing for JAK2 exon 12 mutation should be done for those with suspected PV and negative for the JAK2 V617F mutation. Alternatively, molecular testing using the multi-gene NGS panel that includes JAK2, CALR, and MPL can be used as part of initial workup for all patients.

NCCN MPL Disorders 2019

Guglielmelli P, Rotunno G, Fanelli T, et al. Validation of the differential prognostic impact of type 1/type 1-like versus type 2/type 2-like CALR mutations in myelofibrosis. Blood Cancer J. 2015; 5:e360.

Sokol K, Tremblay D, Bhalla S, et al. Implications of Mutation Profiling in Myeloid Malignancies-PART 2: Myeloproliferative Neoplasms and Other Myeloid Malignancies. Oncology (Williston Park). 2018; 32(5):e45-e51.