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Clinicopathological differences exist between CALR- and JAK2-mutated myeloproliferative neoplasms despite a similar molecular landscape: data from targeted next-generation sequencing in the diagnostic laboratory

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Abstract

Mutations in CALR have recently been detected in JAK2-negative myeloproliferative neoplasms (MPNs) and are key pathological drivers in these diseases. CALR-mutated MPNs are shown to have numerous clinicopathological differences to JAK2-mutated MPNs. The basis of these differences is poorly understood. It is unknown whether these differences result directly from any differences in intracellular signalling abnormalities induced by JAK2/CALR mutations or whether they relate to other phenomena such as a differing spectrum of genetic lesions between the two groups. We aimed to review the clinicopathological and molecular features of CALR- and JAK2-mutated MPNs from samples referred for diagnostic testing using a custom-designed targeted next-generation sequencing (NGS) panel. Eighty-nine CALR-mutated cases were compared with 70 JAK2-mutated cases. CALR-mutated MPNs showed higher platelet counts and a female predominance as compared to JAK2-mutated MPNs in our cohort. We have also observed differences between CALR mutation subtypes in terms of disease phenotype, mutational frequency and allelic burden. Type 1 CALR mutations were found to be more common in myelofibrosis, associated with a higher frequency and number of additional mutations and a higher mutant allelic burden as compared to type 2 CALR mutations. Despite these biological differences, our molecular characterisation suggests that CALR- and JAK2-mutated MPNs are broadly similar in terms of the quantity, frequency and spectrum of co-occurring mutations and therefore observed biological differences are likely to not be heavily influenced by the nature and quantity of co-mutated genes.

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Authors and Affiliations

  1. Division of Cancer Medicine, Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Melbourne, Australia

    Rishu Agarwal, Piers Blombery, Michelle McBean, Kate Jones, Andrew Fellowes & David A. Westerman

  2. Bioinformatics Core, Peter MacCallum Cancer Centre, East Melbourne, Melbourne, Australia

    Ken Doig

  3. University of Melbourne, Parkville, Melbourne, Australia

    Ken Doig & David A. Westerman

  4. Jarrett Street Specialist Centre, North Gosford, Gosford, Australia

    Cecily Forsyth

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  1. Rishu Agarwal
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Agarwal, R., Blombery, P., McBean, M. et al. Clinicopathological differences exist between CALR- and JAK2-mutated myeloproliferative neoplasms despite a similar molecular landscape: data from targeted next-generation sequencing in the diagnostic laboratory. Ann Hematol 96, 725–732 (2017). https://doi.org/10.1007/s00277-017-2937-6

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