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.
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.
Division of Cancer Medicine, Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Melbourne, Australia. Rishu.Agarwal@petermac.org.
Rishu
http://orcid.org/0000-0002-6713-0403
R
Agarwal
Division of Cancer Medicine, Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Melbourne, Australia.
Piers
P
Blombery
Division of Cancer Medicine, Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Melbourne, Australia.
Michelle
M
McBean
Division of Cancer Medicine, Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Melbourne, Australia.
Kate
K
Jones
Division of Cancer Medicine, Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Melbourne, Australia.
Andrew
A
Fellowes
Bioinformatics Core, Peter MacCallum Cancer Centre, East Melbourne, Melbourne, Australia.|University of Melbourne, Parkville, Melbourne, Australia.
Ken
K
Doig
Jarrett Street Specialist Centre, North Gosford, Gosford, Australia.
Cecily
C
Forsyth
Division of Cancer Medicine, Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne, Melbourne, Australia.|University of Melbourne, Parkville, Melbourne, Australia.
David A
DA
Westerman
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D015415:Biomarkers; D037282:Calreticulin / Q000235:genetics*; D016000:Cluster Analysis; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000175:diagnosis* / Q000235:genetics*; D010641:Phenotype; D055815:Young Adult
D015415:Biomarkers; D037282:Calreticulin; D053614:Janus Kinase 2
Calreticulin; Essential thrombocythaemia; Myeloproliferative neoplasms; Primary myelofibrosis; Targeted amplicon sequencing