JAK2/STAT5 Pathway Mutation Frequencies in South African BCR/ABL Negative MPN Patients.

Abstract

Background: Mutations in JAK2/STAT5 proliferation pathway genes are key in the diagnosis of myeloproliferative neoplasms (MPN^BCR/ABLneg), with JAK2V617F being found in 50-97% of MPN^BCR/ABLneg subtypes. Low JAK2V617F positivity at our facility suggested that our South African MPN^BCR/ABLneg population may have a different mutational landscape.

Objectives: We aimed to determine the JAK2/STAT5 mutation frequencies associated with our local MPN^BCR/ABLneg population, thus determining the relevance of these molecular tests in this group. We also investigated the haematopathological relevance of each test request, to assess testing practises.

Method: This study involved the retrospective audit of 886 patients for whom JAK2V617F mutation testing had been requested for a suspected MPN diagnosis. FBC indices, erythropoietin levels and bone marrow biopsy results were used to classify the patients. JAK2V617F ^negative patient DNA was tested for calreticulin (CALR) exon9, myeloproliferative leukaemia protein (MPL) codon515 and JAK2 exon12 mutations.

Results: Only 23% of the patients demonstrated JAK2V617F positivity, with an additional 29 cases of CALR/MPL mutations being detected. Mutations were only detected in patients with abnormal FBC indices, as expected, yet 37% of the test requests were not associated with abnormal parameters at the time of testing. Mutation frequencies were as follows: Polycythaemia Vera: 97% JAK2V617F/3% (JAK2, CALR, MPL) triple negative; Essential thrombocythemia: 72% JAK2V617F/23%CALR/5%triple negative; Primary Myelofibrosis: 78%JAK2V617F/16%CALR/6%triple negative.

Conclusion: Our study demonstrated that our MPN^BCR/ABLneg patients have a similar genetic landscape to other MPN populations, with >93% being able to be diagnosed by testing for the JAK2V617F and CALR exon9 mutations alone. Adoption of the WHO 2016 guidelines is recommended to guide testing practices.