In this study we have looked at the prevalence of the JAK2 mutation in a large patient cohort examined for suspected myeloproliferative neoplasm. The mutation was detected in around a fifth of the patients. This does not necessarily mean that none of those with negative results had a myeloproliferative disease. In addition to the classic JAK2 mutation, JAK2V617F, a number of other mutations related to these disorders have been discovered in recent years.
Previous studies have found mutation in exon 12 of the JAK2 gene in about 3 % of patients with polycythaemia vera, while mutations in the gene that codes for the thrombopoietin receptor (MPL) (19) have been found in about 3 % of those with essential thrombocytosis and in 10 % of those with primary myelofibrosis. Nonetheless, the situation before 2013 was that no causal explanation had been found for 30 – 45 % of patients with essential thrombocytosis and primary myelofibrosis. In 2016, two research teams using exon sequencing have found somatic mutations in the CALR gene in 25 – 35 % of these patients (20, 21).
On the basis of these results it is therefore possible today to explain up to 97 % of all cases of myeloproliferative neoplasm with mutations in the JAK2, MPL or CALR genes (20). Analysis of mutations in the MPL and CALR genes is now available at Haukeland University Hospital, but no results have been included in this study.
The possibility that an alternative distinction, between JAK2-mutation-positive and JAK2-mutation-negative myeloproliferative neoplasms, might be more appropriate has been discussed. The reason for this is that mutation-negative status has a distinctly different phenotype. Another idea is that mutation-positive myeloproliferative neoplasms are distributed along a continuum according to allele burden. Tests from animal models have previously shown that the level of expression of the JAK2 mutation has a bearing on the development of a particular disease (22, 23).
As JAK2 mutation analysis has been established as an integral part of the assessment of patients with suspected myeloproliferative neoplasms (11), all those suspected of having these disorders in the Bergen Hospital Trust between the period February 2006 and February 2012 should have undergone this analysis.
It is striking that as many as 25 % of those with polycythaemia vera were mutation-negative, as this was inconsistent with findings in the international literature, where < 10 % was reported (20, 24). It is unlikely that the discrepancy is due to the analytical method, errors in previous papers or an epidemiology peculiar to Norway. A more likely explanation is a certain amount of overdiagnosis of polycythaemia vera, and that patients with other types of polycythaemia were incorrectly given this diagnosis.
Polycythaemia is a collective designation for disorders with elevated haematocrit, and a distinction is made between absolute and relative polycythaemias (25). In absolute polycythaemia, the total erythrocyte volume is pathologically high, as in polycythaemia vera, while in relative polycythaemias the erythrocyte volume is normal, but haematocrit is still elevated. Secondary polycythaemias are absolute polycythaemias that are often due to hypoxia related to underlying heart and lung disease. Relative polycythaemia is associated with smoking, and heavy smoking may be a cause of secondary polycythaemia (25).
The fact that there are almost twice as many smokers among those with JAK2 mutation-negative polycythaemia vera (38 % compared with 68 %) and a lower degree of leuko- or thrombocytosis in the JAK2 mutation-negative group provides support for the overdiagnosis theory. Patients with polycythaemia vera also often have a certain degree of thrombocytosis and leukocytosis, in contrast to those with other types of polycythaemia (24). On the other hand, those who are positive for the JAK2 exon 12 mutation often have isolated erythrocytosis (18, 26).
As further support, the PCR analyses performed in the initial period (2006 – 2008) had a higher detection threshold for the JAK2 mutation (17), which may have led to some patients with a low allele burden not being classified as JAK2 mutation-positive up to 2008. Other limitations implicit in the study are that the diagnosis applied is based on the judgement of the doctor providing treatment and is not tested further.
Previous research found a higher haemoglobin level, lower erythropoietin level and higher leukocytes for JAK2 mutation-positive patients than for CALR-positive patients with essential thrombocytosis (27). MPL and CALR mutations were not investigated in our patient cohort, but we assume that a large proportion of the JAK2 mutation-negative patients with essential thrombocytosis or primary myelofibrosis would test positive for these markers. Our data show significantly elevated levels of haemoglobin, haematocrit and leukocytes in the JAK2 mutation-positive patient cohort. This is consistent with the belief that the JAK2V617F mutation is related to a more aggressive subgroup of essential thrombocytosis than other mutations (28).
Since 2005, the JAK2 mutation has proved to be an important marker in the diagnosis of myeloproliferative neoplasms. The previous WHO diagnostic criteria did not include MPL or CALR mutations (12), but these are now incorporated in the new WHO classification (24, 29) and implemented in the diagnostic criteria in the Norwegian national action programme with guidelines for the diagnosis, treatment and follow-up of malignant blood diseases (30). Monitoring of the JAK2 mutation allele burden may also be indicated after an allogeneic bone marrow graft to treat primary myelofibrosis, and in the future may also play a part by identifying patients with a higher risk of relapse (4, 31).
JAK2V617F analyses together with other mutation analyses – for JAK2 exon 12, MPL and CALR – are central markers in the assessment of patients suspected of having myeloproliferative neoplasms. Our study has shown that there has probably been overdiagnosis of polycythaemia vera, with the result that not all those who have previously received the diagnosis would have met the present criteria. JAK2 mutation-positive myeloproliferative neoplasms have clinical features that distinguish them from mutation-negative, and future risk classification and treatment algorithms may take account of this.