The online version of this article has a Supplementary Appendix. CN and HSB contributed JAK2 V617F is present in the majority of patients with myeloproliferative cancer; however, its prevalence and clinical significance in the general population is unknown. We screened for presence of the mutation in 10,507 participants from the Copenhagen City Heart Study with up to 17.6 years of follow up. Prevalence of the mutation was 0.2% (n=18). All 18 mutation positives died during follow up corresponding to a multifactorially adjusted hazard ratio for early death of 3.0 (95%CI:1.9-4.9). Corresponding hazard ratios for men versus women and 1-year age increases were 1.4 (1.1-1.9) and 1.1 (1.1-1.1). Multifactorially adjusted hazard ratios for any cancer, hematologic cancer and myeloproliferative cancer were 3.7 (1.7-8.0), 58 (13-261) and 161 (12-2,197), respectively. Corresponding hazard ratios were 1.2 (0.8-2.0), 2.3 (0.2-25), 1.3 (0.3-5.4) for men versus women, and 1.0 (1.0-1.1), 1.1 (0.9-1.2), 0.9 (0.8-1.1) for 1-year age increases. In the general population, JAK2 V617F is associated with increased morbidity and mortality, although only present in 18 of 10,507 (0.2%).

SummaryThe JAK2 V617F somatic mutation is present in the majority of patients with myeloproliferative cancer (polycythaemia vera, essential thrombocytosis, and primary myelofibrosis). However, the diagnostic value of the JAK2 V617F somatic mutation for myeloproliferative cancer in the general population is unknown. We examined this question in 49 488 individuals from the Copenhagen General Population Study. We also examined the association between JAK2 V617F somatic mutation, rs10974944 germline genotype, haematological phenotype, any cancer, haematological cancer, myeloproliferative cancer, ischaemic heart disease, and venous thromboembolism. The JAK2 V617F somatic mutation was present in 0Á1% (n = 68), increasing across rs10974944 germline genotypes (P-trend = 0Á001). JAK2 V617F somatic mutation positives versus negatives had higher erythrocyte (P = 2 9 10 À5 ), thrombocyte (P = 2 9 10 À16 ), and leucocyte (P = 4 9 10 À9 ) counts, and had 2Á7-/2Á5-fold risk of cancer (prevalent/incident), 44-/28-fold risk of haematological cancer, 221-/97-fold risk of myeloproliferative cancer, 2Á2-/1Á2-fold risk of ischaemic heart disease, and 3Á1-/1Á0-fold risk of venous thromboembolism. By combining conventional haematological parameters with a test for the JAK2 V617F somatic mutation, myeloproliferative cancer could be identified or ruled out with a sensitivity of 47-100% and a specificity of 98-100%. In conclusion, in the general population the JAK2 V617F somatic mutation has a high diagnostic value for myeloproliferative cancer when combined with conventional haematological parameters.

JAK2V617F mutation. Of these, 52 were still alive and were reinvited for testing in 2012; 48 of them were re-examined ( Figure 1).