HFEC282Y Mutation as a Genetic Modifier Influencing Disease Susceptibility for Chronic Myeloproliferative Disease

Abstract

Iron metabolism has been implicated in carcinogenesis and several studies assessed the potential role of genetic variants of proteins involved in iron metabolism (HFE C282Y, TFR S142G) in different malignancies. Few reports addressed this issue with relation to chronic myeloproliferative disorders (CMPD). The aims of our study were (a) to examine the potential associations of CMPD development with genetic modifiers of iron metabolism in a large cohort of CMPD patients; (b) to examine associations of genetic variants of proteins involved in iron metabolism; and acquired JAK2 V617F mutation with clinical characteristics of CMPD. HFE C282Y was genotyped in 328 CMPD patients and 996 blood donors as controls, HFE H63D, and TFR S142G were tested in CMPD patients and 171 first time blood donors. JAK2 V617F mutation was tested in CMPD patients and in 122 repeated blood donors. Decreased C282Y allele frequency (allele frequency F 95% confidence interval) was found in the CMPD group (1.8% F 1.0%) compared with controls (3.4% F 0.8%; P = 0.048). TFR S142G allele frequency was reduced among V617F-negative CMPD patients (34.8% F7.6%) compared with controls (47.8% F 5.4%; P = 0.02). The frequency of JAK2 V617F was 75.9% (249 of 328) in the CMPD group. At presentation, elevated hemoglobin levels were found in V617F-positive patients compared with V617F-negative counterparts (P < 0.000). Vascular complications (26.6% versus 15.2%; P = 0.039) as well as female gender (57.4% versus 41.8%; P = 0.019) were more common in V617F-positive patients. We found that HFE C282Y might be associated with a protective role against CMPD. Because chronic iron deficiency or latent anemia may trigger disease susceptibility for CMPD, HFE C282Y positivity may be a genetic factor influencing this effect. (Cancer Epidemiol Biomarkers Prev 2009;18(3):929 -34)

Analysis of phenotype and outcome in essential thrombocythemia with CALR or JAK2 mutations

“…CALR mutant patients were younger than JAK2 V617F-positive ones (P<0.001), consistent with previous studies on JAK2 V617F-positive versus JAK2 V617F-negative myeloproliferative neoplasms. 19,20 Also in agreement with previously published data, the CALR mutation-positive group had more males (56.8 %) compared to the JAK2 V617F-positive group (39.2%). 9,12,13 Patients with a CALR mutation also had higher platelet counts (mean ± SD: 989.8±371.3x10 Table 1).…”

Distinct clinical characteristics of myeloproliferative neoplasms with calreticulin mutations

“…In our previous study comparing the clinical characteristics of JAK2 mut and JAK2 neg MPN patients (n=328), 19 we already noted a female predominance, older age at presentation, higher hemoglobin values and a higher incidence of coagulation complications (thrombotic and hemorrhagic) in JAK2 V617F-positive MPN patients versus V617F-negative counterparts (including CALR mut patients). The identification of the CALR mutation allowed a more straight forward comparison of MPN patients with a homogeneous genetic background.…”

“…19,20 According to World Health Organization 2008 criteria, 215 patients had JAK2 V617F positive PV, 289 had ET and 99 had PMF. Laboratory parameters and clinical features at the time of diagnosis were collected retrospectively.…”

Iron homeostasis governs erythroid phenotype in Polycythemia Vera

“…We hypothesise that PV patients with HFE mutations have relatively suppressed hepcidin, which supports iron availability for erythropoiesis, increasing the likelihood of clinical presentation and diagnosis of PV. Previous small studies have examined the incidence and effects of HFE C282Y mutations in PV and have not observed associations 55, 56 . However, our study was able to take advantage of the large UK Biobank dataset and utilise an unbiased approach to establish the role of HFE in PV diagnosis.…”