Characteristics of myeloproliferative neoplasms in patients exposed to ionizing radiation following the Chernobyl nuclear accident

Abstract

Myeloproliferative neoplasms (MPNs) driver mutations are usually found in JAK2, MPL and CALR genes, however, 10–15% of cases are triple negative (TN). A previous study showed lower rate of JAK2 V617F in Primary Myelofibrosis (PMF) patients exposed to low doses of ionizing radiation (IR) from Chernobyl accident. To examine distinct driver mutations, we enrolled 281 Ukrainian IR-exposed and unexposed MPN patients. Genomic DNA was obtained from peripheral blood leukocytes. JAK2 V617F, MPL W515, type 1- and 2-like CALR mutations were identified by Sanger Sequencing and RT-PCR. Chromosomal alterations were assessed by oligo-SNP microarray platform. Additional genetic variants were identified by whole exome and targeted sequencing. Statistical significance was evaluated by Fisher’s exact test and Wilcoxon’s rank sum test (R, version 3.4.2). IR-exposed MPN patients exhibited a different genetic profile versus unexposed: lower rate of JAK2 V617F (58.4% vs 75.4%, P = 0.0077), higher rate of type 1-like CALR mutation (12.2% vs 3.1%, P = 0.0056), higher rate of TN cases (27.8% vs 16.2%, P = 0.0366), higher rate of potentially pathogenic sequence variants (mean numbers: 4.8 vs 3.1, P = 0.0242). Furthermore, we identified several potential drivers specific to IR-exposed TN MPN patients: ATM p.S1691R with copy-neutral loss of heterozygosity at 11q; EZH2 p.D659G at 7q and SUZ12 p.V71M at 17q with copy number loss. Thus, IR-exposed MPN patients represent a group with distinct genomic characteristics worthy of further study.

Impact of Host, Lifestyle and Environmental Factors in the Pathogenesis of MPN

“…The study found that ionizing radiation exposed MPN patients display a different genetic profile compared to unexposed patients where the incidence of JAK2 V617F mutation was significantly less in the radiation exposed patients. Other findings included a higher rate of type-1 like CALR mutations and triple negative MPN in the ionizing radiation exposed group versus unexposed patients [ 88 ]. A study by Mele et al, reported that living in tuff houses, a building material containing gamma-emitting radionuclides, increases the risk for ET [ 89 ].…”

Copy number alterations and copy-neutral loss of heterozygosity in Ukrainian patients with primary myelofibrosis

“…Thus, oncogenic microalterations can be studied, in particular, in MPN patients. This increases the search power for identification of potentially involved genes in MPN development (as 10-15% of MPN patients are negative for known mutations of the specific driver genes) [2,[5][6][7].…”

Extramedullary Hematopoiesis of the Liver and Spleen

“…However, it has been observed that patients who test positive for the JAK2 genetic mutation have a higher risk for developing MPNs [52,53]. A low dose of ionizing radiation has been associated with an increased risk of developing MPNs, due to somatic mutations in the JAK2 gene (JAK2 V617F variant) [54]. New data point out that there is an association between environmental exposure and somatic mutations in environment-sensitive genes, such as homozygosity of CYP1A1 rs4646903, CYP1A2, EPHX1 rs2234922, and Tp53 alleles [55].…”