Abstract 3093: Genomic characteristics of myeloproliferative neoplasms in patients exposed to ionizing radiation following the Chernobyl nuclear accident
Authors: Poluben Larysa , Puligandla Maneka , Neuberg Donna , Bryke Christine R. , Hsu Nancy , Klymenko Sergiy , Mishcheniuk Olga , Shumeiko Oleksandr , Balk Steven , Yuan Xin , Voznesensky Olga , Pihan German , Adam Miriam , Fraenkel Ernest , Fraenkel Paula G. 
Published: August 2018

Abstract
Philadelphia-chromosome negative chronic myeloproliferative neoplasms (MPNs) are a unique group of hematological malignancies including Polycytemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF) characterized by impaired function and structure of bone marrow. MPN driver mutations are usually found in Janus Kinase 2 (JAK2), Thrombopoietin Receptor (MPL) and Calreticulin (CALR) genes, however, 10-15% of MPN cases are triple negative (TN) for these mutations. A previous study showed a lower rate of JAK2 V617F mutations in PMF patients exposed to sublethal doses of ionizing radiation (IR) from the Chernobyl accident in Ukraine. We hypothesized a lower rate of the usual driver mutations in IR-exposed MPN patients. To examine whether there are distinct driver mutations, 281 Ukrainian IR-exposed and unexposed MPN patients, were enrolled in the study. Their records were reviewed for classification by the WHO 2016 MPN criteria. Genomic DNA was obtained from the peripheral blood leukocytes of 281 MPN patients to identify JAK2 V617F, MPL W515, and type 1- and 2-like CALR mutations by allele-specific PCR, Sanger Sequencing and RT-PCR, respectively. Copy number alterations and copy-neutral loss of heterozygosity (cnLOH) were assessed in 30 PMF patients by high-density Affymetrix CytoScan HD oligo-SNP microarray platform. Whole exome sequencing was used to identify additional genetic variants in these 30 PMF patients. Statistical significance for categorical variables and continuous variables were evaluated by Fisher's exact test and Wilcoxon's rank sum test using Statistical Analysis R, version 3.4.2. Clinical features of exposed and unexposed MPN patients were similar. More PMF IR-exposed patients were transfusion dependent (32.4%) than PMF unexposed patients (14.1%) (p = 0.04). JAK2 V617F was detected in 58% of IR-exposed and in 74% of unexposed MPN patients (p = 0.007). JAK2 V617F was also less frequent in IR-exposed PV patients, but not statistically significant. Type 1-like CALR mutation was detected in 12% of exposed and 3% of unexposed patients (p = 0.033). Overall, exposed patients were TN in 28% of IR-patients versus 16% of unexposed patients (p = 0.027). Among other genetic variants, ATM S1691R mutation with cnLOH at 11q22.3 was identified in one TN IR-exposed PMF patient. Previously the mutation was reported, but not in MPN patients. Missense mutations in EZH2 at 7q36.1 and SUZ12 at 17q11.2 with copy number loss were also identified in TN IR-exposed PMF patients. Our results confirm a lower rate of JAK2 V617F and higher rate of TN cases among IR-exposed MPN patients versus unexposed. We also demonstrated a higher frequency of type 1-like CALR mutation in IR-exposed MPN patients and new potential MPN driver mutations. Thus, IR-exposed MPN patients represent a disease group with distinct genomic characteristics worthy of further study.
Citation Format: Larysa Poluben, Maneka Puligandla, Donna Neuberg, Christine R. Bryke, Nancy Hsu, Sergiy Klymenko, Olga Mishcheniuk, Oleksandr Shumeiko, Steven Balk, Xin Yuan, Olga Voznesensky, German Pihan, Miriam Adam, Ernest Fraenkel, Paula G. Fraenkel. Genomic characteristics of myeloproliferative neoplasms in patients exposed to ionizing radiation following the Chernobyl nuclear accident [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3093.