MOLECULAR GENETIC ABNORMALITIES IN THE GENOME OF PATIENTS WITH Ph-NEGATIVE MYELOPROLIFERATIVE NEOPLASIA AFFECTED BY IONIZING RADIATION AS A RESULT OF THE CHORNOBYL NUCLEAR ACCIDENT. / MOLEKULIaRNO-GENETYChNI ANOMALIÏ U GENOMI KhVORYKh NA Rh-NEGATYVNI MIIeLOPROLIFERATYVNI NEOPLAZIÏ, IaKI ZAZNALY DIÏ IONIZUIuChOÏ RADIATsIÏ VNASLIDOK AVARIÏ NA ChAES.

OBJECTIVE: to determine the frequency of major somatic mutations in the JAK2, MPL and CALR genes in the genomeof patients with Ph-negative myeloproliferative neoplasms that occur in individuals who have been exposed to ionizing radiation as a result of the Chornobyl accident. MATERIALS AND METHODS: Molecular genetic analysis of genomic DNA samples isolated from blood was performed in90 patients with Ph-negative myeloproliferative neoplasia (MPN) with a history of radiation exposure and 191patients with spontaneous MPN utilizing allele-specific polymerase chain reaction (PCR). RESULTS: The presence of major mutations in the genes JAK2, CALR and MPL was revealed in patients with MPN witha history of radiation exposure with a frequency 58.9 % (53 of 90), 12.2 % (11 of 90), and 0 % respectively, and without exposure with frequency 75.4 % (144 of 191), 3.1 % (6 out of 191) and 1.6 % (3 out of 191) respectively.Mutations JAK2 V617F in patients with spontaneous MPN were observed in each clinical form: polycythemia vera (PV),essential thrombocythemia (ET) and primary myelofibrosis (PMF). CALR mutations were detected exclusively inpatients with PMF and ET, significantly more often in groups with a radiation exposure history (18.9 % and 33.3 %,vs. 4.2 % and 6.5 %) than without one. At the same time, the occurence of MPL mutations was determined only inpatients with spontaneous MPN in 1.6 % of casees. Triple negative mutation status of genes JAK2, MPL and CALR prevailed in the group of patients with MPN with a history of radiation exposure and was 27.8 %, against 16.2 % inpatients without radiation exposure (p = 0.05). CONCLUSIONS: Genomic research of patients with Ph-negative MPN revealed features of molecular genetic damage inthose patients who were exposed to IR as a result of the Chornobyl accident and those with spontaneous MPN. Thedata obtained by determining of JAK2, MPL and CALR genes mutational status in the genome of patients with MPN isnecessary to expand the understanding of the mechanism of leukogenesis, especially caused by radiation.

MUTATIONS OF GENES BRCA1 AND BRCA2 IN WOMEN WITH OVARIAN CANCER EXPOSED TO FACTORS OF CHORNOBYL NUCLEAR ACCIDENT. / MUTATsIÏ U GENAKh BRCA1 TA BRCA2 U ZhINOK, KhVORYKh NA RAK IaIeChNYKIV, IaKI ZAZNALY VPLYVU ChYNNYKIV ChORNOBYL'S'KOÏ KATASTROFY.

OBJECTIVE: to determine a frequency of germline mutations 185delAG, 5382insC in BRCA1 gene and 6174delT in BRCA2 gene in Ukrainian patients with OC including women who were exposed to the factors of Chornobyl nuclear accident. MATERIAL AND METHODS: In the study we enrolled 306 OC patients of different age who were tested for the presence of the major BRCA1 and BRCA2 gene mutations using allele specific multiplex polymerase chain reaction. RESULTS: The mutation frequency in patients exposed to IR with OC (main group) was 5.3 % (2 from 38). Among unexposed patients (control group) 11,2 % (30 from 268) of cases with mutation were identified. However, the dif- ference between the groups was not significant (p = 0.39). It was shown that the BRCA1/2 mutations frequency in the patient of both groups was 10,4 % (32 from 306). The mutation BRCA1 5382insC was positive in 87.5 % (28 from 32) of cases, nevertheless nobody was identified with the allelic variant BRCA2 6174delT among both groups. There was a tendency toward an earlier age of the OC manifestation in the patients exposed to IR due to Chornobyl nuclear accident compared to BRCA-positive women of the control group (р = 0.06). When comparing BRCA-positive and BRCA-negative patients with OC of the main group, there was a statistical significance regarding the earlier age of the disease manifestation in the patients with mutations (р = 0.04). However, such difference was not observed in the control group (р = 0.22). CONCLUSIONS: The frequency of the mutations in exposed to IR and unexposed patients with OC does not differ and depends on a spectrum of studied BRCA1/2 gene mutations, level of DNA amplification and sample number. The allel- ic variant BRCA1 5382insC is dominant and accounts for 87.5 % of the total number of the found mutations. Due to the radiation factor the OC in the BRCA1-positive individuals is realized at the earlier age than in patients negative for these mutations. The incidence of OC after the Chornobyl accident was observed 27-38 years later in a cohort of women who were from 4 to 40 years old at the moment of the nuclear explosion.

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

AIM: To examine frequencies and spectrum of genomic alterations in Ukrainian patients diagnosed with primary myelofibrosis (PMF). MATERIALS AND METHODS: We enrolled 30 Ukrainian patients diagnosed with PMF who were previously tested for usual mutations in mye-loproliferative neoplasms driver genes (JAK2, MPL and CALR). Genomic DNA samples were obtained from peripheral blood leukocytes of these patients. Copy number alterations and copy-neutral loss of heterozygosity (cnLOH) were assessed using a high-density CytoScan HD microarray platform. Statistical significance was evaluated by the Fisher exact test. RESULTS: We identified frequent genomic alterations, but no significant difference in the rates of copy-number loss, copy-number gain, cnLOH, or multiple genomic alterations were found in the groups of PMF patients that were positive for one of the usual mutations in driver genes or negative for such mutations (33.3% and 55.6%, p = 0.4181, 19.0% and 11.1%, p = 1.0000, 61.9% and 44.4%, p = 0.4434, 33.3% and 55.6%, p = 0.4181, respectively). The most frequent alterations were cnLOH at 1p36-1p22, 9p24.3-9p13.3 and 11q12.3-11q25; copy number loss at 7q21-7q36.3 and 13q12.3-13q14.3. Copy number alterations and cnLOH commonly affected the EZH2, LAMB4, CBL, CUX1, ATM, RB1 and TP53 genes, in addition to JAK2, MPL and CALR. CONCLUSION: We demonstrated the spectrum of genomic alterations in the groups of the Ukrainian PMF patients with or without the usual mutations in the specific driver genes. We identified several potential genes, which may be involved in the myeloproliferative neoplasms development and their phenotype modification (EZH2, LAMB4, CBL, CUX1, ATM, RB1 and TP53).

EVALUATION OF BURDENSOME SYMPTOMS IN PATIENTS WITH RADIATION6ASSOCIATED AND SPONTANEOUS MYELOPROILIFERATIVE NEOPLASMS WITH THE USE OF OPTIMIZED SELF-ASSESSMENT MPN-SAF TSS. / OTsINKA OBTIaZhLYVYKh SYMPTOMIV U KhVORYKh NA RADIATsIINO-ASOTsIIOVANI TA SPONTANNI MIIeLOPROLIFERATYVNI NEOPLAZIÏ Z VYKORYSTANNIaM ADAPTOVANOÏ ShKALY SAMOOTsINKY MPN-SAF TSS.

OBJECTIVE: To investigate the intensity of burdensome symptoms using self-assessment MPN-SAF TSS in patientswith radiation-associated and spontaneous myeloproiliferative neoplasms (MPNs). MATERIALS AND METHODS: The study included 89 patients with radiation-associated and spontaneous MPNs, the bur-densome symptoms of MPN were determined using MPN-SAF TSS. RESULTS: The average score for complaints in patients with radiation-associated MPNs was significantly higher thanin patients with spontaneous MPNs - 43.46 and 25.04 points, respectively (p = 0.003). MPN patients classified bysubtypes also showed differences regarding intensity of burdensome MPN symptoms, demonstrating significantlyhigher average score of complaints among primary myelofibrosis patients (35.60), compared to polycythemia vera(29.60) and essential thrombocythemia (18.05) patients, (p = 0.005). Our study did not reveal any influence of theJAK2 V617F mutation on MPN burdensome symptoms intensity in MPN patients. CONCLUSIONS: We demonstrated a higher intensity of the MPN burdensome symptoms determined by the optimizedself-assessment MPN-SAF TSS in patients with radiation-associated, and in primary myelofibrosis patients, indicat-ing increased severity of patient's general conditions at the stage of diagnosis verification. It is advisable to usethe optimized MPN-SAF TSS at the moment of molecular genetic testing during the diagnosis of MPN for selectionor modifying treatment strategies in order to achieve better quality of life for patients.