Browsing by Author "Kovalova, Zhanna"

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    Analysis of possible genetic risk factors contributing to development of childhood acute lymphoblastic leukaemia in the Latvian population
    (2016) Kreile, Madara; Piekuse, Linda; Rots, Dmitrijs; Dobele, Zane; Kovalova, Zhanna; Lace, Baiba; Scientific Laboratory of Molecular Genetics; Onkoloģijas institūts
    Introduction: Childhood acute lymphoblastic leukaemia (ALL) is a complex disease caused by a combination of genetic susceptibility and environmental exposure. Previous genome-wide association studies have reported several single nucleotide polymorphisms (SNPs) associated with the incidence of ALL. Several variations in genes encoding enzymes involved in carcinogenesis are suggested as being associated with an increased risk of ALL development. Material and methods: We enrolled 77 paediatric ALL patients and 122 healthy controls, and in addition parental DNA was also available for 45 probands. SNPs rs10821936 (ARID5B), rs4132601(IKZF1), rs2239633 (CEBPE), rs3731217 (CDKN2A) and rs1800566 (NQO1) and the presence of GSTT1 and GSTM1 null variants were detected. For statistical analysis the hybrid method of two designs 'Haplin' was used as well as linkage disequilibrium for family-based association studies. Results: We identified the SNP rs10821936 in the ARID5B gene as being statistically significantly associated with childhood ALL, especially if the C allele is in a homozygous state, relative risk (RR) 4.65, 95% CI: 2.03-10.6, p = 0.0006. Statistically significant differences were not found in other SNPs. We found risk combinations including all five variations, the strongest association being found in a combination where all five genetic variants are in a homozygous state, CCTTTTTTCC, p = 0.032. Conclusions: The identified SNP rs10821936 could serve as a potential risk marker for childhood ALL development. Further studies in an independent population are needed for verification.
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    Characterization of Pediatric Acute Myeloid Leukemia With t(7;12)(q36;p13)
    (2024-11) Östlund, Anders; Waraky, Ahmed; Staffas, Anna; Sjögren, Helene; De Moerloose, Barbara; Arad-Cohen, Nira; Cheuk, Daniel; Navarro, Jose Maria Fernandez; Jahnukainen, Kirsi; Kaspers, Gertjan J  L; Kovalova, Zhanna; Pasauliene, Ramune; Saks, Kadri; Zeller, Bernward; Norén-Nyström, Ulrika; Hasle, Henrik; Fogelstrand, Linda; Abrahamsson, Jonas; Palmqvist, Lars
    Acute myeloid leukemia (AML) with t(7;12)(q36;p13) is a recurrent translocation in AML in infants or very young children and was recently included in the World Health Organization (WHO) Classification of Hematolymphoid Tumors. AML with t(7;12) is reported to involve MNX1 and ETV6 signaling; however, the mechanism of leukemogenesis is not well understood, and the presence of MNX1::ETV6 fusion transcripts has only been confirmed in approximately 50% of cases. In contrast, high expression of MNX1 has been seen in all investigated cases. In this study, we investigated the clinical as well as biological characteristics of 12 pediatric AML with t(7;12) and performed whole transcriptome (WTS) and whole genome sequencing (WGS) on six of these. There was no significant difference in event-free survival or overall survival of these t(7;12) AML patients compared with other AML in the same age group. Interestingly, WTS identified several fusion transcripts involving ETV6 but not together with MNX1. WGS identified the genomic breakpoints and revealed that a common fusion partner on chromosome 7 was NOM1. Principal component analysis (PCA) of the WTS data showed that all t(7;12) AML cases cluster together, separate from all other pediatric AML subtypes; all cases had high expression of MNX1, MNX1-AS1, and MNX1-AS2. Hence, t(7;12) AML, despite expressing different fusion transcripts and with varying translocation breakpoints, constitutes a phenotypically homogenous subgroup. This underlines that the leukemia-driving event most likely is ectopic expression of MNX1 and that this therefore should be the defining Classifying criteria of this type of AML.
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    Complex and monosomal karyotype are distinct cytogenetic entities with an adverse prognostic impact in paediatric acute myeloid leukaemia. A NOPHO-DBH-AML study
    (2018-11) Bager, Ninna; Juul-Dam, Kristian L.; Sandahl, Julie D.; Abrahamsson, Jonas; Beverloo, Berna; de Bont, Eveline S.J.M.; Ha, Shau Yin; Jahnukainen, Kirsi; Jónsson, Ólafur G.; Kaspers, Gertjan L.; Kovalova, Zhanna; Lausen, Birgitte; De Moerloose, Barbara; Noren-Nyström, Ulrika; Palle, Josefine; Saks, Kadri; Zeller, Bernward; Kjeldsen, Eigil; Hasle, Henrik
    Data on occurrence, genetic characteristics and prognostic impact of complex and monosomal karyotype (CK/MK) in children with acute myeloid leukaemia (AML) are scarce. We studied CK and MK in a large unselected cohort of childhood AML patients diagnosed and treated according to Nordic Society for Paediatric Haematology and Oncology (NOPHO)-AML protocols 1993–2015. In total, 800 patients with de novo AML were included. CK was found in 122 (15%) and MK in 41 (5%) patients. CK and MK patients were young (median age 2·1 and 3·3 years, respectively) and frequently had FAB M7 morphology (24% and 22%, respectively). Refractory disease was more common in MK patients (15% vs. 4%) and stem cell transplantation in first complete remission was more frequent (32% vs. 19%) compared with non-CK/non-MK patients. CK showed no association with refractory disease but was an independent predictor of an inferior event-free survival (EFS; hazard ratio [HR] 1·43, P = 0·03) and overall survival (OS; HR 1·48, P = 0·01). MK was associated with a poor EFS (HR 1·57, P = 0·03) but did not show an inferior OS compared to non-MK patients (HR 1·14, P = 0·62). In a large paediatric cohort, we characterized AML with non-recurrent abnormal karyotype and unravelled the adverse impact of CK and MK on prognosis.
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    Lack of association between polymorphisms in genes MTHFR and MDR1 with risk of childhood acute lymphoblastic leukemia
    (2014) Kreile, Madara; Rots, Dmitrijs; Piekuse, Linda; Cebura, Elizabete; Grutupa, Marika; Kovalova, Zhanna; Lace, Baiba; Rīga Stradiņš University
    Background: Acute lymphoblastic leukemia (ALL) is a complex disease caused by interactions between hazardous exogenous or/and endogenous agents and many mild effect inherited susceptibility mutations. Some of them are known, but their functional roles still requireinvestigation. Age is a recognized risk factor; children with disease onset after the age of ten have worse prognosis, presumably also triggered by inherited factors. Materials and Methods: The MDR1 gene polymorphisms rs1045642, rs2032582 and MTHFR gene polymorphisms rs1801131 and rs1801133 were genotyped in 68 ALL patients in remission and 102 age and gender matched controls; parental DNA samples were also available for 42 probands. Results: No case control association was found between analyzed polymorphisms and a risk of childhood ALL development. Linkage disequilibrium was not observed in a family-based association study either. Only marginal association was observed between genetic marker rs2032582A and later disease onset (p=0.04). Conclusions: Our data suggest that late age of ALL onset could be triggered by mild effect common alleles.
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    Natural clearance of hepatitis C virus in hemophilia patients
    (2008) Simanis, Raimonds; Lejniece, Sandra; Sochnevs, Arturs; Eglite, Jelena; Chernevska, Gunta; Kovalova, Zhanna; Gardovska, Dace; Jeruma, Agita; Kuse, Velga; Viksna, Ludmila; Department of Infectology; Department of Internal Diseases; Klīniskās imunoloģijas un imunoģenētikas starpkatedru laboratorija; Department of Paediatrics
    Objective. The objective of this study was to investigate the prevalence of HCV (hepatitis C virus) infection in hemophilia patients in Latvia and to analyze association between natural clearance of HCV and human leukocyte antigen (HLA) class II genes. Material and methods. From 61 hemophilic patients participating in this study, 38 were adults and 23 were pediatric patients younger than 18 years. To analyze association between HLA class II alleles and natural clearance of HCV, the gene frequency was compared in hemophilia patients group and the control group of 60 healthy subjects, all men. Serum HCV RNA was qualitatively determined and HLA class II alleles were identified by polymerase chain reaction (PCR) method. Results. HCV infection is common among hemophilia patients in Latvia. Antibodies to HCV were found in 45 of 61 (74%) hemophilia patients. In 41% of hemophilia patients (18 of 44), HCV infection resolved spontaneously. Children cleared HCV more frequently than adults (7 of 11 comparing to 11 of 33, respectively; OR=3.50; P<0.05). The frequency difference was found to be statistically significant when comparing HLA alleles distribution in the sample of hemophilia patients who naturally cleared HCV (n=18) and in the control group (n=60) (corresponding frequency of HLA-DRB1*07 allele - 4 (11.11%) and 9 (1.67%); OR=7.38; P<0.05). Conclusions. Natural clearance of HCV infection is frequently found in hemophilia patients in Latvia. Children are more likely to clear virus naturally than adults. There is an association between natural clearance of HCV and HLA allele DRB1*07 in hemophilia patients.