1. The influence of folate pathway polymorphisms on high-dose methotrexaterelated toxicity and survival in children with non-Hodgkin malignant lymphomaNina Erčulj, Barbara Faganel Kotnik, Maruša Debeljak, Janez Jazbec, Vita Dolžan, 2014, original scientific article Abstract: Background. We evaluated the influence of folate pathway polymorphisms on high-dose methotrexate (HD-MTX) related toxicity in paediatric patients with T-cell non-Hodgkin lymphoma (NHL). Patients and methods. In total, 30 NHL patients were genotyped for selected folate pathway polymorphisms. Results. Carriers of at least one MTHFR 677T allele had significantly higher MTX area under the time-concentration curve levels at third MTX cycle (P = 0.003). These patients were also at higher odds of leucopoenia (P = 0.006) or thrombocytopenia (P = 0.041) and had higher number of different HD-MTX-related toxicity (P = 0.035) compared to patients with wild-type genotype. Conclusions. Our results suggest an important role of MTHFR 677C>T polymorphism in the development of HD-MTXrelated toxicity in children with NHL.
Keywords: childhood, non-Hodgkin lymphoma, polymorphism
Published in DiRROS: 16.04.2024; Views: 37; Downloads: 20
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2. Polymorphisms in folate pathway and pemetrexed treatment outcome in patients with malignant pleural mesotheliomaKatja Goričar, Viljem Kovač, Vita Dolžan, 2014, original scientific article Abstract: Introduction. A combination of pemetrexed and cisplatin has been shown to improve the outcome in patients with malignant pleural mesothelioma (MPM), however, there is a great heterogeneity in treatment response among patients. The aim of our study was to evaluate the influence of polymorphisms in folate pathway and transporter genes on pemetrexed treatment outcome in Slovenian patients with MPM. Methods. MPM patients treated with pemetrexed in the course of a prospective randomized clinical trial were genotyped for nineteen polymorphisms in five genes of folate pathway and six transporter genes. Logistic regression was used to assess the influence of polymorphisms on treatment efficacy and toxicity, while Cox regression was used to determine their influence on progression-free and overall survival. Results. Patients with at least one polymorphic MTHFD 1 rs2236225 allele had a significantly lower response rate (p = 0.005: odds ratio [OR] = 0.12; 95% confidence interval [CI] = 0.03-0.54) and shorter progression-free survival (p = 0.032: hazard ratio [HR) = 3.10: 95% CI = 1.10-8.74) than non-carriers. Polymorphisms in transporter genes did not influence survival; however, several were associated with toxicity. Liver toxicity was significantly lower in carriers of polymorphic ABCC2 rs2273697 (p = 0.028: OR = 0.23; 95% CI = 0.06-0.85). SLC01Bl rs4149056 (p = 0.028: OR = 0.23: 95% CI = 0.06-0.85) and rsll045879 (p = 0.014: OR = 0.18; 95% CI = 0.05-0.71) alleles compared to non-carriers, as well as in patients with SLC01Bl GCAC haplotype (p = 0.048; OR = 0.17; 95% CI = 0.03-0.98). Gastrointestinal toxicity was much more common in patients with polymorphic ABCC2 rs717620 allele (p = 0.004: OR = 10.67; 95% CI = 2.15-52.85) and ABCC2 CAG haplotype (p = 0.006: OR = 5.67: 95% CI = 1.64-19.66). Conclusions. MTHFD 1 polymorphism affected treatment response and survival. while polymorphisms in ABCC2 and SLC01Bl transporter genes influenced the risk for toxicity. These polymorphisms could serve as potential markers of pemetrexed treatment outcome in patients with MPM.
Keywords: polymorphisms, folate pathway, mesothelioma
Published in DiRROS: 16.04.2024; Views: 32; Downloads: 7
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3. Genetic polymorphisms in homologous recombination repair genes in healthy Slovenian population and their influence on DNA damageKatja Goričar, Nina Erčulj, Maja Zadel, Vita Dolžan, 2012, original scientific article Abstract: Background. Homologous recombination (HR) repair is an important mechanism involved in repairing double-strand breaks in DNA and for maintaining genomic stability. Polymorphisms in genes coding for enzymes involved in this pathway may influence the ca pa city for DNA repair. The aim of this study was to select tag single nucleotide polymorphisms (SNPs) in specific genes involved in HR repair, to determine their allele frequencies in a healthy Slovenian population and their influence on DNA damage detected with comet assay. Materials and methods. In total 373 individuals were genotyped for nine tag SNPs in three genes: XRCC3 722C>T, XRCC3 -316A>G, RAD51 -98G>C, RAD51 -61G>T, RAD51 1 522T>G, NBS1 553G>C, NBS1 1197A>G, NBS1 37117C>T and NBS1 3474A>C using competitive allele-specific amplification (KASPar assay). Comet assay was performed in a subgroup of 26 individuals to determine the influence of selected SNPs on DNA damage. Results. We observed that age significantly affected genotype frequencies distribution of XRCC3 -316A>G (P = 0.039) in healthy male blood donors. XRCC3 722C>T (P = 0.005), RAD51 -61G>T IP = 0.023) and NBS1 553G>C (P = 0.008) had a statistically significant influence on DNA damage. Conclusions. XRCC3 722C> T, RAD51 -61 G> T and NBS 1 553G>C polymorphisms significantly affect the repa ir of damaged DNA and may be of clinical importance as they are common in Slovenian population.
Published in DiRROS: 22.03.2024; Views: 68; Downloads: 21
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4. Genetic polymorphisms of xenobiotic metabolizing enzymes in human colorectal cancerVita Dolžan, Metka Ravnik-Glavač, Katja Breskvar, 1998, published scientific conference contribution Abstract: It was proposed that both hereaditary and environmental factors contribute to the development of colorectal cancer (CRC). Carcinogenic polycyclic aromatic hydrocarbons (PAHs) from food or tobacco smoke can form DNA adducts and thus initiate carcinogenesis after metabolic activation via cytochrome P4501A1 (CYP1A1). Intermediate metabolites are detoxified by conjugation with glutathione S-transferases. Our aim was to look for inherited metabolic suceptibility to CRC. We used PCR-based genotyping approach to determine the frequencies of polymorphic alleles of two cytochromes P450 (CYP2D6 and CYP1A1)and two glutathione S-transferases (GSTM1 and GSTT1) in DNA samples from 31 sporadic, 25 familial CRC cases and 73 healthy controls. The difference in frequencies of poor metabolisers due to CYP2D6 gene polymorphismwas close to the limit of statistical significance between sporadiCRC and healthy control group (lambda 2=5.52, m=2, p=0.06) despite the small sample size. The frequencies of either CYP1A1 MspI, GST M1 or GST T1 genotypes were not significantly different in both CRC cases and in controls. Although our study suggests some difference in metabolic susceptibility between sporadic and familial CRC, further studies are needed to investigate the combined effect of polymorphic genes involved in carcinogen metabolism in a larger group of patients with defined exposure to dietary carcinogens and smoking.
Published in DiRROS: 19.01.2024; Views: 161; Downloads: 37
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5. Novejši pristopi k zdravljenju mezotelioma plevreDanijela Štrbac, Vita Dolžan, 2023, published scientific conference contribution Abstract: Pleuralni mezoteliom je redek tumor katerega zdravljenje kljub sodobnemu pristopu z imunoterapijo ne prinaša želenih rezultatov, zaradi slabše imunološke odzivnosti tumorja in njegove genetske raznolikosti. Novejši pristopi k zdravljenju se osredotočajo predvsem na tumorske vakcine, CA R-T terapijo in gensko terapijo. Raziskovanje miRNA pa odkriva tudi nove biološke označevalce pri mezoteliomu.
Keywords: mezoteliom, obsevanje, onkološko zdravljenje
Published in DiRROS: 19.06.2023; Views: 353; Downloads: 137
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6. Dinamika dolžine telomerov v levkocitih po zdravljenju z obsevanjem pri raku dojkTanja Marinko, Sara Redenšek Trampuž, Ana Trstenjak, Vita Dolžan, Katarina Trebušak Podkrajšek, Katja Goričar, 2023, published scientific conference contribution Abstract: Obsevanje je del standardnega zdravljenja bolnic z rakom dojk. Odgovor na zdravljenje z obsevanjem je pri vsakem posamezniku drugačen in je odvisen tudi od genetskih dejavnikov. Eden od novejših genetskih označevalcev odgovora na obsevanje je dolžina telomerov. Telomeri ščitijo kromosome pred krajšanjem in vzdržujejo genomsko stabilnost. Rezultati naše raziskave kažejo, da se dinamika spreminjanja dolžine telomerov takoj po zdravljenju z obsevanjem in v šestih mesecih po obsevanju pri bolnicah z neinvazivnim rakom dojk spreminja in bi lahko služila kot biološki označevalec odgovora na obsevanje. Molekularni mehanizmi, povezani s tem procesom, ostajajo zaenkrat večinoma neraziskani.
Keywords: rak dojk, obsevanje, onkološko zdravljenje
Published in DiRROS: 16.06.2023; Views: 337; Downloads: 130
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