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Systems Medicine Conference in Slovenia

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The influence of the polymorphisms of the DNA repair mechanisms on the risk of malignant mesothelioma

Nika Kotnik, dr.med1,prof. dr. Alenka Franko, dr.med2,prof. dr. Vita Dolžan, dr.med3,asist. dr. Katja Goričar3,prof. dr Metoda Dodič Fikfak,

1Institute of Oncology, Ljubljana, Slovenia,2Institute of Occupational, Traffic and Sports Medicine, Ljubljana, Slovenia,3Pharmacogenetics Laboratory, Institute of Biochemistry, Ljubljana, Slovenia

Introduction The association between exposure to asbestos and malignant mesothelioma (MM) has been clearly proved. Asbestos stimulates the production of reactive oxidative species (ROS). Our previous studies have shown that genetic polymorphisms in mangan superoxide dismutase (SOD2) and catalase (CAT), which remove ROS, represent a high risk for asbestosis among workers occupationally exposed to asbestos. NAD(P)H:quinone oxidoreductase 1 (NQO1) protects proteins and DNA from oxidative damage. NQO1 Proline (Pro)187Serine (Ser) polymorphism changes its enzyme activity diminishing the defense against ROS damage to DNA. Human 8-oxogvanine glycosilase 1 (hOGG1) catalyses DNA damage repair by base excision, preventing mutations. Our previous studies have shown that hOGG1 Ser326Cysteine (Cys) polymorphism reduces DNA repair ability in young, healthy population. The aim of our study is to investigate whether functional polymorphisms in NQO1, CAT, SOD2 and hOGG1 genes influence the risk of MM, to investigate the interactions between polymorphisms of the genes which remove ROS (NQO1, SOD2 in CAT) and hOGG1, which removes oxidized guanine from DNA molecules and to investigate the interactions between asbestos exposure and polymorphisms mentioned above. Results We performed a case-control study. Cases were patients with MM treated at the Institute of Oncology Ljubljana between March 2007 and December 2013. Control subjects were workers who were occupationally exposed to asbestos and did not have any asbestos-related disease. Real-time PCR based methods were used for the analysis of NQO1, CAT, SOD2 and hOGG1 polymorphisms. Logistic regression analysis was used to assess the association between MM and different variables. The risk for MM was increased by smoking (OR = 9.3; 95% CI = 4.828–17.977; p < 0.005) and slightly by age (OR = 1.1; 95% CI = 1.075–1.140; p < 0.005). Gender did not exert a statistical influence on the MM risk. Middle and high asbestos exposure represented 7-times higher risk for MM (OR = 7.049; 95% CI = 3.594–13.826; p < 0.001) than low levels of exposure. NQO1 rs1800566 was the only polymorphism significantly associated with the increased risk for MM (OR = 1.731; 95% CI = 1.017–2.964; p = 0.043). The carriers of at least one polymorphic allele increased the risk for MM. An important interaction was found between CAT rs1001179 and hOGG1 rs1052133. Conclusions. Our results showed that polymorphism NQO1 may be associated with an increased risk of MM. We also showed that interactions between polymorphic CAT in hOGG genes influence the risk of MM although there was no independent association between either CAT or hOGG polymorphism and mesothelioma risk. The results of this and future studies could significantly add to our understanding of pathogenesis of MM, enable its prevention, contribute to earlier diagnosis and identification of new targets for a more effective treatment of this aggressive cancer.

2006 - University of Ljubljana, Faculty of Medicine, Center for Functional Genomics and Bio-chips.