Persistent infection with one or more highly oncogenic human papillomaviruses (HPVs) or high-risk-HPV (HR-HPV) is necessary but not a sufficient aetiological agent for the development of cervical neoplasia. A number of viral, host, environmental and behavioural factors are suggested to be associated with the progression of cervical disorder. This study aimed to evaluate the impact of environmental and behavioural cofactors on the development of cervical disorders in HR-HPV-infected women in Serbia. A total of 541 women have been tested by PCR for the presence of HPV on the cervix. HPV genotypes were determined by direct DNA sequencing. Women identified as HR-HPV-positive were further classified into four subgroups according to their cytological status. All relevant information about demographical and behavioural factors was obtained by interviewer-based questionnaire. A number of analytical and descriptive statistical methods were used for processing the data. The cofactors found to be of significance for the progression of cervical disease were older age, body mass index >25, lower educational level, long-term smoking, previous genital infections and cervical interventions. On the other hand, condom use was found to have a protective role. Information about these cofactors might be very important for the development of more efficient cancer prevention programmes and promotion of anti-HPV vaccination.

Both therapeutic options are associated with an activation of thrombogenic and fibrinolytic markers within 3 months of use. Tibolone appears to produce a better balance between thrombogenesis and fibrinolysis. Since our results show a lower incidence of thrombotic events, further studies are required.

Cervical cancer highly correlates with infection caused by highly oncogenic types of human papillomavirus (high risk HPV, HR HPV), which is one of the most common sexually transmitted pathogens and is a key factor in the development of cervical disease. However, malignant transformation of cells and tumor development are multifactorial and result from the interaction of a large number of factors such as virus genotype and its oncogenic potential, the state of the infected cells, the immune response of the host, as well as many cofactors such as smoking, oral contraceptives, multiparity, early beginning of sexual life, promiscuity, poor socio-economic conditions, poor diet, etc. Recently, an increasing number of studies have focused on examining the role of genetic basis of the pathogenesis and evolution of HR HPV cervical disease. It is known that genes polymorphisms that encode proteins involved in the functioning of Th1 and Th17 cell response may be associated with better or worse prognosis of cervical disease in women with persistent HR HPV infection. Therefore, the single nucleotide polymorphisms (SNP) of the genes encoding TNF, IFN-γ and IL-12 can be considered as putative biomarkers that may have predictive value for the development of the HR HPV cervical carcinoma.Key words: cervical cancer, HR HPV, gene polymorphism, TNF, IFN-γ and IL-12 Sažetak Karcinom grlića materice visoko korelira sa infekcijom uzrokovanom visoko onkogenim tipovima humanog papiloma virusa (engl. high risk HPV, HR HPV), koji je jedan od najčešće seksualno prenosivih patogena i ključni faktor u nastanku cervikalnog tumora. Ipak, maligna transformacija ćelija i nastanak tumora su multifaktorijalni i rezultat su interakcije velikog broja činilaca kao što su: genotip virusa i njegov onkogeni potencijal, stanje inficirane ćelije, imunskog odgovora domaćina, ali i brojnih kofaktora kao što su pušenje, oralni kontraceptivi, multiparitet, rano stupanje u seksualne odnose, promiskuitet, loši socioekonomski uslovi, ishrana i dr. U novije vreme sve veći broj istraživanja usmeren je na ispitivanje uloge genetske osnove u patogenezi i evoluciji HR HPV cervikalne bolesti. Poznato je da polimorfizmi određenih gena koji kodiraju proteine uključene u funkcionisanje Th1 i Th17 ćelijskog odgovora mogu biti povezani sa boljom ili lošijom prognozom cervikalne bolesti kod žena sa perzistentnom HR HPV infekcijom. Stoga se polimorfizmi pojedinačnih nukleotida (SNP) gena za TNF, IFN-γ i IL-12 mogu smatrati biomarkerima koji mogu da imaju prediktivnu ulogu za nastanak HR HPV karcinoma grlića materice.Ključne reči: karcinom grlića materice, genski polimorfizmi, TNF, IFN-γ i IL-12

Gene polymorphisms result from evolutionary processes representing mutations that survive in the population with a frequency higher than 1%. The most investigated type of gene polymorphisms are single nucleotide polymorphisms (SNPs). The SNPs of IL-12B (rs 3212227) A/C among a population of kidney graft CMV-seropositive recipients have an impact on a clinical events in cytomegalovirus (CMV) disease. Constitutive -308 G/A TNF-? polymorphism (rs1800629) is related to the susceptibility of HR-HPV-associated cervical dysplasia and cancer. SNP located 3 kb upstream of the IL- 28B gene (rs12979860) seems to be the strongest host genetic predictor of sustained virologic response (SVR) in hepatitis C genotype 1 patients. It is very important to identify viral and host genetic markers that may facilitate the risk of developing viral disease or some viral-associated cancers. In addition, these markers could be useful in the choice of effective treatments and preventive strategies against virally induced infection. [Projekat Ministarstva nauke Republike Srbije, br. 175073 i br. 175038]