hrvatski

Genetic variability and oncogenic potential of human papillomavirus type 16 in Croatia: Characterization of a novel variant

Cervical cancer is caused by at least 15 high risk Human papillomavirus (HPV) types, of which HPV 16 is found in almost 60% of cases. Therefore, HPV detection and genotyping became an important tool in diagnosis and monitoring of precancerous lesions and cervical cancer. Even though the prevalence of HPV infection is very high in the population, the incidence of cervical cancer is relatively low. One of the potential risk factors for cervical cancerogenesis is the variability of viral genome conferring different level of the oncogenic potential to the same HPV type. The studies presented in this thesis have revealed the importance of the used methodology for HPV genotyping for epidemiological and prospective studies ; the possibility to conduct large scale epidemiological studies of HPV variability by combining the pre-screening with high resolution melting (HRM) method and DNA sequencing of ambiguous meting profiles ; and the presence of a novel HPV 16 variant that is significantly associated with low grade lesions compared to reference variant which has unique mutations within the E1 region. Furthermore, the relative abundance of this variant among HPV 16 positive women in Croatia (around 10%) and probably elsewhere, suggests its importance for identification and management of cervical cancer and its precursors. (Rak vrata maternice uzrokuje barem 15 tipova visokorizičnih humanih papiloma virusa (HPV), od kojih se HPV 16 nalazi u gotovo 60% slučajeva. Stoga su otkrivanje HPV i genotipizacija postali važno sredstvo u dijagnostici i praćenju prekanceroza i raka vrata maternice. Iako je prevalencija HPV infekcija vrlo visoka u populaciji, incidencija raka vrata maternice je relativno niska. Jedan od potencijalnih faktora rizika nastanka raka vrata maternice je varijabilnost virusnog genoma koji doprinosi različitim stupnjevima onkogenog potencijala istog tipa HPV-a. Istraživanja prikazana u ovom radu su otkrila: važnost metodologije koja se koristi za HPV genotipizaciju u epidemiološkim i prospektivnim studijama ; mogućnost za provođenje velikog broja analiza metodom određivanja krivulja mekšanja visoke razlučivosti (HRM, engl. high resolution melting) kombiniranom s metodom određivanja slijeda nukleotida DNA u epidemiološkim studijama o HPV varijabilnosti ; i otkrivanje nove varijante HPV tipa 16 koja je značajno povezana s niskim stupnjem lezije vrata maternice u usporedbi s referentnom varijantom a sadrži mutacije u E1 regiji jedinstvene za ovu varijantu. Osim toga, relativno visoka učestalost ove varijante među HPV 16-pozitivnim ženama u Hrvatskoj (oko 10%), a vjerojatno i drugdje, sugerira njenu važnost kod otkrivanja i praćenja prekanceroza i raka vrata maternice.)

HPV; types; variants; E1 duplication; E6; oncogenic potential

Ova disertacija je napisana po skandinavskom modelu. Jezik izvornika je engleski. Rad obuhvaća rezultate slijedeća tri znanstvena rada: (1) Sabol, Ivan ; Salakova, Martina ; Smahelova, Jana ; Pawlita, Michael ; Schmitt, Markus, Milutin Gašperov, Nina ; Grce, Magdalena ; Tachezy, Ruth. Evaluation of different techniques for the identification of human papillomavirus(HPV) types of low prevalence. Journal of clinical microbiology. 46 (2008), 5 ; 1606-1613 (članak, znanstveni) ; (2) Sabol, Ivan ; Čretnik, Maja ; Hadžisejdić, Ita ; Si-Mohammed, Ali ; Matovina, Mihaela ; Grahovac, Blaženka ; Levanat, Sonja ; Grce, Magdalena. A New Approach for the Evaluation of the Human Papillomavirus Type 16 Variability with High Resolution Melting Analysis. Journal of Virological Methods. 162 (2009), 1-2 ; 142-147 (članak, znanstveni). (3) Sabol, Ivan ; Matovina, Mihaela ; Milutin Gašperov, Nina ; Grce, Magdalena. Identification of a novel human papillomavirus type 16 E1 gene variant with potentially reduced oncogenicity. Journal of Medical Virology. 80 (2008), 12 ; 2134-2140 (članak, znanstveni).