Burden and prevention of HPV related diseases: Situation in Croatia

The role of persistent infection of high-risk human papillomaviruses (HR-HPV) in cervical cancer has become convincingly established. Other anogenital cancers in women and men are also caused, to a lesser extent, by HR-HPV. In addition, most of the benign anogenital warts and laryngeal papillomatosis are caused by low-risk (LR) HPV types. All these HPV-associated diseases represent high public health burden worldwide, cervical cancer being the leading one. Nowadays, several opportunities are available to prevent cervical cancer and other HPV-related diseases. The most promising cancer preventing intervention is the HPV vaccination against the most common HPV types (16 and 18). However, secondary prevention like education and early detection of the disease by screening have demonstrated in the past great efficacy and should be continued and improved by novel prognostic methods (HPV testing and other biomarkers) in countries where it is already in place and implement in those countries that are lacking cancer control programmes. Herein, the current knowledge on HPVs, HPV-related diseases and their preventive approaches are discussed. In addition, the situation in Croatia is presented

Advances in Cervical Cancer Control and Future Perspectives

The knowledge that the persistent infection with high-risk (HR) human papillomavirus (HPV) is the etiological factor in the development of cervical cancer has led to the development of the HPV DNA detection methods as well as the prophylactic vaccine against the most common HR-HPV types, HPV 16 and 18. Despite HPV vaccination, cervical cancer screening will remain the main preventive measure for both vaccinated and non-vaccinated women, but the nature of screening and management of women with cervical disease is being adapted to the new technologies. Although, HPV DNA detection is more sensitive that cytology, its specificity is lower, since most HPV infections are transient. Therefore, other methods are considered to improve the management of women with cervical disease. Typing of HPV DNA and viral load measurements are still used for research purposes only. Detection of viral oncogene E6/E7 transcripts, which is the marker of the productive infection, is a promising tool for follow-up of HPV DNA-positive women. The detection of p16INK4a over-expression, as an indirect test of E6/E7 expression, is used for confirmation of cervical neoplasia. Despite the lack of standardization, the detection of p16INK4a is useful in clinical settings, however its reproducibility in the management of low-grade and borderline cases is low. Future perspectives include the determination of the methylation status of several cellular genes that could predict the progression of the disease

Methylated Host Cell Gene Promoters and Human Papillomavirus Type 16 and 18 Predicting Cervical Lesions and Cancer

Change in the host and/or human papillomavirus (HPV) DNA methylation profile is probably one of the main factors responsible for the malignant progression of cervical lesions to cancer. To investigate those changes we studied 173 cervical samples with different grades of cervical lesion, from normal to cervical cancer. The methylation status of nine cellular gene promoters, CCNA1, CDH1, C13ORF18, DAPK1, HIC1, RARβ2, hTERT1, hTERT2 and TWIST1, was investigated by Methylation Specific Polymerase Chain Reaction (MSP). The methylation of HPV18 L1-gene was also investigated by MSP, while the methylated cytosines within four regions, L1, 5’LCR, enhancer, and promoter of the HPV16 genome covering 19 CpG sites were evaluated by bisulfite sequencing. Statistically significant methylation biomarkers distinguishing between cervical precursor lesions from normal cervix were primarily C13ORF18 and secondly CCNA1, and those distinguishing cervical cancer from normal or cervical precursor lesions were CCNA1, C13ORF18, hTERT1, hTERT2 and TWIST1. In addition, the methylation analysis of individual CpG sites of the HPV16 genome in different sample groups, notably the 7455 and 7694 sites, proved to be more important than the overall methylation frequency. The majority of HPV18 positive samples contained both methylated and unmethylated L1 gene, and samples with L1-gene methylated forms alone had better prognosis when correlated with the host cell gene promoters’ methylation profiles. In conclusion, both cellular and viral methylation biomarkers should be used for monitoring cervical lesion progression to prevent invasive cervical cancer

Human Papillomavirus in the Lesions of the Oral Mucosa According to Topography

Background. The association between human papillomavirus (HPV) types and oral lesions has been shown in many studies. In light of the possibility of early detection of HPV genotypes in oral epithelium, and considering the significance which HPV has in the development of malignant and potentially malignant disorders of oral mucosa, the purpose of this study was to investigate the prevalence of HPV DNA in different oral lesions in the Croatian population. In addition, we wanted to elucidate whether HPV infection is associated predominantly with either the lesion or particular anatomic site of the oral cavity. Methodology/Principal Findings. The study included 246 subjects with different oral lesions, and 73 subjects with apparently healthy oral mucosa (controls). Oral lesions were classified according to their surface morphology and clinical diagnosis. Epithelial cells were collected with the cytobrush from different topographic sites in the oral cavity of oral lesions and controls. The presence of HPV DNA was evaluated by consensus and type-specific primer-directed polymerase chain reaction. The HPV positivity was detected in 17.7% of oral lesions, significantly more than in apparently healthy mucosa (6.8%), with a higher presence in benign proliferative mucosal lesions (18.6%). High-risk HPV types were predominantly found in potentially malignant oral disorders (HPV16 in 4.3% and HPV31 in 3.4%), while benign proliferative lesions as well as healthy oral mucosa contained mainly undetermined HPV type (13.6 and 6.8%, respectively). Conclusions/Significance. Distribution of positive HPV findings on oral mucosa seems to be more associated to particular anatomical site than diagnosis itself. Samples taken from vermilion border, labial commissures, and hard palate were most often HPV positive. Thus, topography plays a role in HPV prevalence findings in oral lesions. Because of the higher prevalence of the high-risk HPV types in potentially malignant oral disorders, these lesions need to be continuously controlled and treated