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A general concern exists that cervical cancer screening using human papillomavirus (HPV) testing may lead to considerable overtreatment. We evaluated the trade‐off between benefits and overtreatment among different screening strategies differing by primary tests (cytology, p16/Ki‐67, HPV alone or in combinations), interval, age and diagnostic follow‐up algorithms. A Markov state‐transition model calibrated to the Austrian epidemiological context was used to predict cervical cancer cases, deaths, overtreatments and incremental harm–benefit ratios (IHBR) for each strategy. When considering the same screening interval, HPV‐based screening strategies were more effective compared to cytology or p16/Ki‐67 testing (e.g., relative reduction in cervical cancer with biennial screening: 67.7% for HPV + Pap cotesting, 57.3% for cytology and 65.5% for p16/Ki‐67), but were associated with increased overtreatment (e.g., 19.8% more conizations with biennial HPV + Papcotesting vs. biennial cytology). The IHBRs measured in unnecessary conizations per additional prevented cancer‐related death were 31 (quinquennial Pap + p16/Ki‐67‐triage), 49 (triennial Pap + p16/Ki‐67‐triage), 58 (triennial HPV + Pap cotesting), 66 (biennial HPV + Pap cotesting), 189 (annual Pap + p16/Ki‐67‐triage) and 401 (annual p16/Ki‐67 testing alone). The IHBRs increased significantly with increasing screening adherence rates and slightly with lower age at screening initiation, with a reduction in HPV incidence or with lower Pap‐test sensitivity. Depending on the accepted IHBR threshold, biennial or triennial HPV‐based screening in women as of age 30 and biennial cytology in younger women may be considered in opportunistic screening settings with low or moderate adherence such as in Austria. In organized settings with high screening adherence and in postvaccination settings with lower HPV prevalence, the interval may be prolonged. What's new? While human papillomavirus (HPV)‐based testing is effective for cervical cancer detection, trade‐offs between benefits and harms, particularly overtreatment associated with HPV testing, remain poorly defined. This study, using model simulations, suggests that over the same screening interval, HPV testing is more effective than conventional Pap cytology and p16/Ki‐67 staining but carries a risk of overtreatment, particularly in settings with short screening intervals. Relative to annual cytology, HPV and Pap cotesting results in similar benefit but fewer unnecessary treatments. The findings indicate that harm‐benefit ratios for different screening methods vary depending on screening setting, interval, adherence, and HPV‐vaccination status. [ABSTRACT FROM AUTHOR]

Background: In order to evaluate the newly implemented gender-neutral HPV vaccination program, knowledge on the pre-vaccine prevalence of HPV infection is of paramount importance. Data on HPV infection among the women with no known previous cytological abnormalities are inexistent in Austria. This study presents data on the prevalence and distribution of HPV genotypes among women with no known cytological abnormalities in west Austria.Methods: Women between 18 and 65 years of age attending annual cervical cancer screening examinations were included in the study. Data on socio-demographic and reproductive factors were collected using structured questionnaires. Corresponding cervical swab samples were tested for the presence of HPV DNA and were genotyped. Questionnaire data and HPV status were linked with the corresponding cytological findings.Results: A total of 542 women were included in the study. The mean age of the study participants was 35.9 (SD = 11.5). The prevalence of HPV infection was 20.5 %. HPV 16 (6.5 %), HPV 33 (3.3 %) and HPV 31 (3.0 %) were the dominant genotypes detected. Multivariate analysis showed that women younger than 30 years of age, smokers, women with a higher number of lifetime sexual partners and those living in the eastern districts of the study region were at significantly higher risk of HPV infection.Conclusions: With this study we present the first data on the prevalence of cervical HPV genotypes among a screening population in Austria. The results not only fill the missing information on HPV infection in this group of women in the country, they also provide baseline data for a future evaluation of the impact of the Austrian gender-neutral HPV immunization program. Moreover, our finding of higher HPV prevalence in the eastern compared to the western district of the study region may - at least partly - explain the east-west gradient in the standardized incidence rate of cervical cancer in the region. [ABSTRACT FROM AUTHOR]

Background: Recent studies have revealed a possible role for the human papillomavirus (HPV) in the pathogenesis of breast cancer. In this study, patients having both a history of invasive cervical cancer and breast cancer as second primary cancer were selected for enrolment in a study of breast carcinomas for the presence of HPV. Methods: Paraffin-embedded tissue from cervical cancer, pelvic lymph nodes, breast cancer and axillary lymph nodes of eleven patients were examined for the presence of HPV DNA using a polymerase chain reaction – enzyme immuno assay. DNA extraction was performed with the “QIAamp Tissue Kit” according to the manufacturer’s instructions. Additionally, serum samples taken between diagnosis of cervical and breast cancer, were analyzed for the presence of HPV DNA to examine a possible haematogenous spread of oncogenic HPV DNA. Results: All cervical carcinomas were HPV-positive. HPV DNA was detected in seven out of eleven cases in breast cancer and/or axillary lymph node tissue. Six patients had the same HPV type (HPV-16) in cervical cancer and in the corresponding breast cancer/lymph node tissue. In one case, the same HPV DNA type (HPV 16) was detected in cervical cancer, breast cancer and serum sample. Conclusion: These results suggest that HPV DNA might be transported from the original site of infection to the breast tissue by the bloodstream, and that it is possibly involved in the carcinogenesis of breast neoplasia in some patients. [Copyright &y& Elsevier]

Promoter hypermethylation has been recognized to play an important role in carcinogenesis. We analyzed the methylation status of 25 genes in 14 normal cervical tissue specimens and in 65 tissue specimens from cervical cancer patients using the MethyLight technique. Most of the analyzed genes have been shown to be methylated in various cancers. RB1 was never methylated in any analyzed cervical tissue. DNA methylation status of the remaining 24 genes in every tissue sample was subsequently analyzed using unsupervised agglomerative hierarchical cluster analysis to group specimens and CpG regions. We observed four clusters. All normal cervical tissue specimens were grouped together in one cluster. Neither grade, nor histological type nor age demonstrated any significant association with clusters formed. Interestingly, statistically significantly less patients whose tumor DNA methylation pattern clustered together with normal cervical tissue died within our observation period, as compared to those patients out of the three remaining clusters (P<0.03). Cervical cancer patients, whose DNA methylation pattern clustered together with normal cervical tissue revealed a strong trend to better survival (P=0.066) compared to patients grouped in the remaining cluster. This study shows for the first time that working solely with DNA methylation pattern a subgroup of cervical cancer patients can be defined that demonstrated strong similarity to non-neoplastic probands and had a better prognosis. [Copyright &y& Elsevier]

Changes in the status of DNA methylation are among the most common molecular alterations in human neoplasia, Recent demonstrations of tumor-derived methylated DNA in the blood stream of cancer patients allow the use of these epigenetic markers for risk assessment in cancer patients. We were interested in evaluating the prognostic value of several methylated genes in the serum of cancer patients. Using MethyLight, a high-throughput DNA methylation assay, we analyzed 215 serum samples from patients with cervical (a = 93) or breast cancer (a 122) for DNA methylation changes. In cervical cancer, hypermethylation of three genes (MYOD1, CDH1, and CDH13) in pre-treatment sera was statistically significantly associated with a poorer disease outcome. Additionally, for the first time we used a so-called gene evaluation set to identify the most important DNA methylation changes in the serum of breast cancer patients from a long list of candidate genes. In the gene evaluation set, we detected five genes (ESR1, APC, HSD1 7B4, HId, and RASSF1A) using our criteria for further analysis. Finally, two of the evaluated genes (APC and RASSF1A) proved to be independent prognostic parameters in breast cancer patients. In summary, we detected several prognostic DNA methylation markers in the serum of cervical and breast cancer patients. This finding indicates great potential for the use of these epigenetic markers in clinical, routine risk assessment in patients with various malignancies. [ABSTRACT FROM AUTHOR]

Objectives. Activation of telomerase, the enzyme that synthesizes the telomere ends of linear chromosomes, has been implicated in human cell immortalization and cancer cell pathogenesis. The expression pattern of human telomerase reverse transcriptase (hTERT), the telomerase catalytic subunit gene, is correlated with telomerase activity. The promotor region of the hTERT gene has been located in a CpG island and may therefore be regulated, at least in part, by DNA methylation. The potential for methylation-mediated regulation of hTERT gene expression in ovarian and cervical cancer tissue has not been investigated up to now. The aim of this study was to investigate the expression and methylation pattern of hTERT in ovarian and cervical cancer tissue and their correlation with clinicopathological features and outcome of the disease.Methods. A total of 223 tissues were analyzed for hTERT methylation using MethyLight: 65 patients with cervical cancer and 124 with ovarian cancer were studied. The control group consisted of 20 normal ovarian tissues and 14 normal cervical tissues. Quantitative hTERT expression analysis was carried out in a subgroup of patients using real time PCR.Results. hTERT expression was statistically significantly higher in ovarian and cervical cancer tissue in comparison to normal tissue. While methylation of hTERT in cervical cancer was significantly more frequent in comparison to normal cervical tissue, the difference between ovarian cancer and normal ovarian tissue was not significant. No correlation was detected between hypermethylation of hTERT and hTERT mRNA expression. Both ovarian cancer and normal ovary showed an increase in hTERT methylation with increasing age. hTERT expression was not correlated with prognosis, whereas cervical and ovarian cancer patients with unmethylated hTERT had significantly better overall survival.Conclusion. At least in some tumor entities, hTERT methylation is a function of age and is associated with a poorer outcome, irrespective of hTERT expression. [Copyright &y& Elsevier]

Persistent infection with human papillomavirus (HPV) has been widely recognized to induce carcinoma of the uterine cervix. Viral DNA has been documented to occur as tumor DNA in the circulation of patients with primary tumors caused by viral infection. The aim of this study was to evaluate the utility of serum HPV DNA as tumor marker in cervical cancer patients. Sera taken from 94 cervical cancer patients at the date of diagnosis and follow-up serum samples from 24 patients were examined for HPV DNA using PCR enzyme immunoassay. Serum samples taken at the date of diagnosis were HPV DNA positive in 45% of all investigated samples. Sera which were HPV DNA positive at the time of diagnosis became and also remained negative after primary treatment in patients without recurrence or persistent disease. HPV DNA was positive up to 423 days before the time of clinical diagnosis of recurrence in 10 out of 13 cases (median 72 days, range 0–423 days). Serum HPV DNA seems to reflect biological activity of the tumor. Our results indicate that serum HPV DNA might be a useful additional marker for early detection of recurrence in cervical cancer patients. [Copyright &y& Elsevier]

Objective: Infection with high-risk human papillomavirus (HPV) types such as HPV-16 is a major risk factor for the development of cervical cancer. HPV-16 capsid antibodies are detectable in approximately 50% of patients with HPV-16 DNA-positive cervical cancer. We investigated the prognostic significance of HPV capsid antibodies for survival in patients with cervical cancer in comparison with conventional clinicopathologic features such as staging, histologic grading, histology, age, and treatment modality.Study Design: Serum samples from 68 patients with cervical cancer and 65 healthy female control subjects were analyzed by enzyme-linked immunosorbent assay for HPV-specific immunoglobulin G (IgG) antibodies to baculovirus expressed HPV-6, HPV-11, HPV-16, and HPV-18 L1 virus-like particles (VLPs).Results: HPV-16 L1 IgG antibodies were detectable in 6 of 65 (9%) of the control subjects and in 19 of 68 (28%) of the patients with cervical cancer (P =.007). In the subgroup of patients with HPV-16 DNA-positive cervical cancer (comprising 50% of the investigated samples), HPV-16 L1 antibodies were detected in 40%. HPV-16 L1 seropositivity was in univariate and multivariate analysis in addition to International Federation of Gynecology and Obstetrics stage, the only independent positive prognostic factor for overall survival (P =.01).Conclusion: Antibodies to HPV-16 L1 were found to be an independent prognostic factor for overall survival in patients with cervical cancer. Thus, HPV-16 infection may be involved not only in oncogenesis but also in tumor development and behavior. [ABSTRACT FROM AUTHOR]

Focuses on a study which examined the expression level and subcellular localization of the transforming oncogene E7 protein in cervical carcinogenesis. Generation of polyclonal anti-herpesvirus-16 E7 antibodies; Detection of herpesvirus-16 E7 protein in cervical biopsies; Clinical significance of the study findings.

Abstract: E7 is the major oncoprotein of high-risk human papillomaviruses (HPV) which causes cervical cancer. To date E7 oncoproteins have not been investigated in cervical adenocarcinoma. In this study we generated a rabbit monoclonal anti-HPV-16 E7 antibody, RabMab42-3, which recognizes a conformational epitope in the E7 carboxy-terminal zinc-finger resulting in a strong increase in the sensitivity for the detection of cell-associated HPV-16 E7 protein relative to conventional polyclonal anti-HPV-16 E7 antibodies. Using RabMab42-3, we show that the subcellular localization of endogenous HPV-16 E7 oncoprotein varies during the cell cycle in cervical cancer cells. Moreover, we demonstrate for the first time that the HPV-16 E7 oncoprotein is abundantly expressed in cervical adenocarcinoma in situ and adenocarcinoma, suggesting an important role of HPV-16 E7 for the development of these tumors. Our findings suggest that the HPV-16 E7 oncoprotein could be a useful marker for the detection of cervical adenocarcinoma and their precursors. [ABSTRACT FROM AUTHOR]