TMEM45A, SERPINB5 and p16INK4A transcript levels are predictive for development of high-grade cervical lesions

Women persistently infected with human papillomavirus (HPV) type 16 are at high risk for development of cervical intraepithelial neoplasia grade 3 or cervical cancer (CIN3+). We aimed to identify biomarkers for progression to CIN3+ in women with persistent HPV16 infection. In this prospective study, 11,088 women aged 20-29 years were enrolled during 1991-1993, and re-invited for a second visit two years later. Cervical cytology samples obtained at both visits were tested for HPV DNA by Hybrid Capture 2 (HC2), and HC2-positive samples were genotyped by INNO-LiPA. The cohort was followed for up to 19 years via a national pathology register. To identify markers for progression to CIN3+, we performed microarray analysis on RNA extracted from cervical swabs of 30 women with persistent HPV16-infection and 11 HPV-negative women. Six genes were selected and validated by quantitative PCR. Three genes were subsequently validated within a different and large group of women from the same cohort. Secondly, Kaplan-Meier and Cox-regression analyses were used to investigate whether expression levels of those three genes predict progression to CIN3+. We found that high transcript levels of TMEM45A, SERPINB5 and p16INK4a at baseline were associated with increased risk of CIN3+ during follow-up. The hazard ratios of CIN3+ per 10-fold increase in baseline expression level were 1.6 (95% CI: 1.1-2.3) for TMEM45A, 1.6 (95% CI: 1.1-2.5) for p16INK4a, and 1.8 (95% CI: 1.2-2.7) for SERPINB5. In conclusion, high mRNA expression levels of TMEM45A, SERPINB5 and p16INK4a were associated with increased risk of CIN3+ in persistently HPV16-infected women

Human papillomaviruses and cancer

AbstractHuman papillomaviruses (HPV) are small oncogenic DNA viruses of which more than 200 types have been identified to date. A small subset of these is etiologically linked to the development of anogenital malignancies such as cervical cancer. In addition, recent studies established a causative relationship between these high-risk HPV types and tonsillar and oropharyngeal cancer. Clinical management of cervical cancer and head and neck squamous cell carcinomas (HNSCCs) is largely standardized and involves surgical removal of the tumor tissue as well as adjuvant chemoradiation therapy. Notably, the response to therapeutic intervention of HPV-positive HNSCCs has been found to be better as compared to HPV-negative tumors. Although the existing HPV vaccine is solely licensed for the prevention of cervical cancer, it might also have prophylactic potential for the development of high-risk HPV-associated HNSCCs. Another group of viruses, which belongs to the beta-HPV subgroup, has been implicated in nonmelanoma skin cancer, however, the etiology remains to be established. Treatment of HPV-induced nonmelanoma skin cancer is based on local excision. However, topically applied immune-modulating substances represent non-surgical alternatives for the management of smaller cutaneous tumors. In this review we present the current knowledge of the role of HPV in cancer development and discuss clinical management options as well as targets for the development of future intervention therapies

A review of the clinical performance of the Aptima HPV assay

AbstractThis comprehensive review compiles published data from 62 original articles comparing different HPV tests and one meta-analysis on the clinical performance of the Aptima HR HPV (AHPV) assay in either screening or referral populations as well as for the purpose of test of cure. A number of publications with technical issues were also considered. Besides a brief introduction in the development of E6/E7 mRNA testing, the review summarizes data on analytical sensitivies and specificities, as well as on clinical sensitivity, specificity, NPV and PPV with histological endpoints CIN2+ and CIN3+, where available. Although most studies were of cross-sectional design, five studies with a longitudinal prospective design or component were identified. In addition to the study design, sample size, age and CIN2/3+ prevalence of the respective cohort are listed. This allows direct comparison of the published data in the respective groups. One major outcome of this review is the remarkably stable similar sensitivities of AHPV and HC2 independent from study design for detection of CIN2/3+ combined with a higher specificity of the AHPV. The second outcome was the longitudinal predictive value derived from registry linkage and other prospective studies that would support the applicability of the AHPV test in primary screening with at least a three year screening interval