Clinical Performance of Human Papillomavirus E6 and E7 mRNA Testing for High-Grade Lesions of the Cervix

Abstract

Infection with high-risk (HR) human papillomavirus (HPV) is the major cause of cervical cancer. However, relatively few infections progress to malignant disease. Progression to malignancy requires the overexpression of the E6 and E7 genes in the integrated HPV genome. It follows that the E6 and E7 transcripts could be useful markers of disease progression. The study presented here tests this possibility, using data from colposcopy and from cytological and histological tests to compare RNA assays for the E6 and E7 genes with DNA testing. A total of 180 women underwent colposcopy, cytology, and biopsy of suspected lesions (143 cases). Cervical brush specimens were analyzed for HPV DNA and for E6 and E7 mRNA. DNA from HR HPV was found in 57.8% of the specimens; E6 and E7 transcripts were found in 45%. The rates of detection of HPV DNA and of E6 and E7 transcripts were 33.3% and 25%, respectively, for specimens with normal findings; 51.4% and 31.9%, respectively, for specimens with cervical intraepithelial neoplasia grade 1 (CIN1); and 61.1% and 44.2% for specimens with CIN2, respectively. All specimens with CIN3 and 95.5% of specimens from patients with squamous cell carcinoma were positive by both assays. Thirty-seven patients with normal colposcopy findings did not undergo biopsy. HPV DNA and mRNA transcripts were found in 32.4% and 18.9% of these cases, respectively. Comparisons with cytological tests produced similar results. Overall, the mRNA tests showed a higher specificity than the DNA tests for high-grade lesions (72.7% and 56.2%, respectively) and a higher positive predictive value (59.3% and 49.0%, respectively). These findings suggest that mRNA assays could be more powerful than DNA testing for predicting the risk of progression and offer a strong potential as a tool for triage and patient follow-up.Carcinomas of the anogenital tract, particularly cancer of the cervix, represent the second most frequent type of neoplasm worldwide (43, 57). The major cause of these cancers is infection with high-risk (HR) human papillomavirus (HPV). DNA from HPV has been detected in more than 99% of cervical squamous cell carcinomas (SCCs) and a smaller proportion of adenocarcinomas (3,4,31,33). However, most HPV infections regress spontaneously or progress only after a long period of latency. As a result, the number of infections is far higher than the number of women who develop cancer.The most common types of HPV found in cancer patients are types 16, 18, 31, 33, and 45 (5, 10, 40, 53). Persistent infection with these types is regarded as a significant risk factor (40). The role of HPVs in the etiology of cervical cancer is tightly correlated with the overexpression of two oncogenes (E6 and E7) due to a specific opening in the E2 open reading frame in the integrated viral genome (23, 28). Studies of cervical cancer cell lines and cancer biopsy specimens have shown that the continuous expression of the genes is a necessary condition for the transformation and maintenance of neoplastic and dysplastic cells (46,56,57).Ce...

HPV mRNA test in women with minor cervical lesions: Experience of the University Hospital of North Norway

“…In general, the use of HPV DNA tests generates more positive results than the HPV mRNA test. This is because DNA tests detect the mere presence of the virus and will therefore also detect harmless transient infections which are handled by the immune system (Cattani et al, 2009b). The HPV DNA test Hybrid Capture 2 detects 13 HPV types and the HPV mRNA test PreTect HPV Proofer detects five HPV types.…”

Understanding and incorporating human papillomavirus testing in cervical cancer screening: a South African perspective

“…HPV mRNA assays have approximately the same sensitivity as HPV DNA assays, with a higher speci city and PPV for high-grade lesions. 16,20,21 In subjects with a high expected prevalence of disease (e.g. groups at risk, symptomatic patients, and patients with persistent cytological abnormalities after negative colposcopy results), RNA assays will provide better risk predictions than DNA tests.…”

“…groups at risk, symptomatic patients, and patients with persistent cytological abnormalities after negative colposcopy results), RNA assays will provide better risk predictions than DNA tests. 20 HPV mRNA assays may also predict which women with LSIL or ASCUS (atypical squamous cells of undetermined signi cance) lesions have the potential to progress to cervical cancer (Figure 4). Possible bene ts include reductions in the number of cases referred for colposcopy, improved patient wellbeing, and signi cant reductions in costs.…”

“…Possible bene ts include reductions in the number of cases referred for colposcopy, improved patient wellbeing, and signi cant reductions in costs. 20 The future of cervical cancer screening in South Africa HPV testing is the most objective and reproducible of all cervical screening tests, and is less demanding in terms of training requirements and quality assurance. It has been shown consistently to be superior to cytology in developed countries, and a recent landmark study in rural India showed unequivocally that a single round of HPV DNA testing, followed by treatment, was associated with the most signi cant reduction in the numbers of advanced cervical cancer and deaths from cervical cancer when compared to a single conventional cytologic test or visual inspection of the cervix with acetic acid (VIA).…”

“…It is possible that a single test using an mRNA assay could be more e ective at detecting an hrHPV infection than repeated DNA testing. 20 Detection of hrHPV mRNA is considered to be potentially useful in three clinical applications: 20 • As primary screening;…”