HPV E6/E7 mRNA test for the detection of high grade cervical intraepithelial neoplasia (CIN2+): A systematic review

Abstract

Background: Genital infection with certain types of Human papillomavirus (HPV) is a major cause of cervical cancer globally. For early detection of premalignant dysplasia, evidences are coming out on the usefulness of HPV E6/E7 mRNA test as a potential tool compared with cytology and HPV DNA testing. Taking into account shortage of compiled data on this field, the aim of this systematic review was to describe the latest diagnostic performance of HPV E6/E7 mRNA testing to detect high grade cervical lesions (CIN2+) where by histology as was taken as a ‘gold standard’. Methods: Articles published in English were systematically searched using key words from PubMed/Medline and SCOPUS. In addition, Google Scholar and the Google database were searched manually for grey literature. Two reviewers independently assessed study eligibility, risk of bias and extracted the data. We performed a descriptive presentation of the performance of E6/E7 mRNA testings (interims of sensitivity, specificity, negative and positive predictive values) for the detection of CIN2+. Results: Out of 231 applicable citations, we have included 29 articles with a total of 23,576 study participants (age range, 15-84) who had different cervical pathologies. Among the participants who had cervical histology, the proportion of CIN2+ was between 10.6% and 90.6%. Using histology as a gold standard, 11 studies evaluated the PreTect HPV Proofer, 7 studies evaluated the APTIMA HPV assay (Gen-Probe) and 6 studies evaluated the Quantivirus® HPV assay. The diagnostic performance of those three most common mRNA testing tools to detect CIN2+ was; 1) PreTect Proofer; median sensitivity 83%, median specificity 73%, median PPV 70 and median NPV 88.9%. 2) APTIMA assay; median sensitivity 91.4%, median specificity 46.2%, median PPV 34.3% and median NPV 96.3%. 3) Quantivirus®: median sensitivity 86.1%, median specificity 54.6%, median PPV 54.3%, median NPV 89.3%. Further, the area under the receiver operating characteristics (AU-ROC) curve varied between 63.8% and 90.9%. Conclusions: The reported diagnostic accuracy implies that mRNA tests possess diagnostic relevance to detect CIN2+ and could potentially be considered in areas where there is no histology facility. Further studies including its cost should be considered.

Novel biomarkers with promising benefits for diagnosis of cervical neoplasia: a systematic review

“…In the present review, women were tested for the HPV E6/E7 mRNA, miRNA (miR-9), p16INK4a / ki-67, DNA methylation, SCC-Ag, M-CSF, and VEGF predominately secondary to having positive cervical cytology, and/or VIA and/or positive HPV DNA test. Overexpression of E6 / E7, p16 /ki-67, miR-9, SCC-Ag, M-CSF, VEGF proteins, or JAM3, SOX1, and L1 genes following infection with HPV can be detected based on their elevated levels in plasma, serum, Cervical scraping, or tissue as predictors of increased risk of cervical cancer progression [29,32,54,55]. The proportion of CIN2+ varied between 13.7 and 88.4%, reflecting the diverse spectrum of cervical pathologies of the participants employed in articles we included.…”

“…The proportion of CIN2+ varied between 13.7 and 88.4%, reflecting the diverse spectrum of cervical pathologies of the participants employed in articles we included. From experimental studies, it has been established that woman exposed to HPV E6/E7 mRNA following infection with HPV have higher risk of progressing to highgrade cervical neoplasia due to the integration of viral DNA sequence into host genome causing loss of E2 tumor suppressor gene that regulates expression of E6 and E7 oncogenes [13,54,56]. Consequently, this results in overexpression of the two oncogenes which become useful in evaluating risk of cervical carcinogenesis.…”

HPV16 E7 Oncoprotein As a Predictor of Diagnosis and Prognosis in Patients with Cervical Lesions

“…A systematic review report by Burger et al shows that the sensitivity of HPV DNA detection is 70%-100% and the speci city is only 28%-56%, while the Aptima mRNA detection approved by the FDA for clinical use in cytology is ASC-US population, the sensitivity is 91%-95% and the speci city is 42-61% [21] . Another research showed that the sensitivity is 91.4% and the speci city is 46.2% of Aptima mRNA [22] . The second-generation Hybrid Capture Technology (HC-2) speci cation showed that the sensitivity, speci city, positive predictive value, and negative predictive value of high-grade cervical intraepithelial lesions and cervical cancer were diagnosed in patients with Pap smear diagnosed as ASC-US were: 93.0%, 61.1%, 17.2%, 99.0%.…”

HIV-Associated Cancer Biomarkers: A Requirement for Early Diagnosis

“…Protein expression biomarkers include p16INK4a/ki-67, SCC-Ag, M-CSF and VEGF. However, not all these biomarkers are suitable for the diagnosis of HIV-associated cervical cancer [ 44 , 45 , 46 ].…”