A systematic review and meta-analysis of the diagnostic effectiveness of human papillomavirus methylation biomarkers for detection of cervical cancer

Abstract

Background: The aim of this systematic review and meta-analysis was to assess the evidence for the diagnostic effectiveness of human papillomavirus (HPV) methylation biomarkers for detection of cervical cancer. Methods: PubMed, Embase and Web of Science were searched. Nine articles focusing on HPV methylation for detection of precancerous and cancerous cervical lesions were included. The QUADAS-2 tool was used for quality assessment. The receiver operating characteristic (ROC) was the main diagnostic performance parameter extracted. Results: Of the nine articles included in this study, seven were of moderate quality and two were of high quality. A meta-analysis of the ROC for 27 HPV methylation biomarkers revealed an overall pooled ROC of 0.770 (95% CI: 0.720–0.819; I²: 98.4%; Q: 1537.4; p < 0.01). Four methylation biomarkers had strong diagnostic ability (ROC > 0.900), 17 were moderate (ROC: 0.7000–0.8999) and six were poor (ROC < 0.700). Conclusion: HPV methylation biomarkers hold significant promise as independent screening tests for the detection of cervical precancerous and cancerous lesions.

Plain language summary

This study reviewed the literature to assess the available evidence for the ability of biomarkers based on human papillomavirus (HPV) methylation (i.e., the detection of methyl groups in HPV DNA in cervical specimens) to screen for cervical precancerous and cancerous lesions. Scientific databases were searched, and abstracts screened for relevance. The quality of the included articles was assessed using a quality assessment tool called QUADAS-2. The main diagnostic performance parameter extracted from the included articles was the receiver operating characteristic (ROC), a measure of the ability of a biomarker to detect all true cases (true positives) while excluding all true non-cases (true negatives). After screening, nine articles were included, of which seven were of moderate quality and two were of high quality. ROC data were extracted for 27 biomarkers, of which four methylation biomarkers had high diagnostic ability (i.e., ROC > 0.900), 17 had moderate diagnostic ability (ROC: 0.7000–0.8999) and six had low diagnostic ability (ROC < 0.700). An umbrella meta-analysis (i.e., a weighted-average ROC for all HPV methylation biomarkers) revealed an ROC consistent with moderate diagnostic ability (0.770). The main conclusion from this study was that HPV methylation biomarkers, especially ones with high diagnostic ability, hold significant promise as independent screening tests for the detection of cervical precancerous and cancerous lesions.

Tweetable abstract

Meta-analysis assessing the diagnostic effectiveness of HPV methylation biomarkers. Meta-analysis of 27 HPV methylation biomarkers showed a pooled ROC of 0.770, suggesting promise for the detection of cervical precancerous and malignant lesions.

Keywords::

• biomarker
• cancer
• cervical cancer
• DNA
• epigenetics
• HPV
• methylation
• ROC
• sensitivity
• specificity

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/epi-2022-0160

Author contributions

C Hillyar conceptualized the study, developed the methodology, conducted the searches, analyzed and interpreted the data, drafted, edited and revised the manuscript, and supervised the work; S Kanabar screened the search results, extracted the data, and edited and revised the manuscript; K Pufal extracted the data and edited and revised the manuscript; A Lawson extracted the data and edited and revised the manuscript; J Li Saw Hee extracted the data and edited and revised the manuscript; K Rallis developed the methodology and screened the search results, and edited and revised the manuscript; A Nibber developed the methodology and edited and revised the manuscript; M Sideris interpreted the data and edited and revised the manuscript. All authors read and approved the final version of the manuscript.

Acknowledgments

The authors acknowledge the contribution of S Murphy to the development of the study protocol only.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.