New Publication | WHO/ESGO Guideline Experts Jointly Publish Large-Scale Meta-Analysis: PAX1/JAM3 Dual-Gene Methylation Ranks First in Overall Efficacy for Detecting High-Grade Cervical Lesions
Recently, a systematic review and meta-analysis jointly completed by teams from Imperial College London (UK), Yale University School of Medicine Department of Obstetrics and Gynecology (USA), Belgian Cancer Centre, Brown University (USA), and Helsinki University Hospital (Finland), was published in the European Journal of Cancer.
What makes this publication particularly significant: the author group includes Marc Arbyn (core author of WHO cervical screening guidelines), Maria Kyrgiou, and Laura Burney Ellis—all EU/WHO guideline-writing experts. This meta-analysis will serve as part of the evidence base for the next round of WHO/ESGO cervical guideline updates.
The study included 125 studies and 49,242 women, systematically comparing the diagnostic performance of 32 human and HPV-related methylation biomarkers. It is one of the most comprehensive cervical methylation meta-analyses to date, providing high-level evidence for the application of methylation detection in cervical cancer screening and triage management.
I. Findings in Two Core Scenarios
① Triage After HPV Positivity (CIN3+ as Endpoint)
In the analysis of 51 studies involving 28,977 high-risk HPV-positive women, 13 methylation biomarkers were evaluated—JAM3, C13ORF18, and PAX1 ranked in the top three for overall diagnostic performance. Among these, the JAM3 and PAX1 combination maintained good sensitivity while demonstrating outstanding specificity, enabling more precise identification of high-risk populations requiring colposcopy and histological confirmation, thereby alleviating the current "colposcopy overload" pain point in HPV-positive triage.
② General Population Regardless of HPV Status (CIN2+ as Endpoint)
The PAX1/JAM3 dual-target combination pooled data from 5 studies and 3,929 participants, achieving a diagnostic odds ratio (DOR) of 76.00 for CIN2+ (high-grade precancerous lesions) detection—the highest among all 32 biomarkers/combinations evaluated.
In other words: Regardless of HPV status, a "positive signal" from PAX1/JAM3 dual-target highly corresponds to true CIN2+ lesions—this is critical evidence for advancing methylation detection from "HPV triage adjunct" to "broader clinical use."
II. Summary
This meta-analysis, co-authored by international cervical guideline experts, provides evidence at two levels:
· Single-target level: PAX1 and JAM3 individually rank in the international first tier for CIN3+ detection in HPV+ populations;
· Dual-target level: PAX1/JAM3 achieved the highest comprehensive performance indicator (DOR=76) certified by international guideline experts for CIN2+ detection in the general population.
This systematic review directly positions PAX1 and JAM3 as the globally strongest cervical methylation biomarkers.
The dual-target strategy can, to a certain extent, reduce variability caused by single-gene methylation heterogeneity, providing more robust molecular information for cervical lesion risk assessment. It also aligns with the recent WHO/ESGO guideline direction of "precision triage, reducing excessive colposcopy." These conclusions provide guideline-level evidence for the clinical adoption of PAX1/JAM3 dual-target methylation assays and echo the ESGO 2025 CIN2 active surveillance consensus.
Diagnostic testing accuracy of DNA methylation tests for detection of high-grade cervical intraepithelial neoplasia and cervical cancer: A systematic review and meta-analysis. European Journal of Cancer, 2026; 243
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