Performance ofCADM1, MALandmiR124-2methylation as triage markers for early detection of cervical cancer in self-collected and clinician-collected samples: an exploratory observational study in Papua New Guinea

Abstract

ObjectiveWHO recommends human papillomavirus (HPV) testing for cervical screening, with triage of high-risk HPV (hrHPV) positive women. However, there are limitations to effective triage for low-resource, high-burden settings, such as Papua New Guinea. In this exploratory study, we assessed the performance of host methylation as triage tools for predicting high-grade squamous intraepithelial lesions (HSIL) in self-collected and clinician-collected samples.DesignExploratory observational study.SettingProvincial hospital, same-day cervical screen-and-treat trial, Papua New Guinea.Participants44 hrHPV+women, with paired self/clinician-collected samples (4 squamous cell carcinomas (SCC), 19 HSIL, 4 low-grade squamous intraepithelial lesions, 17 normal).Primary and secondary outcome measuresMethylation levels ofCADM1, MALandmiR124-2analysed by methylation-specific PCRs against the clinical endpoint of HSIL or SCC (HSIL+) measured using liquid-based-cytology/p16-Ki67 stain.ResultsIn clinician-collected samples,MALandmiR124-2methylation levels were significantly higher with increasing grade of disease (p=0.0046 and p<0.0015, respectively).miR124-2was the best predictor of HSIL (area under the curve, AUC 0.819) whileMALof SCC (AUC 0.856). In self-collected samples,MALbest predicted HSIL (AUC 0.595) whilemiR124-2SCC (AUC 0.812). CombinedmiR124-2/MALmethylation yielded sensitivity and specificity for HSIL+ of 90.5% (95% CI 69.6% to 98.8%) and 70% (95% CI 45.7% to 88.1%), respectively, in clinician-collected samples, and 81.8% (95% CI 59.7% to 94.8%) and 47.6% (95% CI 25.7% to 70.2%), respectively, in self-collected samples.miR124-2/MALplus HPV16/HPV18 improved sensitivity for HSIL+ (95.2%, 95% CI 76.2% to 99.9%) but decreased specificity (55.0%, 95% CI 31.5% to 76.9%).ConclusionmiR124-2/MALmethylation is a potential triage strategy for the detection of HSIL/SCC in low-income and middle-income country.