Performance of <i>CADM1, MAL</i> and <i>miR124-2</i> methylation 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

WHO 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. Exploratory observational study. Provincial hospital, same-day cervical screen-and-treat trial, Papua New Guinea. 44 hrHPV+women, with paired self/clinician-collected samples (4 squamous cell carcinomas (SCC), 19 HSIL, 4 low-grade squamous intraepithelial lesions, 17 normal). Methylation levels of <i>CADM1, MAL</i> and <i>miR124-2</i> analysed by methylation-specific PCRs against the clinical endpoint of HSIL or SCC (HSIL+) measured using liquid-based-cytology/p16-Ki67 stain. In clinician-collected samples, <i>MAL</i> and <i>miR124-2</i> methylation levels were significantly higher with increasing grade of disease (p=0.0046 and p<0.0015, respectively). <i>miR124-2</i> was the best predictor of HSIL (area under the curve, AUC 0.819) while <i>MAL</i> of SCC (AUC 0.856). In self-collected samples, <i>MAL</i> best predicted HSIL (AUC 0.595) while <i>miR124-2</i> SCC (AUC 0.812). Combined <i>miR124-2/MAL</i> methylation 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. <i>miR124-2/MAL</i> plus 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%). <i>miR124-2/MAL</i> methylation is a potential triage strategy for the detection of HSIL/SCC in low-income and middle-income country.