Performance of CADM1, MAL and miR124-2 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
John Kaldor,
Steven G Badman,
Josephine Gabuzzi,
Suzanne Garland,
Julia Brotherton,
Monica Molano,
Samuel Phillips,
David Hawkes,
Dorothy A Machalek,
Grace Tan,
Zure Kombati,
Gloria Munnull,
Marion Saville,
Gerald L Murray,
John Bolnga,
Andrew John Vallely,
Prisha Balgovind,
Gholamreza Haqshenas,
Alyssa Marie Cornall,
Pamela Josephine Toliman
Affiliations
John Kaldor
3 Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia
Steven G Badman
3 Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia
Josephine Gabuzzi
7 Papua New Guinea Institute of Medical Research, Goroka, Papua New Guinea
Suzanne Garland
5 The Royal Women`s Hospital, Parkville, Victoria, Australia
Julia Brotherton
4 Australian Centre for the Prevention of Cervical Cancer, Melbourne, Victoria, Australia
Monica Molano
1 Centre for Women’s Infectious Diseases, The Royal Women`s Hospital, Parkville, Victoria, Australia
Samuel Phillips
2 Murdoch Children`s Research Institute, Parkville, Victoria, Australia
David Hawkes
4 Australian Centre for the Prevention of Cervical Cancer, Melbourne, Victoria, Australia
Dorothy A Machalek
1 Centre for Women’s Infectious Diseases, The Royal Women`s Hospital, Parkville, Victoria, Australia
Grace Tan
4 Australian Centre for the Prevention of Cervical Cancer, Melbourne, Victoria, Australia
Zure Kombati
9 Tininga Clinic, Mount Hagen General Hospital, Mount Hagen, Western Highlands Province, Papua New Guinea
Gloria Munnull
7 Papua New Guinea Institute of Medical Research, Goroka, Papua New Guinea
Marion Saville
4 Australian Centre for the Prevention of Cervical Cancer, Melbourne, Victoria, Australia
Gerald L Murray
1 Centre for Women’s Infectious Diseases, The Royal Women`s Hospital, Parkville, Victoria, Australia
John Bolnga
7 Papua New Guinea Institute of Medical Research, Goroka, Papua New Guinea
Andrew John Vallely
3 Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia
Prisha Balgovind
2 Murdoch Children`s Research Institute, Parkville, Victoria, Australia
Gholamreza Haqshenas
5 The Royal Women`s Hospital, Parkville, Victoria, Australia
Alyssa Marie Cornall
2 Murdoch Children`s Research Institute, Parkville, Victoria, Australia
Pamela Josephine Toliman
11 Kirby Institute -Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
Objective 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.Design Exploratory observational study.Setting Provincial hospital, same-day cervical screen-and-treat trial, Papua New Guinea.Participants 44 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 measures Methylation levels of CADM1, MAL and miR124-2 analysed by methylation-specific PCRs against the clinical endpoint of HSIL or SCC (HSIL+) measured using liquid-based-cytology/p16-Ki67 stain.Results In clinician-collected samples, MAL and miR124-2 methylation levels were significantly higher with increasing grade of disease (p=0.0046 and p<0.0015, respectively). miR124-2 was the best predictor of HSIL (area under the curve, AUC 0.819) while MAL of SCC (AUC 0.856). In self-collected samples, MAL best predicted HSIL (AUC 0.595) while miR124-2 SCC (AUC 0.812). Combined miR124-2/MAL 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. miR124-2/MAL 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%).Conclusion miR124-2/MAL methylation is a potential triage strategy for the detection of HSIL/SCC in low-income and middle-income country.
