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Observational Study
. 2024 Jun 19;14(6):e081282.
doi: 10.1136/bmjopen-2023-081282.

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

Monica Molano  1   2 , Dorothy A Machalek  3   4 , Grace Tan  5 , Suzanne Garland  6   7 , Prisha Balgovind  2   6 , Gholamreza Haqshenas  6   7 , Gloria Munnull  8 , Samuel Phillips  2   6 , Steven G Badman  4 , John Bolnga  8   9 , Alyssa Marie Cornall  2   6 , Josephine Gabuzzi  8   9 , Zure Kombati  10 , Julia Brotherton  5   11 , Marion Saville  5 , David Hawkes  5 , John Kaldor  4 , Pamela Josephine Toliman  12 , Andrew John Vallely  4   13 , Gerald L Murray  3   7
Affiliations
Observational Study

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

Monica Molano et al. BMJ Open. .

Abstract

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.

Keywords: human papillomavirus viruses; molecular biology; molecular diagnostics; oncogenes.

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Conflict of interest statement

Competing interests: AJV, JG, JBo, GM, PJT, SGB and JK have received subsidised test kits for research from Cepheid. MS, JBr, GT and DH have received donated test kits for research from Abbott, BD, Cepheid, Hologic, Qiagen, Roche and Seegene. AJV and MS jointly lead the Elimination of Cervical Cancer in the Western Pacific (ECCWP) programme with philanthropic funding support from the Minderoo Foundation and the Frazer Family Foundation; and equipment, tests and consumables donated by Cepheid for HPV-based cervical screening in Papua New Guinea and Vanuatu. SG is a member of the Global Advisory Board for HPV vaccines Merck and has led investigator-initiated grants from Merck on HPV in young women. MM, DAM, SP, PB, GH, ZK and GLM declare no conflicting interests.

Figures

Figure 1
Figure 1
Percentage of DNA methylation of gene CADM1, MAL and miR124-2 according to cytological grade in oncogenic HPV positive clinician-collected cervical samples (cervical) in the top panel and self-collected vaginal samples (vaginal) in the bottom panel. Whiskers correspond to the 1st and 3rd quartiles (the 25th and 75th percentiles). Overall significance by Kruskal-Wallis is indicated. HPV, human papillomavirus; HSIL, high-grade squamous intraepithelial lesions; LSIL, low-grade squamous intraepithelial lesions; SCC, squamous cell carcinomas.
Figure 2
Figure 2
Receiver operating characteristic (ROC) curve values of the performance of DNA methylation of CADM1, MAL and miR124-2 for distinguishing HSIL from LSIL/normal, and SCC from LSIL/normal, stratified by type; clinician-collected cervical samples (A, C) or self-collected vaginal samples (B, D). HSIL, high-grade squamous intraepithelial lesions; LSIL, low-grade squamous intraepithelial lesions; SCC, squamous cell carcinomas.
Figure 3
Figure 3
Percentage methylation of gene CADM1, MAL and miR124-2 comparing paired clinician-collected cervical samples (Cervical) and self-collected vaginal samples (Vaginal). Comparisons assessed by Wilcoxon signed rank test, with whiskers corresponding to the 1st and 3rd quartiles (the 25th and 75th percentiles). HSIL, high-grade squamous intraepithelial lesions; LSIL, low-grade squamous intraepithelial lesions; SCC, squamous cell carcinomas.
See this image and copyright information in PMC

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