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

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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.

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Most cited references 42

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Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

Hyuna Sung, Jacques Ferlay, Rebecca Siegel … (2021)

This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.

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STARD 2015: an updated list of essential items for reporting diagnostic accuracy studies

Patrick Bossuyt, Johannes Reitsma, David Bruns … (2015)

Incomplete reporting has been identified as a major source of avoidable waste in biomedical research. Essential information is often not provided in study reports, impeding the identification, critical appraisal, and replication of studies. To improve the quality of reporting of diagnostic accuracy studies, the Standards for Reporting Diagnostic Accuracy (STARD) statement was developed. Here we present STARD 2015, an updated list of 30 essential items that should be included in every report of a diagnostic accuracy study. This update incorporates recent evidence about sources of bias and variability in diagnostic accuracy and is intended to facilitate the use of STARD. As such, STARD 2015 may help to improve completeness and transparency in reporting of diagnostic accuracy studies.

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Detecting cervical precancer and reaching underscreened women by using HPV testing on self samples: updated meta-analyses

Marc Arbyn, Sara Smith, Sarah Temin … (2018)

Abstract Objective To evaluate the diagnostic accuracy of high-risk human papillomavirus (hrHPV) assays on self samples and the efficacy of self sampling strategies to reach underscreened women. Design Updated meta-analysis. Data sources Medline (PubMed), Embase, and CENTRAL from 1 January 2013 to 15 April 2018 (accuracy review), and 1 January 2014 to 15 April 2018 (participation review). Review methods Accuracy review: hrHPV assay on a vaginal self sample and a clinician sample; and verification of the presence of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) by colposcopy and biopsy in all enrolled women or in women with positive tests. Participation review: study population included women who were irregularly or never screened; women in the self sampling arm (intervention arm) were invited to collect a self sample for hrHPV testing; women in the control arm were invited or reminded to undergo a screening test on a clinician sample; participation in both arms was documented; and a population minimum of 400 women. Results 56 accuracy studies and 25 participation trials were included. hrHPV assays based on polymerase chain reaction were as sensitive on self samples as on clinician samples to detect CIN2+ or CIN3+ (pooled ratio 0.99, 95% confidence interval 0.97 to 1.02). However, hrHPV assays based on signal amplification were less sensitive on self samples (pooled ratio 0.85, 95% confidence interval 0.80 to 0.89). The specificity to exclude CIN2+ was 2% or 4% lower on self samples than on clinician samples, for hrHPV assays based on polymerase chain reaction or signal amplification, respectively. Mailing self sample kits to the woman’s home address generated higher response rates to have a sample taken by a clinician than invitation or reminder letters (pooled relative participation in intention-to-treat-analysis of 2.33, 95% confidence interval 1.86 to 2.91). Opt-in strategies where women had to request a self sampling kit were generally not more effective than invitation letters (relative participation of 1.22, 95% confidence interval 0.93 to 1.61). Direct offer of self sampling devices to women in communities that were underscreened generated high participation rates (>75%). Substantial interstudy heterogeneity was noted (I2>95%). Conclusions When used with hrHPV assays based on polymerase chain reaction, testing on self samples was similarly accurate as on clinician samples. Offering self sampling kits generally is more effective in reaching underscreened women than sending invitations. However, since response rates are highly variable among settings, pilots should be set up before regional or national roll out of self sampling strategies.

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Author and article information

Journal

Journal ID (nlm-ta): BMJ Open

Journal ID (iso-abbrev): BMJ Open

Journal ID (hwp): bmjopen

Journal ID (publisher-id): bmjopen

Title: BMJ Open

Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )

ISSN (Electronic): 2044-6055

Publication date Collection: 2024

Publication date (Electronic): 19 June 2024

Volume: 14

Issue: 6

Electronic Location Identifier: e081282

Affiliations

[1 ] departmentCentre for Women’s Infectious Diseases , Ringgold_2282The Royal Women's Hospital , Parkville, Victoria, Australia

[2 ] Ringgold_34361Murdoch Children's Research Institute , Parkville, Victoria, Australia

[3 ] departmentKirby Institute , Ringgold_7800University of New South Wales , Sydney, New South Wales, Australia

[4 ] Australian Centre for the Prevention of Cervical Cancer , Melbourne, Victoria, Australia

[5 ] Ringgold_2282The Royal Women's Hospital , Parkville, Victoria, Australia

[6 ] departmentDepartment of Obstetrics, Gynaecology and Newborn Health , Ringgold_2281The University of Melbourne , Melbourne, Victoria, Australia

[7 ] Ringgold_116896Papua New Guinea Institute of Medical Research , Goroka, Papua New Guinea

[8 ] departmentObstetrics and Gynaecology , Modilon General Hospital , Madang, Papua New Guinea

[9 ] departmentTininga Clinic , Mount Hagen General Hospital , Mount Hagen, Western Highlands Province, Papua New Guinea

[10 ] departmentSchool of Population Global Health , Ringgold_2281The University of Melbourne , Melbourne, Victoria, Australia

[11 ] departmentKirby Institute -Faculty of Medicine , Ringgold_7800University of New South Wales , Sydney, New South Wales, Australia

[12 ] departmentSexual and Reproductive Health Unit , Ringgold_116896Papua New Guinea Institute of Medical Research , Goroka, Eastern Highlands Province, Papua New Guinea

Author notes

[Correspondence to ] Dr Monica Molano; monica.molanoluque@ 123456thewomens.org.au

AJV and GLM are joint senior authors.

Author information

Monica Molano http://orcid.org/0000-0002-9167-1234

John Bolnga http://orcid.org/0000-0003-1214-9817

Andrew John Vallely http://orcid.org/0000-0003-1558-4822

Article

Publisher ID: bmjopen-2023-081282

DOI: 10.1136/bmjopen-2023-081282

PMC ID: 11191780

PubMed ID: 38904134

SO-VID: 197c5fc9-a545-418e-a013-ddad1c17d5d9

License:

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

History

Date received : 23 October 2023

Date accepted : 02 June 2024

Funding

Funded by: Government of Papua New Guinea;

Award ID: ICRAS 297/1

Funded by: NHMRC Centre for Research Excellence;

Award ID: APP1135172

Funded by: FundRef http://dx.doi.org/10.13039/501100000925, National Health and Medical Research Council;

Award ID: 1013209

Award ID: 1104938

Award ID: APP1197951

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ScienceOpen disciplines: Medicine

Keywords: molecular diagnostics,molecular biology,oncogenes,human papillomavirus viruses

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ScienceOpen disciplines: Medicine

Keywords: molecular diagnostics, molecular biology, oncogenes, human papillomavirus viruses

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

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Abstract

Objective

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Primary and secondary outcome measures

Results

Conclusion

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European Journal of Microbiology and Immunology

Most cited references 42

Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

STARD 2015: an updated list of essential items for reporting diagnostic accuracy studies

Detecting cervical precancer and reaching underscreened women by using HPV testing on self samples: updated meta-analyses

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