DNA methylation-based biomarkers in cervical cancer screening

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DNA methylation-based biomarkers in cervical cancer screening

Wednesday, 15.12.2021

Cervical cancer screening is an essential tool for reduction of associated incidence and mortality. Currently, high-risk Human Papilloma Virus (hr-HPV) testing is the first line of cervical cancer screening. This method is highly sensitive but with limited specificity. Thus, the research teams from IPOPorto and Administração Regional de Saúde do Norte tested DNA methylation-based biomarkers in formalin-fixed paraffin embedding samples and cervical smears for triage of women positive for hr-HPV. These markers were able to identify histological HSIL+ with high specificity and good sensitivity. Hence, this molecular test might be an important tool for increasing the cost-effectiveness of the cervical cancer screening Program of Northern Portugal.

 

Authors and Affiliations:

Sofia Salta1,2, Leonardo Maia-Moço1, Helena Estevão-Pereira1, José Pedro Sequeira1,3, Renata Vieira1,4, Carla Bartosch1,4,5, Sara Petronilho1,4,5, Paula Monteiro4, Ana Sousa4,6, Inês Baldaque 7, Jéssica Rodrigues 8,9, Hugo Sousa 6,7, Fernando Tavares 10, Rui Henrique 1,4,5, Carmen Jerónimo1,5

1Cancer Biology & Epigenetics Group, IPO Porto Research Center of IPO Porto (CI-IPOP) / RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto) / Porto Comprehensive Cancer Center (Porto.CCC), R. Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal

2Doctoral Program in Molecular Pathology and Genetics, School of Medicine and Biomedical Sciences -University of Porto (ICBAS-UP), 4050-313, Porto, Portugal.

3Master in Oncology, School of Medicine and Biomedical Sciences-University of Porto (ICBAS-UP), 4050-313, Porto, Portugal.

4Department of Pathology, Portuguese Oncology Institute of Porto (IPO Porto), R. Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.

5Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), Rua Jorge Viterbo Ferreira 228, 4050-513, Porto, Portugal

6Molecular Oncology and Viral Pathology Group, IPO Porto Research Center of IPO Porto (CI-IPOP) / RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto) / Porto Comprehensive Cancer Center (Porto.CCC), R. Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal

7Virology Service, Portuguese Oncology Institute of Porto (IPO Porto), R. Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.

8Cancer Epidemiology Group, IPO Porto Research Center of IPO Porto (CI-IPOP) / RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto) / Porto Comprehensive Cancer Center (Porto.CCC), R. Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal

9Centre of Mathematics (CMAT), University of Minho, Campus de Gualtar, 4710 - 057 Braga, Portugal

10Administração Regional de Saúde do Norte, I.P., Rua de Santa Catarina 1288, 4000-477, Porto, Portugal.

 

Abstract:

Cervical cancer remains a health concern. Effective screening programs are critical to reduce the incidence and mortality. High-risk HPV (hr-HPV) testing as primary screening tool discloses high sensitivity but suboptimal specificity. Adequate triage tests to reduce unnecessary colposcopy referrals and overdiagnosis/overtreatment are crucial. Hence, we aimed to validate a panel of DNA methylation-based markers as triage test for women hr-HPV+ in the population-based Regional Cervical Cancer Screening Program of Northern Portugal. Firstly, CADM1, MAL, FAM19A4 and hsa-miR124-2 promoter methylation levels were assessed by multiplex QMSP in a testing set of 402 FFPE tissue samples (159 normal samples and 243 cervical lesions, including 39 low-grade intraepithelial squamous lesions [LSIL], 59 high-grade intraepithelial squamous lesions [HSIL] and 145 cancerous lesions). Then, preliminary validation was performed in 125 hr-HPV+ cervical scrapes (including 59 normal samples, 30 LSIL, 34 HSIL and 2 cancerous lesions). Higher MALme , FAM19A4me and hsa-miR124-2me methylation levels were disclosed in histological HSIL or worse (HSIL+) in testing set. Individually, markers depicted over 86% specificity for HSIL+ detection. In validation set, all these genes significantly differed between histological HSIL+ and low-grade squamous intraepithelial lesions or less. In combination, these markers reached 74% specificity and 61% sensitivity for identification of histological HSIL+. We concluded that host gene methylation might constitute a useful referral triage tool of hr-HPV+ women enrolled in the Cervical Cancer Screening Program of Northern Portugal.

 

Journal: International Journal of Cancer

 

Link: https://onlinelibrary.wiley.com/doi/10.1002/ijc.33778