Evaluation of a methylation classifier for predicting pre-cancer lesion among women with abnormal results between HPV16/18 and cytology

Abstract

Background: Although HPV testing and cytology detection are successful for cervical screening in China, additional procedures are urgently required to avoid misdiagnosis and overtreatment. In this multicenter study, we collected cervical samples during screening in clinics. A total of 588 women with HPV16/18+ and/or cytology result ≥HSIL+ (high-grade squamous intraepithelial lesion or worse) were referred to colposcopy for pathological diagnosis. Methylation of S5 was quantified by pyrosequencing. Results: The S5 classifier separates women with ≥HSIL+ from <HSIL with a high area under the curve (AUC) of 0.86 (95% CI 0.840-0.910). The cutoff of 2.85 was conducted in our study. Remarkably, all cancer cases (n = 67) were detected by S5. The sensitivity of S5 for "≥HSIL+" was 89.1% (95% CI 86.2-92.4%), and the specificity was 76.6% (95% CI 72.2-78.9%). S5 could reduce unnecessary colposcopy referrals by 74% (95% CI 71.3-78.1%) with virtually no loss of sensitivity for HSIL+, and the follow-up data support the utility of the S5 classifier. Conclusion: The S5 classifier with high sensitivity and specificity provided increasing diagnostic information for women with HPV16/18+ and/or cytology results and could reduce the numerous unnecessary colposcopy referrals and avoid overtreatment.

Cervical cancer: Epidemiology, risk factors and screening

“…Recently, the correlation between increased HPV CpG site methylation levels and high-grade cervical lesions has also been demonstrated in numerous studies and has facilitated the development of quantitative assays targeted CpG methylation ( 50 , 51 ). .…”

Epigenetic and Transcriptomic Regulation Landscape in HPV+ Cancers: Biological and Clinical Implications

“…S5 evaluates the methylation of EPB41L3 and the late region of HPV16, −18, −31, and −33 with a sensitivity of 74% and a specificity of 90% ( Lorincz et al, 2016 ; Cook et al, 2019 ). Additionally, in cases with ASCUS, S5 can discriminate between low-grade (>CIN1 LSIL) and high-grade (CIN2+, HSIL) lesions ( Hernandez-Lopez et al, 2019 ; Gu et al, 2020 ). Recently, a multicenter analysis demonstrated a sensitivity of 99.8% for detecting CIN3 and invasive carcinoma ( Banila et al, 2022 ).…”

Epigenetic approaches for cervical neoplasia screening (Review)

“…The S5 methylation assay provided a 90% sensitivity and a 49% specificity for detecting high-grade cervical lesions in a cohort of women from United Kingdom ( 97 ). In a Mexican study, the S5 classifier was able to detect all cancer cases, reducing the number of colposcopies required by 30-50% as opposed to triage by cytology and HPV16/18 genotyping ( 42 ) Considering that only a small percentage of lesions progress to cervical cancer and the process is rather slow, it is important to identify accordingly the women who are at risk of developing a malignancy and avoid unnecessary expenses and treatment for the women who are most likely to overcome naturally the infection ( 42 , 98 ).…”