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. 2022 Jan 13;9(5):ofac013.
doi: 10.1093/ofid/ofac013. eCollection 2022 May.

Triage by PAX1 and ZNF582 Methylation in Women With Cervical Intraepithelial Neoplasia Grade 3: A Multicenter Case-Control Study

Kun Fu  1   2   3 , Ming Lei  1   2   3 , Li-Sha Wu  2   3   4 , Jing-Cheng Shi  5 , Si-Yu Yang  1   2   3 , Wen-Qing Yang  1   2   3 , Jin-Yun Xu  1   2   3 , Ya-Nan Kang  1 , Zhen-Ying Yang  6 , Xuan Zhang  7 , Kang-Ni Huang  8 , Chi Han  9 , Yan Tian  1   2   3 , Yu Zhang  1   2   3
Affiliations

Triage by PAX1 and ZNF582 Methylation in Women With Cervical Intraepithelial Neoplasia Grade 3: A Multicenter Case-Control Study

Kun Fu et al. Open Forum Infect Dis. .

Abstract

Background: The colposcopy-conization inconsistency is common in women with cervical intraepithelial neoplasia grade 3 (CIN3). No adequate method has been reported to identify the final pathology of conization. In this study, we explored the ability of PAX1 and ZNF582 methylation to predict the pathological outcome of conization in advance.

Methods: This was a multicenter study and included 277 histologically confirmed CIN3 women who underwent cold knife conization (CKC) from January 2019 to December 2020. The methylation levels of PAX1 (PAX1m) and ZNF582 (ZNF582m) were determined by quantitative methylation-specific polymerase chain reaction (qMSP) and expressed in ΔCp. Receiver operating characteristic curves were used to evaluate predictive accuracy.

Results: The final pathological results in 48 (17.33%) patients were inflammation or low-grade squamous intraepithelial lesion (LSIL), 190 (68.59%) were high-grade squamous intraepithelial lesion (HSIL), and 39 (14.08%) were squamous cervical cancer (SCC). PAX1m and ZNF582m increased as lesions progressed from inflammation/LSIL, HSIL, to SCC. PAX1 and ZNF582 methylation yielded better prediction performance compared with common screening strategies, whether individually or combined. A 4.33-fold increase in the probability of inflammation/LSIL was observed in patients with lower ZNF582 methylation levels (ΔCpZNF582 ≥ 19.18). A 6.53-fold increase in SCC risk was observed in patients with elevated ZNF582 methylation (ΔCpZNF582 < 7.09).

Conclusions: DNA methylation would be an alternative screening method to triage and predict the final outcome of conization in CIN3 cases.

Keywords: DNA methylation; PAX1; ZNF582; cervical intraepithelial neoplasia grade 3; triage.

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Figures

Figure 1.
Figure 1.
The flowchart of patients. Abbreviations: AIS, adenocarcinoma in situ; CIN, cervical intraepithelial neoplasia; SCC, squamous cervical cancer.
Figure 2.
Figure 2.
The methylation value of PAX1 and ZNF582 in patients with different clinical outcomes. A, ΔCpPAX1 according to different grades of lesions. B, ΔCpZNF582 according to different grades of lesions. The dotted line corresponds to the threshold for distinguishing inflammation/LSIL/HSIL from SCC, and the dashed line corresponds to the threshold for distinguishing inflammation/LSIL from HSIL/SCC. Statistically significant (P < .05). Abbreviations: CIN, cervical intraepithelial neoplasia; hrHPV, high-risk HPV; HSIL, high-grade squamous intraepithelial lesion; LSIL, low-grade squamous intraepithelial lesion; SCC, squamous cervical cancer.
Figure 3.
Figure 3.
Receiver operating characteristic curves for the performance of PAX1, ZNF582 methylation, and the combination model of the 2 genes. A, inflammation/LSIL vs HSIL/SCC. B, inflammation/LSIL/HSIL vs SCC. C, inflammation/LSIL vs SCC. Abbreviations: AUC, area under the receiver operating characteristic curve; HSIL, high-grade squamous intraepithelial lesion; LSIL, low-grade squamous intraepithelial lesion; SCC, squamous cervical cancer.
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