Department of Pathology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, 410004, China.
Department of Medical Statistics, Hunan Hoomya Gene Technology Co., Ltd., Changsha, 410205, China.
BMC Cancer. 2024 Sep 20;24(1):1171. doi: 10.1186/s12885-024-12920-4.
The risk of cervical cancer progression in high-risk human papillomavirus (HR-HPV)-positive women is associated with cervical lesion severity and molecular heterogeneity. Classification systems based on p16 and Ki67 expression cumulative scores (0-3 each)-p16/Ki67 collectively known as an immunoscore [IS]-are an accurate and reproducible method for grading cervical intraepithelial neoplasia (CIN) lesions. Meanwhile, DNA methylation is an early event in the development of cervical cancer. Hence, this study evaluated the relationship among CIN, p16/Ki-67 IS, and PAX1/ZNF582 methylation.
In this study, 414 HPV-positive paraffin-embedded specimens were collected, and PAX1/ZNF582 methylation and the p16/ki67 IS were determined. A total of 43 invalid samples were excluded and 371 were included in the statistical analyses. There were 103 cervicitis, 95 CIN1, 71 CIN2, 89 CIN3, and 13 squamous cell carcinoma (SCC) cases. The association between PAX1/ZNF582 methylation and p16/Ki6 immunohistochemical staining scores was analyzed.
The ΔCp of PAX1 (PAX1 methylation) and ZNF582 (ZNF582 methylation) decreased with cervical lesion severity (Cuzick trend test, all P < 0.001). The severity of the cervical lesions and p16, Ki67, and p16/Ki67 IS showed an increasing trend (Multinomial Cochran-Armitage trend test, all P < 0.001). The prevalence of PAX1/ZNF582 increased with an increase in the IS of p16, Ki67, and p16/Ki67 (Cochran-Armitage trend test, all P < 0.001). In cervical SCC, the IS was 5-6, and the PAX1/ZNF582 was positive. Meanwhile, heterogeneity was observed in CIN lesions: 10 cases had an IS of 3-4 and were PAX1/ZNF582-positive in ≤ CIN1; 1 case had an IS of 0-2 and was PAX1/ZNF582-positive in CIN2/3.
Significant heterogeneity was observed in CIN lesions for p16 and Ki67 immunohistochemical staining scores and PAX1/ZNF582 methylation. This may help clinicians personalize the management of CIN based on the predicted short-term risk of cancer progression, minimizing the rate of missed CIN1 diagnoses and incorrect treatment of CIN2/3.
高危型人乳头瘤病毒（HR-HPV）阳性妇女的宫颈癌进展风险与宫颈病变严重程度和分子异质性相关。基于 p16 和 Ki67 表达累积评分（每个评分 0-3 分）的分类系统 - p16/Ki67 联合称为免疫评分（IS）- 是分级宫颈上皮内瘤变（CIN）病变的一种准确且可重复的方法。同时，DNA 甲基化是宫颈癌发展的早期事件。因此，本研究评估了 CIN、p16/Ki-67 IS 和 PAX1/ZNF582 甲基化之间的关系。
本研究共收集了 414 例 HPV 阳性石蜡包埋标本，检测了 PAX1/ZNF582 甲基化和 p16/ki67 IS。排除 43 例无效样本，最终纳入 371 例进行统计分析。其中宫颈炎 103 例，CIN1 95 例，CIN2 71 例，CIN3 89 例，鳞癌（SCC）13 例。分析了 PAX1/ZNF582 甲基化与 p16/Ki6 免疫组化染色评分之间的关系。
PAX1（PAX1 甲基化）和 ZNF582（ZNF582 甲基化）的ΔCp 值随宫颈病变严重程度降低（Cuzick 趋势检验，均 P<0.001）。宫颈病变的严重程度以及 p16、Ki67 和 p16/Ki67 IS 呈递增趋势（多分类 Cochran-Armitage 趋势检验，均 P<0.001）。PAX1/ZNF582 的阳性率随 p16、Ki67 和 p16/Ki67 IS 的增加而升高（Cochran-Armitage 趋势检验，均 P<0.001）。在宫颈 SCC 中，IS 为 5-6，且 PAX1/ZNF582 阳性。同时，CIN 病变中观察到异质性：10 例 IS 为 3-4，≤CIN1 中 PAX1/ZNF582 阳性；1 例 IS 为 0-2，CIN2/3 中 PAX1/ZNF582 阳性。
p16 和 Ki67 免疫组化染色评分以及 PAX1/ZNF582 甲基化在 CIN 病变中存在显著异质性。这有助于临床医生根据癌症进展的短期预测风险对 CIN 进行个体化管理，最大限度地减少 CIN1 漏诊和 CIN2/3 治疗不当的风险。
