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Characterization of cervical biopsies of women with HIV and HPV co-infection using p16ink4a, ki-67 and HPV E4 immunohistochemistry and DNA methylation.
Modern Pathology ( IF 7.5 ) Pub Date : 2020-04-06 , DOI: 10.1038/s41379-020-0528-x
Wieke W Kremer 1 , Frederique J Vink 1 , Marjolein van Zummeren 1 , Greta Dreyer 2 , Lawrence Rozendaal 1 , John Doorbar 3 , Maaike C G Bleeker 1 , Chris J L M Meijer 1
Affiliation  

This study aims to characterize cervical intraepithelial neoplasia (CIN) in women living with HIV using biomarkers. Immunohistochemical (IHC) staining for human papillomavirus (HPV) E4 protein indicates CIN with productive HPV infection, whereas Ki-67 and p16ink4a indicate CIN with transforming characteristics, which may be further characterized using DNA hypermethylation, indicative for advanced transforming CIN. Cervical biopsies (n = 175) from 102 HPV positive women living with HIV were independently reviewed by three expert pathologists. The consensus CIN grade was used as reference standard. IHC staining patterns were scored for Ki-67 (0–3), p16ink4a (0–3), and E4 (0–2) and correlated to methylation levels of four cellular genes in corresponding cervical scrapes. Reference standards and immunoscores were obtained from 165 biopsies:15 no dysplasia, 91 CIN1, 31 CIN2, and 28 CIN3. Ki-67 and p16ink4a scores increased with increasing CIN grade, while E4 positivity was highest in CIN1 and CIN2 lesions. E4 positive CIN1 lesions had higher Ki-67 and p16ink4a scores and higher methylation levels compared with E4 negative CIN1 lesions. E4 positive biopsies with low cumulative Ki-67/p16 ink4a immunoscores (0-3) had significantly higher methylation levels compared with E4 negative biopsies. No significant differences in Ki-67 and p16ink4a scores and methylation levels were observed between E4 negative and positive CIN2 or CIN3 lesions. The presence of high methylation levels in scrapes of CIN lesions with IHC characteristics of both productive (E4 positive) and transforming infections (increased Ki-67/p16ink4a expression) in women living with HIV might indicate a rapid aggressive course of HPV infections towards cancer in these women.



中文翻译:

使用 p16ink4a、ki-67 和 HPV E4 免疫组织化学和 DNA 甲基化对 HIV 和 HPV 合并感染女性的宫颈活检进行表征。

本研究旨在使用生物标志物来表征感染 HIV 的女性的宫颈上皮内瘤变 (CIN)。人乳头瘤病毒 (HPV) E4 蛋白的免疫组织化学 (IHC) 染色表明 CIN 具有生产性 HPV 感染,而 Ki-67 和 p16 ink4a表明 CIN 具有转化特征,可以使用 DNA 高甲基化进一步表征,表明晚期转化 CIN。来自 102 名感染 HIV 的 HPV 阳性女性的宫颈活检(n  = 175)由三位专家病理学家独立审查。共识 CIN 等级用作参考标准。对 Ki-67 (0–3)、p16 ink4a的 IHC 染色模式进行评分(0–3) 和 E4 (0–2),并与相应宫颈刮痕中四种细胞基因的甲基化水平相关。从 165 个活检中获得参考标准和免疫评分:15 个无异型增生、91 个 CIN1、31 个 CIN2 和 28 个 CIN3。Ki-67 和 p16 ink4a评分随着 CIN 分级的增加而增加,而 E4 阳性在 CIN1 和 CIN2 病变中最高。与E4 阴性 CIN1 病变相比,E4 阳性 CIN1 病变具有更高的 Ki-67 和 p16 ink4a评分以及更高的甲基化水平。与 E4 阴性活检相比,具有低累积 Ki-67/p16 ink4a免疫评分 (0-3) 的 E4 阳性活检具有显着更高的甲基化水平。Ki-67 和 p16 ink4a无显着差异在 E4 阴性和阳性 CIN2 或 CIN3 病变之间观察评分和甲基化水平。在感染 HIV 的女性中,具有生产性(E4 阳性)和转化性感染(Ki-67/p16 ink4a表达增加)的 IHC 特征的 CIN 病变擦伤中存在高甲基化水平可能表明 HPV 感染对癌症的快速侵袭性过程在这些女人中。

更新日期:2020-04-24
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