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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

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Title: Characterization of cervical biopsies of women with HIV and HPV co-infection using p16ink4a, ki-67 and HPV E4 immunohistochemistry and DNA methylation
Authors: Wieke W. Kremer, Frederique J. Vink, Marjolein van Zummeren, Greta Dreyer, Lawrence Rozendaal, John Doorbar, Maaike C.G. Bleeker, Chris J. L.M. Meijer
Source: Kremer, W W, Vink, F J, van Zummeren, M, Dreyer, G, Rozendaal, L, Doorbar, J, Bleeker, M C G & Meijer, C J L M 2020, '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, vol. 33, no. 10, pp. 1968-1978. https://doi.org/10.1038/s41379-020-0528-x, https://doi.org/10.1038/s41379-020-0528-x
Publisher Information: Elsevier BV, 2020.
Publication Year: 2020
Subject Terms: Adult, 0301 basic medicine, Biopsy, Uterine Cervical Neoplasms, HIV Infections/complications, HIV Infections, 03 medical and health sciences, 0302 clinical medicine, Biomarkers, Tumor, Humans, Tumor/analysis, Papillomavirus Infections/complications, Cyclin-Dependent Kinase Inhibitor p16, Oncogene Proteins, Uterine Cervical Neoplasms/pathology, Coinfection, Papillomavirus Infections, Oncogene Proteins, Viral, DNA Methylation, Middle Aged, Uterine Cervical Dysplasia, Immunohistochemistry, 3. Good health, Ki-67 Antigen, Cervical Intraepithelial Neoplasia/pathology, Cyclin-Dependent Kinase Inhibitor p16/analysis, Female, Neoplasm Grading/methods, Viral/analysis, Neoplasm Grading, Biomarkers, Ki-67 Antigen/analysis
Description: 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.
Document Type: Article
Language: English
ISSN: 0893-3952
DOI: 10.1038/s41379-020-0528-x
Access URL: https://pubmed.ncbi.nlm.nih.gov/32249820
https://pubmed.ncbi.nlm.nih.gov/32249820/
https://www.ncbi.nlm.nih.gov/pubmed/32249820
https://www.nature.com/articles/s41379-020-0528-x
https://www.nature.com/articles/s41379-020-0528-x.pdf
https://www.narcis.nl/publication/RecordID/oai%3Apure.atira.dk%3Apublications%2Fc117bde6-9ea8-4872-ad9b-2d65bfb6381a
https://www.scilit.net/article/17650780f898ee81195372732b36017f
https://research.vumc.nl/en/publications/8c1b7a24-ce9e-4eef-9914-337ca1ae2b4c
https://pure.amsterdamumc.nl/en/publications/f5905707-e640-473a-9295-945a8e2e3f6d
https://doi.org/10.1038/s41379-020-0528-x
Rights: Elsevier Non-Commercial
Accession Number: edsair.doi.dedup.....8553f3390b268cc0c63f5c1b050c6f58
Database: OpenAIRE
Description
Abstract: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.
ISSN:08933952
DOI:10.1038/s41379-020-0528-x