Dataset Information

Host Cell Deoxyribonucleic Acid Methylation Markers for the Detection of High-grade Anal Intraepithelial Neoplasia and Anal Cancer.

ABSTRACT:

Background

High-grade anal intraepithelial neoplasia (AIN2/3; HGAIN) is highly prevalent in human immunodeficiency virus positive (HIV+) men who have sex with men (MSM), but only a minority will eventually progress to cancer. Currently, the cancer risk cannot be established, and therefore all HGAIN is treated, resulting in overtreatment. We assessed host cell deoxyribonucleic acid (DNA) methylation markers for detecting HGAIN and anal cancer.

Methods

Tissue samples of HIV+ men with anal cancer (n = 26), AIN3 (n = 24), AIN2 (n = 42), AIN1 (n = 22) and HIV+ male controls (n = 34) were analyzed for methylation of 9 genes using quantitative methylation-specific polymerase chain reaction. Univariable and least absolute shrinkage and selection operator logistic regression, followed by leave-one-out cross-validation, were used to determine the performance for AIN3 and cancer detection.

Results

Methylation of all genes increased significantly with increasing severity of disease (P < 2 × 10-6). HGAIN samples revealed heterogeneous methylation patterns, with a subset resembling cancer. Four genes (ASCL1, SST, ZIC1,ZNF582) showed remarkable performance for AIN3 and anal cancer detection (area under the curve [AUC] > 0.85). ZNF582 (AUC = 0.89), detected all cancers and 54% of AIN3 at 93% specificity. Slightly better performance (AUC = 0.90) was obtained using a 5-marker panel.

Conclusions

DNA methylation is associated with anal carcinogenesis. A marker panel that includes ZNF582 identifies anal cancer and HGAIN with a cancer-like methylation pattern, warrantingvalidation studies to verify its potential for screening and management of HIV+ MSM at risk for anal cancer.

SUBMITTER: van der Zee RP

PROVIDER: S-EPMC6424081 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Publications

Host Cell Deoxyribonucleic Acid Methylation Markers for the Detection of High-grade Anal Intraepithelial Neoplasia and Anal Cancer.

van der Zee Ramon P RP Richel Olivier O van Noesel Carel J M CJM Novianti Putri W PW Ciocanea-Teodorescu Iuliana I van Splunter Annina P AP Duin Sylvia S van den Berk Guido E L GEL Meijer Chris J L M CJLM Quint Wim G V WGV de Vries Henry J C HJC Prins Jan M JM Steenbergen Renske D M RDM

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20190301 7

<h4>Background</h4>High-grade anal intraepithelial neoplasia (AIN2/3; HGAIN) is highly prevalent in human immunodeficiency virus positive (HIV+) men who have sex with men (MSM), but only a minority will eventually progress to cancer. Currently, the cancer risk cannot be established, and therefore all HGAIN is treated, resulting in overtreatment. We assessed host cell deoxyribonucleic acid (DNA) methylation markers for detecting HGAIN and anal cancer.<h4>Methods</h4>Tissue samples of HIV+ men wit ...[more]

PMID: 30060049

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Project description:IntroductionAnal cancer precursors, or high-grade anal intraepithelial neoplasia (HGAIN), are highly prevalent in HIV-seropositive (HIV+) men who have sex with men (MSM). Around 30% of lesions regress within 1 year, but current histopathological assessment is unable to distinguish between HGAIN likely to regress and HGAIN likely to persist or progress to cancer. We aim to assess if host cell DNA methylation markers can predict regression of HGAIN, thus determining the need for immediate treatment or active surveillance. This could reduce overtreatment and the associated anal and psycho-sexual morbidity.Methods and analysisThis is an active surveillance cohort study in three centres located in Amsterdam, the Netherlands, in 200 HIV+ MSM diagnosed with HGAIN. Participants will not be treated, but closely monitored during 24 months of follow-up with 6 monthly visits including cytology, and high-resolution anoscopy with biopsies. The primary study endpoint is histopathological regression of each baseline HGAIN lesion at the end of the study. Regression is defined as ≤low grade anal intraepithelial neoplasia in the exit biopsy at 24 months. Regression proportions in lesions with low versus high methylation levels (ASCL1, ZNF582), other biomarkers (HPV genotype, HPV-E4, p16INK4A, Ki-67) and immunological markers at baseline will be compared. Main secondary endpoints are the histological and clinical outcome (ie, the number of octants affected by HGAIN) of each baseline HGAIN lesion and overall HGAIN disease (i.e., all lesions combined) after each visit. The health-related quality of life of the study group will be compared with that of a control group of 50 HIV+ MSM receiving regular HGAIN treatment.Ethics and disseminationEthics approval was obtained from the Institutional Review Board of the Academic Medical Center (Amsterdam, The Netherlands; reference no. 2021_099). Participants are required to provide written informed consent. Findings will be disseminated through publication in peer-reviewed scientific journals and presentations at international scientific conferences; dissemination to policy makers and the target patient group will be achieved through our (inter-)national network, professional associations and collaboration with a patient representative organisation.Trial registration numberNL9664.

Dataset Information

Host Cell Deoxyribonucleic Acid Methylation Markers for the Detection of High-grade Anal Intraepithelial Neoplasia and Anal Cancer.

Background

Methods

Results

Conclusions

Publications

Host Cell Deoxyribonucleic Acid Methylation Markers for the Detection of High-grade Anal Intraepithelial Neoplasia and Anal Cancer.

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