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Clin Infect Dis. 2018 Jul 27. doi: 10.1093/cid/ciy601. [Epub ahead of print]

Host cell DNA methylation markers for the detection of high-grade anal intraepithelial neoplasia and anal cancer.

Author information

1
Cancer Center Amsterdam, Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
2
Department of Internal Medicine, Division of Infectious Diseases, Academic Medical Center, Amsterdam, The Netherlands.
3
Department of Dermatology, Academic Medical Center, Amsterdam, The Netherlands.
4
Amsterdam Infection & Immunity Institute (AI&II), Amsterdam, The Netherlands.
5
Cancer Center Amsterdam, Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands.
6
Department of Epidemiology and Biostatistics, Amsterdam Public Health Research Institute, VU University Medical Center, Amsterdam, The Netherlands.
7
Department of Internal Medicine, OLVG, Amsterdam, The Netherlands.
8
DDL Diagnostic Laboratory, Rijswijk, The Netherlands.
9
STI Outpatient Clinic, Department of Infectious Diseases, Public Health Service of Amsterdam (GGD Amsterdam), Amsterdam, The Netherlands.

Abstract

Background:

High-grade anal intraepithelial neoplasia (AIN2/3; HGAIN) is highly prevalent in 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 are treated, resulting in overtreatment. We assessed the potential of host cell 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 controls (n=34) were analyzed for DNA methylation of nine genes using quantitative methylation-specific-PCR. Univariable and LASSO logistic regression, followed by leave-one-out-cross-validation (LOOCV) were used to determine the performance for the detection of AIN3 and cancer.

Results:

Methylation of all genes increased significantly with increasing severity of disease (p<2x10-6). HGAIN revealed a heterogeneous methylation pattern, with a subset resembling cancer. Four genes (ASCL1, SST, ZIC1 and ZNF582) showed remarkable performance for AIN3 and anal cancer detection (AUC>0.85). The most potent marker, ZNF582 (AUC=0.89), detected all cancers and 54% of AIN3 at 93% specificity. Slightly better performance (AUC=0.90) was obtained using a marker panel including five markers.

Conclusions:

DNA methylation is significantly associated with anal carcinogenesis. A methylation marker panel, including ZNF582, can identify anal cancer and HGAIN with a cancer-like methylation pattern. Validation studies are warranted to verify their potential for the screening and management of HIV+ MSM at risk for anal cancer.

PMID:
30060049
DOI:
10.1093/cid/ciy601

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