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

Ramon P. van der Zee, Olivier Richel, Carel J. M. van Noesel, Putri W. Novianti, Iuliana Ciocanea-Teodorescu, Annina P. van Splunter, Sylvia Duin, Guido E. L. van den Berk, Chris J. L. M. Meijer, Wim G. V. Quint, Henry J. C. de Vries, Jan M. Prins, Renske D. M. Steenbergen

Research output: Contribution to journalArticleAcademicpeer-review

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.
Original languageEnglish
Pages (from-to)1110-1117
JournalClinical Infectious Diseases
Volume68
Issue number7
Early online date27 Jul 2018
DOIs
Publication statusPublished - 2019

Cite this

van der Zee, Ramon P. ; Richel, Olivier ; van Noesel, Carel J. M. ; Novianti, Putri W. ; Ciocanea-Teodorescu, Iuliana ; van Splunter, Annina P. ; Duin, Sylvia ; van den Berk, Guido E. L. ; Meijer, Chris J. L. M. ; Quint, Wim G. V. ; de Vries, Henry J. C. ; Prins, Jan M. ; Steenbergen, Renske D. M. / Host Cell Deoxyribonucleic Acid Methylation Markers for the Detection of High-grade Anal Intraepithelial Neoplasia and Anal Cancer. In: Clinical Infectious Diseases. 2019 ; Vol. 68, No. 7. pp. 1110-1117.
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title = "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.",
author = "{van der Zee}, {Ramon P.} and Olivier Richel and {van Noesel}, {Carel J. M.} and Novianti, {Putri W.} and Iuliana Ciocanea-Teodorescu and {van Splunter}, {Annina P.} and Sylvia Duin and {van den Berk}, {Guido E. L.} and Meijer, {Chris J. L. M.} and Quint, {Wim G. V.} and {de Vries}, {Henry J. C.} and Prins, {Jan M.} and Steenbergen, {Renske D. M.}",
year = "2019",
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Host Cell Deoxyribonucleic Acid Methylation Markers for the Detection of High-grade Anal Intraepithelial Neoplasia and Anal Cancer. / van der Zee, Ramon P.; Richel, Olivier; van Noesel, Carel J. M.; Novianti, Putri W.; Ciocanea-Teodorescu, Iuliana; van Splunter, Annina P.; Duin, Sylvia; van den Berk, Guido E. L.; Meijer, Chris J. L. M.; Quint, Wim G. V.; de Vries, Henry J. C.; Prins, Jan M.; Steenbergen, Renske D. M.

In: Clinical Infectious Diseases, Vol. 68, No. 7, 2019, p. 1110-1117.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Host Cell Deoxyribonucleic Acid Methylation Markers for the Detection of High-grade Anal Intraepithelial Neoplasia and Anal Cancer

AU - van der Zee, Ramon P.

AU - Richel, Olivier

AU - van Noesel, Carel J. M.

AU - Novianti, Putri W.

AU - Ciocanea-Teodorescu, Iuliana

AU - van Splunter, Annina P.

AU - Duin, Sylvia

AU - van den Berk, Guido E. L.

AU - Meijer, Chris J. L. M.

AU - Quint, Wim G. V.

AU - de Vries, Henry J. C.

AU - Prins, Jan M.

AU - Steenbergen, Renske D. M.

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

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UR - https://www.ncbi.nlm.nih.gov/pubmed/30060049

U2 - 10.1093/cid/ciy601

DO - 10.1093/cid/ciy601

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SP - 1110

EP - 1117

JO - Clinical Infectious Diseases

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