TY - JOUR
T1 - Cancer Risk Stratification of Anal Intraepithelial Neoplasia in Human Immunodeficiency Virus-Positive Men by Validated Methylation Markers Associated With Progression to Cancer
AU - van der Zee, Ramon P.
AU - Richel, Olivier
AU - van Noesel, Carel J. M.
AU - Ciocănea-Teodorescu, Iuliana
AU - van Splunter, Annina P.
AU - ter Braak, Timo J.
AU - Nathan, Mayura
AU - Cuming, Tamzin
AU - Sheaff, Michael
AU - Kreuter, Alexander
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.
N1 - Publisher Copyright: © 2020 The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/6/15
Y1 - 2021/6/15
N2 - BACKGROUND: High-grade anal intraepithelial neoplasia (HGAIN; AIN2-3) is highly prevalent in HIV+ men, but only a minority of these lesions progress towards cancer. Currently, cancer progression risk cannot be established; therefore, no consensus exists on whether HGAIN should be treated. This study aimed to validate previously identified host cell DNA methylation markers for detection and cancer risk stratification of HGAIN. METHODS: A large independent cross-sectional series of 345 anal cancer, AIN3, AIN2, AIN1, and normal control biopsies of HIV+ men was tested for DNA methylation of 6 genes using quantitative methylation-specific PCR. We determined accuracy for detection of AIN3 and cancer (AIN3+) by univariable and multivariable logistic regression analysis, followed by leave-one-out cross-validation. Methylation levels were assessed in a series of 10 anal cancer cases with preceding HGAIN at similar anatomic locations, and compared with the cross-sectional series. RESULTS: Methylation levels of all genes increased with increasing severity of disease (P < .05). HGAIN revealed a heterogeneous methylation pattern, with a subset resembling cancer. ZNF582 showed highest accuracy (AUC = 0.88) for AIN3+ detection, slightly improved by addition of ASCL1 and SST (AUC = 0.89), forming a marker panel. In the longitudinal series, HGAIN preceding cancer displayed high methylation levels similar to cancers. CONCLUSIONS: We validated the accuracy of 5 methylation markers for the detection of anal (pre-) cancer. High methylation levels in HGAIN were associated with progression to cancer. These markers provide a promising tool to identify HGAIN in need of treatment, preventing overtreatment of HGAIN with a low cancer progression risk.
AB - BACKGROUND: High-grade anal intraepithelial neoplasia (HGAIN; AIN2-3) is highly prevalent in HIV+ men, but only a minority of these lesions progress towards cancer. Currently, cancer progression risk cannot be established; therefore, no consensus exists on whether HGAIN should be treated. This study aimed to validate previously identified host cell DNA methylation markers for detection and cancer risk stratification of HGAIN. METHODS: A large independent cross-sectional series of 345 anal cancer, AIN3, AIN2, AIN1, and normal control biopsies of HIV+ men was tested for DNA methylation of 6 genes using quantitative methylation-specific PCR. We determined accuracy for detection of AIN3 and cancer (AIN3+) by univariable and multivariable logistic regression analysis, followed by leave-one-out cross-validation. Methylation levels were assessed in a series of 10 anal cancer cases with preceding HGAIN at similar anatomic locations, and compared with the cross-sectional series. RESULTS: Methylation levels of all genes increased with increasing severity of disease (P < .05). HGAIN revealed a heterogeneous methylation pattern, with a subset resembling cancer. ZNF582 showed highest accuracy (AUC = 0.88) for AIN3+ detection, slightly improved by addition of ASCL1 and SST (AUC = 0.89), forming a marker panel. In the longitudinal series, HGAIN preceding cancer displayed high methylation levels similar to cancers. CONCLUSIONS: We validated the accuracy of 5 methylation markers for the detection of anal (pre-) cancer. High methylation levels in HGAIN were associated with progression to cancer. These markers provide a promising tool to identify HGAIN in need of treatment, preventing overtreatment of HGAIN with a low cancer progression risk.
KW - HIV
KW - anal cancer
KW - anal intraepithelial neoplasia
KW - host cell DNA methylation markers
KW - human papillomavirus
UR - http://www.scopus.com/inward/record.url?scp=85108386425&partnerID=8YFLogxK
U2 - https://doi.org/10.1093/cid/ciaa397
DO - https://doi.org/10.1093/cid/ciaa397
M3 - Article
C2 - 32266940
SN - 1058-4838
VL - 72
SP - 2154
EP - 2163
JO - Clinical Infectious Diseases
JF - Clinical Infectious Diseases
IS - 12
ER -