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Peer-reviewedCC BY 4.0International Journal of Cancer

Toward Objective Anal Cancer Screening: From Swab‐Based Genome‐Wide Methylation Marker Discovery to Novel Test Development

  • Kirsten Rozemeijer1,2
  • Jürgen Claesen3,4
  • Fernando Dias Gonçalves Lima1,2,5
  • Albertus T. Hesselink6
  • Phoebe Klingers6
  • Timo ter Braak1,2
  • Yara van den Burgt1,2
  • Chris J. L. M. Meijer6
  • Jan M. Prins7
  • Henry J. C. de Vries5,8,9,10
  • Mark A. van de Wiel3,4
  • Renske D. M. Steenbergen1,2
10 affiliations
  1. 1Department of Pathology Amsterdam UMC, location Vrije Universiteit Amsterdam Amsterdam the Netherlands
  2. 2Cancer Center Amsterdam, Imaging and Biomarkers Amsterdam the Netherlands
  3. 3Department of Epidemiology and Data Science Amsterdam UMC, location Vrije Universiteit Amsterdam Amsterdam the Netherlands
  4. 4Amsterdam Public Health Amsterdam the Netherlands
  5. 5Department of Dermatology University of Amsterdam, Amsterdam UMC Amsterdam the Netherlands
  6. 6Self‐Screen B.V. Amsterdam the Netherlands
  7. 7Department of Internal Medicine University of Amsterdam, Amsterdam UMC Amsterdam the Netherlands
  8. 8Center for Sexual Health, Department of Infectious Diseases Public Health Service Amsterdam Amsterdam the Netherlands
  9. 9Amsterdam Institute for Global Health and Development Amsterdam the Netherlands
  10. 10Amsterdam Institute for Infection and Immunity, Infectious Diseases Amsterdam the Netherlands
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Abstract

Anal high‐grade squamous intraepithelial lesions (HSIL:AIN2/3) are precursors to anal cancer, and early detection and treatment through screening is crucial for effective cancer prevention. Current guidelines recommend anal swab‐based screening and highlight the need for objective biomarkers to improve risk stratification. While DNA methylation markers have shown strong potential in anal biopsies, their performance in anal swabs is reduced, likely due to sample‐type dependency. This study aimed to identify a DNA methylation classifier specifically derived from anal swabs of men who have sex with men living with HIV (MSMLWH) to enhance diagnostic accuracy. Genome‐wide methylation profiling was performed on anal swabs from 36 HSIL:AIN3 cases, 34 controls (<low‐grade squamous intraepithelial lesions [<LSIL]), and 7 anal cancer patients using the 850 K Infinium MethylationEPIC BeadChip (Illumina). Candidate CpG sites were selected via logistic regression with adaptive multi‐group ridge penalties using co‐data and an empirical Bayes approach (ecpc). The top candidate markers were validated using quantitative methylation‐specific PCR (qMSP) on an independent series of 204 swabs to identify an optimal methylation classifier. Ecpc analysis identified 50 CpG sites with a combined area‐under‐the‐curve (AUC) of 0.80. All 10 candidate markers evaluated by qMSP showed significant increases in methylation levels associated with disease severity (p < 0.001). From these, a 3‐gene methylation classifier (NOVA1; TBXT; ZNF788) was identified, demonstrating excellent performance with an AUC of 0.80 (95% confidence interval: 0.72–0.88) in distinguishing HSIL:AIN3+ from ≤LSIL. This study identified a robust 3‐gene methylation classifier with strong potential for detecting HSIL:AIN3 and anal cancer when applied to anal swabs from MSMLWH.

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Cite

BibTeXRIS
BibTeX
@article{rozemeijer2026toward,
  title = {{Toward Objective Anal Cancer Screening: From Swab‐Based Genome‐Wide Methylation Marker Discovery to Novel Test Development}},
  author = {Kirsten Rozemeijer and Jürgen Claesen and Fernando Dias Gonçalves Lima and Albertus T. Hesselink and Phoebe Klingers and Timo ter Braak and Yara van den Burgt and Chris J. L. M. Meijer and Jan M. Prins and Henry J. C. de Vries and Mark A. van de Wiel and Renske D. M. Steenbergen},
  journal = {International Journal of Cancer},
  year = {2026},
  month = aug,
  doi = {10.1002/ijc.70708},
  url = {https://doi.org/10.1002/ijc.70708},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Toward Objective Anal Cancer Screening: From Swab‐Based Genome‐Wide Methylation Marker Discovery to Novel Test Development
AU  - Kirsten Rozemeijer
AU  - Jürgen Claesen
AU  - Fernando Dias Gonçalves Lima
AU  - Albertus T. Hesselink
AU  - Phoebe Klingers
AU  - Timo ter Braak
AU  - Yara van den Burgt
AU  - Chris J. L. M. Meijer
AU  - Jan M. Prins
AU  - Henry J. C. de Vries
AU  - Mark A. van de Wiel
AU  - Renske D. M. Steenbergen
PY  - 2026
DA  - 2026/08/27
JO  - International Journal of Cancer
DO  - 10.1002/ijc.70708
UR  - https://doi.org/10.1002/ijc.70708
AB  - Anal high‐grade squamous intraepithelial lesions (HSIL:AIN2/3) are precursors to anal cancer, and early detection and treatment through screening is crucial for effective cancer prevention. Current guidelines recommend anal swab‐based screening and highlight the need for objective biomarkers to improve risk stratification. While DNA methylation markers have shown strong potential in anal biopsies, their performance in anal swabs is reduced, likely due to sample‐type dependency. This study aimed to identify a DNA methylation classifier specifically derived from anal swabs of men who have sex with men living with HIV (MSMLWH) to enhance diagnostic accuracy. Genome‐wide methylation profiling was performed on anal swabs from 36 HSIL:AIN3 cases, 34 controls (<low‐grade squamous intraepithelial lesions [<LSIL]), and 7 anal cancer patients using the 850 K Infinium MethylationEPIC BeadChip (Illumina). Candidate CpG sites were selected via logistic regression with adaptive multi‐group ridge penalties using co‐data and an empirical Bayes approach (ecpc). The top candidate markers were validated using quantitative methylation‐specific PCR (qMSP) on an independent series of 204 swabs to identify an optimal methylation classifier. Ecpc analysis identified 50 CpG sites with a combined area‐under‐the‐curve (AUC) of 0.80. All 10 candidate markers evaluated by qMSP showed significant increases in methylation levels associated with disease severity (p < 0.001). From these, a 3‐gene methylation classifier (NOVA1; TBXT; ZNF788) was identified, demonstrating excellent performance with an AUC of 0.80 (95% confidence interval: 0.72–0.88) in distinguishing HSIL:AIN3+ from ≤LSIL. This study identified a robust 3‐gene methylation classifier with strong potential for detecting HSIL:AIN3 and anal cancer when applied to anal swabs from MSMLWH.
SN  - 0020-7136
SN  - 1097-0215
ER  -