Performance of CADM1/MAL-methylation analysis for monitoring of women treated for high-grade CIN

Gynecol Oncol. 2016 Oct;143(1):135-142. doi: 10.1016/j.ygyno.2016.07.089. Epub 2016 Jul 16.


Introduction: Recent studies have shown that CADM1/MAL-methylation testing detects high-grade CIN lesions with a high short-term progression risk for cervical cancer. Women treated for CIN2/3 are at risk of post-treatment disease, representing either persistent (incompletely treated) or incident (early onset) lesions. Here, we evaluated CADM1/MAL-methylation analysis as potential tool for detecting recurrent high-grade CIN lesions (rCIN2/3).

Methods and materials: A multicenter prospective clinical cohort study was conducted among 364 women treated for CIN2/3. Cervical scrapes were taken prior to treatment, and six and 12months post-treatment and tested for cytology, hrHPV (plus genotype) and CADM1/MAL-methylation. When at six months either of these tests was positive, a colposcopy-directed biopsy was obtained. At 12months, all women underwent an exit-colposcopy with biopsy. In case of rCIN2/3, re-treatment was done.

Results: We found 28 rCIN2 (7.7%) and 14 rCIN3 (3.8%), resulting in a total recurrence rate of 11.5%. All 14 women with rCIN3 and 15/28 (54%) with rCIN2 showed hrHPV type-persistence. Of these, 9/14 (64%) rCIN3 and 8/15 (53%) rCIN2 were CADM1/MAL-methylation positive. All incident rCIN2, characterized by hrHPV genotype-switch, were CADM1/MAL-methylation negative. All three carcinomas found after re-treatment were CADM1/MAL-methylation positive. CADM1/MAL-methylation positivity at both baseline and follow-up significantly increased the risk of ≥rCIN3 (from 0.7% to 18.4%), and ≥rCIN2 (from 8.2% to 36.8%), compared to a consistently CADM1/MAL-methylation negative result (p-value: <0.001).

Conclusion: Post-treatment monitoring by CADM1/MAL-methylation analysis identifies women with an increased risk of rCIN2/3. Our results confirm previous data indicating that CADM1/MAL-methylation analysis provides a high reassurance against cancer.

Keywords: Cytology; DNA methylation; Human papillomavirus DNA test; Post-treatment; Re-LLETZ; Recurrent high-grade cervical intraepithelial neoplasia.

Publication types

  • Multicenter Study

MeSH terms

  • Adult
  • Cell Adhesion Molecule-1
  • Cell Adhesion Molecules / genetics*
  • DNA Methylation*
  • Female
  • Humans
  • Immunoglobulins / genetics*
  • Middle Aged
  • Myelin and Lymphocyte-Associated Proteolipid Proteins / genetics*
  • Prospective Studies
  • Uterine Cervical Dysplasia / genetics*
  • Uterine Cervical Neoplasms / genetics*


  • CADM1 protein, human
  • Cell Adhesion Molecule-1
  • Cell Adhesion Molecules
  • Immunoglobulins
  • MAL protein, human
  • Myelin and Lymphocyte-Associated Proteolipid Proteins