title: Performance of CADM1/MAL-methylation analysis for monitoring of women treated for high-grade CIN.
abstract: BACKGROUND
  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
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands; Department of Obstetrics and Gynecology, Flevo Hospital, Almere, The Netherlands. Electronic address: m.uijterwaal@vumc.nl.
authors.forename: M H
authors.initials: MH
authors.lastname: Uijterwaal
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: ma.vanzummeren@vumc.nl.
authors.forename: M
authors.initials: M
authors.lastname: van Zummeren
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: m.kocken@vumc.nl.
authors.forename: M
authors.initials: M
authors.lastname: Kocken
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: r.luttmer1@vumc.nl.
authors.forename: R
authors.initials: R
authors.lastname: Luttmer
authors.affiliation: Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: h.berkhof@vumc.nl.
authors.forename: J
authors.initials: J
authors.lastname: Berkhof
authors.affiliation: Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: b.witte@vumc.nl.
authors.forename: B I
authors.initials: BI
authors.lastname: Witte
authors.affiliation: Department of Obstetrics and Gynecology, Flevo Hospital, Almere, The Netherlands. Electronic address: mbaal@flevoziekenhuis.nl.
authors.forename: W M
authors.initials: WM
authors.lastname: van Baal
authors.affiliation: Department of Obstetrics and Gynecology, Sint Antonius Hospital, Nieuwegein, The Netherlands. Electronic address: p.graziosi@antoniusziekenhuis.nl.
authors.forename: G C M
authors.initials: GCM
authors.lastname: Graziosi
authors.affiliation: Department of Gynecological Oncology, UMCU Utrecht Cancer Center, The Netherlands. Electronic address: r.verheijen@umcutrecht.nl.
authors.forename: R H M
authors.initials: RHM
authors.lastname: Verheijen
authors.affiliation: Department of Obstetrics and Gynecology, Erasmus MC University Medical Center, Rotterdam, The Netherlands. Electronic address: t.helmerhorst@erasmusmc.nl.
authors.forename: T J M
authors.initials: TJM
authors.lastname: Helmerhorst
authors.affiliation: Department of Obstetrics and Gynecology, Onze Lieve Vrouwen Gasthuis West, Amsterdam, The Netherlands. Electronic address: d.dijken@olvg.nl.
authors.forename: D K E
authors.initials: DKE
authors.lastname: van Dijken
authors.affiliation: Department of Obstetrics and Gynecology, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: jwm.spruijt@vumc.nl.
authors.forename: J W M
authors.initials: JWM
authors.lastname: Spruijt
authors.affiliation: Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands. Electronic address: f.vankemenade@erasmusmc.nl.
authors.forename: F J
authors.initials: FJ
authors.lastname: van Kemenade
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: d.vd.vegt@quicknet.nl.
authors.forename: N
authors.initials: N
authors.lastname: Fransen-Daalmeijer
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: M.Lettink@vumc.nl.
authors.forename: M
authors.initials: M
authors.lastname: Bekker-Lettink
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: dam.heideman@vumc.nl.
authors.forename: D A M
authors.initials: DAM
authors.lastname: Heideman
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: pjf.snijders@vumc.nl.
authors.forename: P J F
authors.initials: PJF
authors.lastname: Snijders
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: r.steenbergen@vumc.nl.
authors.forename: R D M
authors.initials: RDM
authors.lastname: Steenbergen
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: cjlm.meijer@vumc.nl.
authors.forename: C J L M
authors.initials: CJLM
authors.lastname: Meijer
mesh_terms: D000328:Adult; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics*; D008875:Middle Aged; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins / Q000235:genetics*; D011446:Prospective Studies; D002583:Uterine Cervical Neoplasms / Q000235:genetics*; D002578:Uterine Cervical Dysplasia / Q000235:genetics*
chemical_list: C403514:CADM1 protein, human; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; C569026:MAL protein, human; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins
keywords: Cytology; DNA methylation; Human papillomavirus DNA test; Post-treatment; Re-LLETZ; Recurrent high-grade cervical intraepithelial neoplasia