title: CADM1 and MAL methylation status in cervical scrapes is representative of the most severe underlying lesion in women with multiple cervical biopsies.
abstract: Recent studies have shown that CADM1/MAL methylation levels in cervical scrapes increase with severity and duration of the underlying cervical intraepithelial neoplasia (CIN) lesion. Multiple lesions of different histological grades and duration are frequently present on the cervix. To gain more insight into the possible epigenetic heterogeneity and its consequences for the methylation status in cervical scrapes, we performed an exploratory study of CADM1/MAL methylation in different grades of CIN lesions present in women with multiple cervical biopsies. CADM1-M18 and MAL-M1 methylation was assessed using a standardised, multiplex, quantitative methylation specific PCR on 178 biopsies with various grades of CIN in 65 women, and in their corresponding cervical scrapes. CADM1/MAL methylation positivity increased with disease severity, from 5.5% in normal biopsies to 63.3% and 100% in biopsies with CIN3 and cervical cancer, respectively. In the majority (8/9) of women where besides a CIN2/3 lesion a biopsy from normal cervical tissue was present, the CIN2/3 biopsy was CADM1/MAL methylation positive and the normal biopsy was CADM1/MAL methylation negative. A good concordance (78%) was found between CADM1/MAL methylation results on the scrapes and the biopsy with the worst diagnosis, particularly between samples of women with CIN3 and cervical cancer (92% and 100% concordance, respectively). Thus, in women with multiple cervical biopsies, CADM1/MAL methylation increases with severity of the lesion and is lesion-specific. CADM1/MAL methylation status in cervical scrapes appears to be representative of the worst underlying lesion, particularly for CIN3 and cervical cancer.
authors.affiliation: DDL Diagnostic Laboratory, Rijswijk, The Netherlands.
authors.forename: Romy
authors.initials: R
authors.lastname: van Baars
authors.affiliation: DDL Diagnostic Laboratory, Rijswijk, The Netherlands.
authors.forename: Jacolien
authors.initials: J
authors.lastname: van der Marel
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Peter J F
authors.initials: PJ
authors.lastname: Snijders
authors.affiliation: Department of Obstetrics and Gynaecology, Hospital Clínic, Barcelona, Spain.
authors.forename: Agata
authors.initials: A
authors.lastname: Rodriquez-Manfredi
authors.affiliation: Roosevelt Kliniek, Leiden, The Netherlands.
authors.forename: Bram
authors.initials: B
authors.lastname: ter Harmsel
authors.affiliation: DDL Diagnostic Laboratory, Rijswijk, The Netherlands.
authors.forename: Henk A M
authors.initials: HA
authors.lastname: van den Munckhof
authors.affiliation: Department of Pathology, CRESIB (Centre De Recerca En Salut Internacional De Barcelona)-Hospital Clinic, Faculty of Medicine-University of Barcelona, Barcelona, Spain.
authors.forename: Jaume
authors.initials: J
authors.lastname: Ordi
authors.affiliation: Department of Obstetrics and Gynaecology, Hospital Clínic, Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: del Pino
authors.affiliation: DDL Diagnostic Laboratory, Rijswijk, The Netherlands.
authors.forename: Miekel M
authors.initials: MM
authors.lastname: van de Sandt
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.
authors.forename: N
authors.initials: N
authors.lastname: Wentzensen
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Chris J L M
authors.initials: CJ
authors.lastname: Meijer
authors.affiliation: DDL Diagnostic Laboratory, Rijswijk, The Netherlands.
authors.forename: Wim G V
authors.initials: WG
authors.lastname: Quint
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules / Q000235:genetics*; D003127:Colposcopy; D019175:DNA Methylation; D005260:Female; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000235:genetics*; D008875:Middle Aged; D060885:Multiplex Polymerase Chain Reaction; D017472:Receptors, Interleukin-1 / Q000235:genetics*; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000473:pathology*; D014626:Vaginal Smears; D055815:Young Adult; D002578:Uterine Cervical Dysplasia / Q000235:genetics / Q000473:pathology*
chemical_list: C403514:CADM1 protein, human; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; D008562:Membrane Glycoproteins; D017472:Receptors, Interleukin-1; C434984:TIRAP protein, human
keywords: DNA methylation; cervical cancer; cervical intraepithelial neoplasia; human papillomavirus; tumour suppressor genes