title: CADM1 and MAL promoter methylation levels in hrHPV-positive cervical scrapes increase proportional to degree and duration of underlying cervical disease.
abstract: Combined detection of cell adhesion molecule 1 (CADM1) and T-lymphocyte maturation-associated protein (MAL) promoter methylation in cervical scrapes is a promising triage strategy for high-risk human papillomavirus (hrHPV)-positive women. Here, CADM1 and MAL DNA methylation levels were analysed in cervical scrapes of hrHPV-positive women with no underlying high-grade disease, high-grade cervical intraepithelial neoplasia (CIN) and cervical cancer. CADM1 and MAL methylation levels in scrapes were first related to CIN-grade of the corresponding biopsy and second to CIN-grade stratified by the presence of 'normal' or 'abnormal' cytology as present in the accompanying scrape preceding the cervical biopsy. The scrapes included 167 women with ≤ CIN1, 54 with CIN2/3 and 44 with carcinoma. In a separate series of hrHPV-positive scrapes of women with CIN2/3 (n = 48), methylation levels were related to duration of preceding hrHPV infection (PHI; <5 and ≥ 5 years). Methylation levels were determined by quantitative methylation-specific PCR and normal cytology scrapes of hrHPV-positive women with histologically ≤ CIN1 served as reference. CADM1 and MAL methylation levels increased proportional to severity of the underlying lesion, showing an increase of 5.3- and 6.2-fold in CIN2/3, respectively, and 143.5- and 454.9-fold in carcinomas, respectively, compared to the reference. Methylation levels were also elevated in CIN2/3 with a longer duration of PHI (i.e. 11.5- and 13.6-fold, respectively). Moreover, per histological category, methylation levels were higher in accompanying scrapes with abnormal cytology than in scrapes with normal cytology. Concluding, CADM1 and MAL promoter methylation levels in hrHPV-positive cervical scrapes are related to the degree and duration of underlying cervical disease and markedly increased in cervical cancer.
authors: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Mariska
authors: M
authors: Bierkens
authors: Albertus T
authors: AT
authors: Hesselink
authors: Chris J L M
authors: CJ
authors: Meijer
authors: Daniëlle A M
authors: DA
authors: Heideman
authors: G Bea A
authors: GB
authors: Wisman
authors: Ate G J
authors: AG
authors: van der Zee
authors: Peter J F
authors: PJ
authors: Snijders
authors: Renske D M
authors: RD
authors: Steenbergen
mesh_terms: D000328:Adult; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules / Q000235:genetics*; D002584:Cervix Uteri / Q000473:pathology / Q000821:virology*; D019175:DNA Methylation; D005260:Female; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics*; D008875:Middle Aged; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins / Q000235:genetics*; D027383:Papillomaviridae / Q000302:isolation & purification*; D011401:Promoter Regions, Genetic; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000821:virology*; D002578:Uterine Cervical Dysplasia / Q000235:genetics / Q000821:virology*
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: DNA methylation; cervical scrapes, human papillomavirus; high-grade cervical intraepithelial neoplasia; tumour suppressor genes