title: Global methylation silencing of clustered proto-cadherin genes in cervical cancer: serving as diagnostic markers comparable to HPV.
abstract: Epigenetic remodeling of cell adhesion genes is a common phenomenon in cancer invasion. This study aims to investigate global methylation of cell adhesion genes in cervical carcinogenesis and to apply them in early detection of cancer from cervical scraping. Genome-wide methylation array was performed on an investigation cohort, including 16 cervical intraepithelial neoplasia 3 (CIN3) and 20 cervical cancers (CA) versus 12 each of normal, inflammation and CIN1 as controls. Twelve members of clustered proto-cadherin (PCDH) genes were collectively methylated and silenced, which were validated in cancer cells of the cervix, endometrium, liver, head and neck, breast, and lung. In an independent cohort including 107 controls, 66 CIN1, 85 CIN2/3, and 38 CA, methylated PCDHA4 and PCDHA13 were detected in 2.8%, 24.2%, 52.9%, and 84.2% (P < 10(-25) ), and 2.8%, 24.2%, 50.6%, and 94.7% (P < 10(-29) ), respectively. In diagnosis of CIN2 or more severe lesion of the cervix, a combination test of methylated PCDHA4 or PCDHA13 from cervical scraping had a sensitivity, specificity, positive predictive value, and negative predictive value of 74.8%, 80.3%, 73%, and 81.8%, respectively. Testing of this combination from cervical scraping is equally sensitive but more specific than human papillomavirus (HPV) test in diagnosis of CIN2 or more severe lesions. The study disclosed a collective methylation of PCDH genes in cancer of cervix and other sites. At least two of them can be promising diagnostic markers for cervical cancer noninferior to HPV.
authors.affiliation: Department of Research, Center for Cervical Cancer Prevention, Buddhist Tzu Chi General Hospital, Hualien, Taiwan; Institute of Medical Sciences, School of Medicine, Tzu Chi University, Hualien, Taiwan.
authors.forename: Kai-Hung
authors.initials: KH
authors.lastname: Wang
authors.forename: Cuei-Jyuan
authors.initials: CJ
authors.lastname: Lin
authors.forename: Chou-Jen
authors.initials: CJ
authors.lastname: Liu
authors.forename: Dai-Wei
authors.initials: DW
authors.lastname: Liu
authors.forename: Rui-Lan
authors.initials: RL
authors.lastname: Huang
authors.forename: Dah-Ching
authors.initials: DC
authors.lastname: Ding
authors.forename: Ching-Feng
authors.initials: CF
authors.lastname: Weng
authors.forename: Tang-Yuan
authors.initials: TY
authors.lastname: Chu
mesh_terms: D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001374:Azacitidine / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics; D015820:Cadherins / Q000235:genetics*; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D018899:CpG Islands; D019175:DNA Methylation / Q000187:drug effects; D018450:Disease Progression; D005260:Female; D020868:Gene Silencing; D056426:Genetic Loci; D006801:Humans; D008875:Middle Aged; D005810:Multigene Family; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D027383:Papillomaviridae / Q000235:genetics; D030361:Papillomavirus Infections / Q000150:complications / Q000821:virology; D012720:Severity of Illness Index; D002583:Uterine Cervical Neoplasms / Q000175:diagnosis* / Q000235:genetics*
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D015820:Cadherins; D001374:Azacitidine
keywords: Cancer biomarker; DNA methylation; HPV; cervical cancer; clustered proto-cadherin