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.
Highlights
Discovery and application of cancer biomarkers has been hampered by the extensive heterogeneities of tumorigenesis
While tumor-promoting genetic and epigenetic changes may differ among cancers of various sites and individual cancers of the same site [1], the universal carcinogenic effect of human papillomavirus virus (HPV) in virtually all cervical cancers stands out as an exception [2]
Cancer Medicine published by John Wiley & Sons Ltd
Summary
Discovery and application of cancer biomarkers has been hampered by the extensive heterogeneities of tumorigenesis. While tumor-promoting genetic and epigenetic changes may differ among cancers of various sites and individual cancers of the same site [1], the universal carcinogenic effect of human papillomavirus virus (HPV) in virtually all cervical cancers stands out as an exception [2]. The invariable site of transformation at the squamous-columnar (SC) junction [3] allows a precise target for screening. Various diagnostic biomarkers such as high-risk HPV DNA, p16, and methylated genes have been discovered from scraping specimens at this site with unprecedented success [4,5,6,7].
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