Molecular biomarkers in cervical cancer diagnosis: a critical appraisal

Litjens, Rogier J.N.T.M.; Hopman, Anton H. N.; Vijver, Koen K. Van de; Ramaekers, Frans C. S.; Kruitwagen, Roy F.P.M.; Kruse, Arnold‐Jan

doi:10.1517/17530059.2013.808621

Cited by 33 publications

(43 citation statements)

References 92 publications

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“…Dozens of methylated genes have been discovered to aid the screening and diagnosis of cervical cancer . Among them, CADM1 , MAL , and PCDH10 have been established as tumor suppressor genes, and their methylation are highly related to the severity of cervical noeplasia .…”

Section: Discussionmentioning

confidence: 99%

Global methylation silencing of clustered proto‐cadherin genes in cervical cancer: serving as diagnostic markers comparable to HPV

et al. 2014

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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.

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Section: Discussionmentioning

confidence: 99%

Global methylation silencing of clustered proto‐cadherin genes in cervical cancer: serving as diagnostic markers comparable to HPV

et al. 2014

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“…Distinguishing low‐grade from high‐grade dysplasia in genital lesions has particular importance for patient management and treatment, which may range from ‘watchful waiting’ to the use of topical therapy, cryotherapy, laser treatments and/or surgical excision. Positive p16 immunostaining has been used as a biomarker of high‐grade dysplasia and malignancy, particularly in cervical specimens . In non‐mucosal skin, p16 immunostaining is able to discriminate typical cases of condyloma acuminatum (CA) from bowenoid papulosis (BP), with perfect concordance to hematoxylin and eosin (H&E) findings …”

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confidence: 99%

Grading of atypia in genital skin lesions: routine microscopic evaluation and use of p16 immunostaining

et al. 2015

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“…Other cross-sectional studies in CIN have revealed patterns of aberrant DNA methylation in specific genes, including for tumor suppressor genes CDKN2A [34–37], MGMT [19, 38], HIC1, APC, CADM1, MAL , and RARβ [6, 9, 12]. However, as these prior studies were cross-sectional, the predictive nature and timing of the gene methylation has not yet been elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…However, because of the cross-sectional design of prior studies, it remains unclear whether the identified epigenetic changes preceded or followed the disease. Also, prior studies focused primarily on gene promoter regions where DNA methylation would be expected to silence genes, whereas the broad profile of aberrant DNA methylation events within genes associated with cervical tumorigenesis remains unknown [6, 12]. This is a major limitation, since differential methylation of intragenic sites (i.e., within exonic and intronic regions) have been associated with differential, and often increased, expression of tumor suppressor genes predictive of clinical progression in cervical cancer [13, 14].…”

Section: Introductionmentioning

confidence: 99%

Novel epigenetic changes in CDKN2A are associated with progression of cervical intraepithelial neoplasia

Wijetunga

Belbin

Burk

et al. 2016

Gynecologic Oncology

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Objective To conduct a comprehensive mapping of the genomic DNA methylation in CDKN2A, which codes for the p16INK4A and p14ARF proteins, and 14 of the most promising DNA methylation marker candidates previously reported to be associated with progression of low-grade cervical intraepithelial neoplasia (CIN1) to cervical cancer. Methods We analyzed DNA methylation in 68 HIV-seropositive and negative women with incident CIN1, CIN2, CIN3 and invasive cervical cancer, assaying 120 CpG dinucleotide sites spanning APC, CDH1, CDH13, CDKN2A, CDKN2B, DAPK1, FHIT, GSTP1, HIC1, MGMT, MLH1, RARB, RASSF1, TERT and TIMP3 using the Illumina Infinium array. Validation was performed using high resolution mapping of the target genes with HELP-tagging for 286 CpGs, followed by fine mapping of candidate genes with targeted bisulfite sequencing. We assessed for statistical differences in DNA methylation levels for each CpG loci assayed using univariate and multivariate methods correcting for multiple comparisons. Results In our discovery sample set, we identified dose dependent differences in DNA methylation with grade of disease in CDKN2A, APC, MGMT, MLH1 and HIC1, whereas single CpG locus differences between CIN2/3 and cancer groups were seen for CDH13, DAPK1 and TERT. Only those CpGs in the gene body of CDKN2A showed a monotonic increase in methylation between persistent CIN1, CIN2, CIN3 and cancers. Conclusion Our data suggests a novel link between early cervical disease progression and DNA methylation in a region downstream of the CDKN2A transcription start site that may lead to increased p16INK4A/p14ARF expression prior to development of malignant disease.

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Molecular biomarkers in cervical cancer diagnosis: a critical appraisal

Cited by 33 publications

References 92 publications

Global methylation silencing of clustered proto‐cadherin genes in cervical cancer: serving as diagnostic markers comparable to HPV

Global methylation silencing of clustered proto‐cadherin genes in cervical cancer: serving as diagnostic markers comparable to HPV

Grading of atypia in genital skin lesions: routine microscopic evaluation and use of p16 immunostaining

Novel epigenetic changes in CDKN2A are associated with progression of cervical intraepithelial neoplasia

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