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1.
Int J Cancer ; 144(4): 746-754, 2019 02 15.
Article in English | MEDLINE | ID: mdl-30259973

ABSTRACT

Objective triage strategies are required to prevent unnecessary referrals for colposcopy in population-based screening programs using primary high-risk human papillomavirus (hrHPV) testing. We have identified several DNA methylation markers with high sensitivity and specificity for detection of high-grade cervical intraepithelial neoplasia or worse (CIN2+) in women referred for colposcopy. Our study assessed diagnostic potential of these methylation markers in a hrHPV-positive screening cohort. All six markers (JAM3, EPB41L3, C13orf18, ANKRD18CP, ZSCAN1 and SOX1) showed similar association across histology in the hrHPV-positive cohort when compared to the Dutch cohort (each p > 0.15). Sensitivity for CIN2+ was higher using methylation panel C13orf18/EPB41L3/JAM3 compared to the other 2 panels (80% vs. 60% (ANKRD18CP/C13orf18/JAM3) and 63% (SOX1/ZSCAN1), p = 0.01). For CIN3+ all three methylation panels showed comparable sensitivity ranging from 68% (13/19) to 95% (18/19). Specificity of SOX1/ZSCAN1 panel (84%, 167/200) was considerably higher compared to ANKRD18CP/C13orf18/JAM3 (68%, 136/200, p = 2 × 10-5 ) and C13orf18/EPB41L3/JAM3 (66%, 132/200, p = 2 × 10-7 ). High negative predictive value (NPV) (91-95% and 96-99%) was observed for CIN2+ and CIN3+, for all three methylation panels, while positive predictive value (PPV) varied from 25 to 40% for CIN2+ and 15-27% for CIN3+. Interestingly, 118/235 samples were negative for all six markers (including 106 controls (89.8%), 6 CIN1 (5.1%), 5 CIN2 (4.2%) and 1 CIN3 (0.8%)). Methylation results from both independent cohorts were comparable as well as high sensitivity for detection of cervical cancer and its high-grade precursors in hrHPV-positive population. Our study therefore validates these methylation marker panels as triage test either in hrHPV-based or abnormal cytology-based screening programs.


Subject(s)
DNA Methylation , Mass Screening/methods , Papillomavirus Infections/genetics , Triage/methods , Uterine Cervical Dysplasia/genetics , Uterine Cervical Neoplasms/genetics , Adult , Biomarkers, Tumor/genetics , Cohort Studies , Colposcopy , Female , Humans , Middle Aged , Papillomaviridae/physiology , Papillomavirus Infections/diagnosis , Papillomavirus Infections/virology , Sensitivity and Specificity , Uterine Cervical Neoplasms/diagnosis , Uterine Cervical Dysplasia/diagnosis
2.
Epigenetics ; 13(7): 769-778, 2018.
Article in English | MEDLINE | ID: mdl-30079796

ABSTRACT

Cervical cancer development following a persistent infection with high-risk human papillomavirus (hrHPV) is driven by additional host-cell changes, such as altered DNA methylation. In previous studies, we have identified 12 methylated host genes associated with cervical cancer and pre-cancer (CIN2/3). This study systematically analyzed the onset and DNA methylation pattern of these genes during hrHPV-induced carcinogenesis using a longitudinal in vitro model of hrHPV-transformed cell lines (n = 14) and hrHPV-positive cervical scrapings (n = 113) covering various stages of cervical carcinogenesis. DNA methylation analysis was performed by quantitative methylation-specific PCR (qMSP) and relative qMSP values were used to analyze the data. The majority of genes displayed a comparable DNA methylation pattern in both cell lines and clinical specimens. DNA methylation onset occurred at early or late immortal passage, and DNA methylation levels gradually increased towards tumorigenic cells. Subsequently, we defined a so-called cancer-like methylation-high pattern based on the DNA methylation levels observed in cervical scrapings from women with cervical cancer. This cancer-like methylation-high pattern was observed in 72% (38/53) of CIN3 and 55% (11/20) of CIN2, whereas it was virtually absent in hrHPV-positive controls (1/26). In conclusion, hrHPV-induced carcinogenesis is characterized by early onset of DNA methylation, typically occurring at the pre-tumorigenic stage and with highest DNA methylation levels at the cancer stage. Host-cell DNA methylation patterns in cervical scrapings from women with CIN2 and CIN3 are heterogeneous, with a subset displaying a cancer-like methylation-high pattern, suggestive for a higher cancer risk.


Subject(s)
Carcinogenesis/genetics , DNA Methylation , Papillomaviridae/isolation & purification , Papillomavirus Infections/complications , Precancerous Conditions/genetics , Uterine Cervical Dysplasia/genetics , Uterine Cervical Neoplasms/genetics , Carcinogenesis/pathology , Female , Humans , Papillomavirus Infections/virology , Precancerous Conditions/pathology , Precancerous Conditions/virology , Tumor Cells, Cultured , Uterine Cervical Neoplasms/pathology , Uterine Cervical Neoplasms/virology , Uterine Cervical Dysplasia/pathology , Uterine Cervical Dysplasia/virology
3.
Oncotarget ; 7(49): 80735-80750, 2016 Dec 06.
Article in English | MEDLINE | ID: mdl-27738327

ABSTRACT

BACKGROUND: Cytology-based screening methods for cervical adenocarcinoma (ADC) and to a lesser extent squamous-cell carcinoma (SCC) suffer from low sensitivity. DNA hypermethylation analysis in cervical scrapings may improve detection of SCC, but few methylation markers have been described for ADC. We aimed to identify novel methylation markers for the early detection of both ADC and SCC. RESULTS: Genome-wide methylation profiling for 20 normal cervices, 6 ADC and 6 SCC using MethylCap-seq yielded 53 candidate regions hypermethylated in both ADC and SCC. Verification and independent validation of the 15 most significant regions revealed 5 markers with differential methylation between 17 normals and 13 cancers. Quantitative methylation-specific PCR on cervical cancer scrapings resulted in detection rates ranging between 80% and 92% while between 94% and 99% of control scrapings tested negative. Four markers (SLC6A5, SOX1, SOX14 and TBX20) detected ADC and SCC with similar sensitivity. In scrapings from women referred with an abnormal smear (n=229), CIN3+ sensitivity was between 36% and 71%, while between 71% and 93% of adenocarcinoma in situ (AdCIS) were detected; and CIN0/1 specificity was between 88% and 98%. Compared to hrHPV, the combination SOX1/SOX14 showed a similar CIN3+ sensitivity (80% vs. 75%, respectively, P>0.2), while specificity improved (42% vs. 84%, respectively, P < 10-5). CONCLUSION: SOX1 and SOX14 are methylation biomarkers applicable for screening of all cervical cancer types.


Subject(s)
Adenocarcinoma in Situ/genetics , Biomarkers, Tumor/genetics , Carcinoma, Adenosquamous/genetics , Carcinoma, Squamous Cell/genetics , DNA Methylation , Uterine Cervical Dysplasia/genetics , Uterine Cervical Neoplasms/genetics , Adenocarcinoma in Situ/pathology , Adult , Aged , Carcinoma, Adenosquamous/pathology , Carcinoma, Squamous Cell/pathology , Case-Control Studies , Early Detection of Cancer , Female , Gene Expression Profiling , Genetic Predisposition to Disease , Genome-Wide Association Study , Glial Cell Line-Derived Neurotrophic Factor Receptors/genetics , Glycine Plasma Membrane Transport Proteins/genetics , Humans , Middle Aged , Phenotype , Predictive Value of Tests , Prognosis , Reproducibility of Results , SOXB1 Transcription Factors/genetics , SOXB2 Transcription Factors/genetics , T-Box Domain Proteins/genetics , Uterine Cervical Neoplasms/pathology , Vaginal Smears , Uterine Cervical Dysplasia/pathology
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