Genome-wide DNA methylation profiling identifies two novel genes in cervical neoplasia
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE143752 | GEO | 2020/01/30
REPOSITORIES: GEO
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Project description:Epigenetic modifications, such as aberrant DNA promoter methylation is frequently observed in cervical cancer. Identification of hypermethylated regions maybe useful for discrimination between normal cervical epithelium and high-grade cervical intraepithelial neoplasia (CIN2/3) or worse may improve current cervical cancer population-based screening programs. In this study, the DNA methylome of high-grade CIN lesions were characterised using genome-wide methylation screening to identify potential biomarkers for early diagnosis of cervical neoplasia. Methyl-DNA Immunoprecipitation (MeDIP) combined with DNA microarray was used to compare DNA methylation profiles of epithelial cells derived from high-grade CIN lesions with normal cervical epithelium resulting in the identification of hypermethylated differentially methylated regions (DMRs). Validation of 9 selected DMRs by MSP or BSP in cervical tissue revealed methylation in 63.2-94.7% high-grade CIN and in 59.3-100% cervical carcinomas. QMSP for the two most significant high-grade CIN-specific methylation markers was applied exploring test performance in a large series of cervical scrapings. Frequency and relative level of methylation were significantly different between normal and cancer samples (p<0.001). Clinical validation of both markers in cervical scrapings from patients referred with an abnormal cervical smear, confirmed that frequency and relative level of methylation were related with increasing severity of the underlying CIN lesion (p<0.001) and the ROC analysis was discriminative (p<0.005). These possible methylation markers represent COL25A1 and KATNAL2 promoters and their observed increased methylation upon progression is in agreement with their biological function (cytoskeleton regulation). In conclusion, our newly identified hypermethylated DMRs represent specific DNA methylation patterns in high-grade CIN lesions and could be potential biomarkers for early detection. Epigenetic modifications, such as aberrant DNA promoter methylation is frequently observed in cervical cancer. Identification of hypermethylated regions maybe useful for discrimination between normal cervical epithelium and high-grade cervical intraepithelial neoplasia (CIN2/3) or worse may improve current cervical cancer population-based screening programs. In this study, the DNA methylome of high-grade CIN lesions were characterised using genome-wide methylation screening to identify potential biomarkers for early diagnosis of cervical neoplasia. Methyl-DNA Immunoprecipitation (MeDIP) combined with DNA microarray was used to compare DNA methylation profiles of epithelial cells derived from high-grade CIN lesions with normal cervical epithelium resulting in the identification of hypermethylated differentially methylated regions (DMRs). Validation of 9 selected DMRs by MSP or BSP in cervical tissue revealed methylation in 63.2-94.7% high-grade CIN and in 59.3-100% cervical carcinomas. QMSP for the two most significant high-grade CIN-specific methylation markers was applied exploring test performance in a large series of cervical scrapings. Frequency and relative level of methylation were significantly different between normal and cancer samples (p<0.001). Clinical validation of both markers in cervical scrapings from patients referred with an abnormal cervical smear, confirmed that frequency and relative level of methylation were related with increasing severity of the underlying CIN lesion (p<0.001) and the ROC analysis was discriminative (p<0.005). These possible methylation markers represent COL25A1 and KATNAL2 promoters and their observed increased methylation upon progression is in agreement with their biological function (cytoskeleton regulation). In conclusion, our newly identified hypermethylated DMRs represent specific DNA methylation patterns in high-grade CIN lesions and could be potential biomarkers for early detection. MeDIP with subsequent microarray analysis was performed on DNA isolated from frozen macrodissected epithelial tissue of CIN3 lesions (n=15) and normal cervices (n=10).
2012-11-01 | E-GEOD-36319 | biostudies-arrayexpress
Project description:Epigenetic modifications, such as aberrant DNA promoter methylation is frequently observed in cervical cancer. Identification of hypermethylated regions maybe useful for discrimination between normal cervical epithelium and high-grade cervical intraepithelial neoplasia (CIN2/3) or worse may improve current cervical cancer population-based screening programs. In this study, the DNA methylome of high-grade CIN lesions were characterised using genome-wide methylation screening to identify potential biomarkers for early diagnosis of cervical neoplasia. Methyl-DNA Immunoprecipitation (MeDIP) combined with DNA microarray was used to compare DNA methylation profiles of epithelial cells derived from high-grade CIN lesions with normal cervical epithelium resulting in the identification of hypermethylated differentially methylated regions (DMRs). Validation of 9 selected DMRs by MSP or BSP in cervical tissue revealed methylation in 63.2-94.7% high-grade CIN and in 59.3-100% cervical carcinomas. QMSP for the two most significant high-grade CIN-specific methylation markers was applied exploring test performance in a large series of cervical scrapings. Frequency and relative level of methylation were significantly different between normal and cancer samples (p<0.001). Clinical validation of both markers in cervical scrapings from patients referred with an abnormal cervical smear, confirmed that frequency and relative level of methylation were related with increasing severity of the underlying CIN lesion (p<0.001) and the ROC analysis was discriminative (p<0.005). These possible methylation markers represent COL25A1 and KATNAL2 promoters and their observed increased methylation upon progression is in agreement with their biological function (cytoskeleton regulation). In conclusion, our newly identified hypermethylated DMRs represent specific DNA methylation patterns in high-grade CIN lesions and could be potential biomarkers for early detection. Epigenetic modifications, such as aberrant DNA promoter methylation is frequently observed in cervical cancer. Identification of hypermethylated regions maybe useful for discrimination between normal cervical epithelium and high-grade cervical intraepithelial neoplasia (CIN2/3) or worse may improve current cervical cancer population-based screening programs. In this study, the DNA methylome of high-grade CIN lesions were characterised using genome-wide methylation screening to identify potential biomarkers for early diagnosis of cervical neoplasia. Methyl-DNA Immunoprecipitation (MeDIP) combined with DNA microarray was used to compare DNA methylation profiles of epithelial cells derived from high-grade CIN lesions with normal cervical epithelium resulting in the identification of hypermethylated differentially methylated regions (DMRs). Validation of 9 selected DMRs by MSP or BSP in cervical tissue revealed methylation in 63.2-94.7% high-grade CIN and in 59.3-100% cervical carcinomas. QMSP for the two most significant high-grade CIN-specific methylation markers was applied exploring test performance in a large series of cervical scrapings. Frequency and relative level of methylation were significantly different between normal and cancer samples (p<0.001). Clinical validation of both markers in cervical scrapings from patients referred with an abnormal cervical smear, confirmed that frequency and relative level of methylation were related with increasing severity of the underlying CIN lesion (p<0.001) and the ROC analysis was discriminative (p<0.005). These possible methylation markers represent COL25A1 and KATNAL2 promoters and their observed increased methylation upon progression is in agreement with their biological function (cytoskeleton regulation). In conclusion, our newly identified hypermethylated DMRs represent specific DNA methylation patterns in high-grade CIN lesions and could be potential biomarkers for early detection.
2012-11-01 | GSE36319 | GEO
Project description:In most cases human papillomavirus (HPV) infections are cleared from the cervical cells by the immune system itself, but in a few cases, where there is persistent HPV infection, it can lead to cervical intraepithelial neoplasia (CIN) progression and ultimately invasive cervical carcinoma. The cytopathic effect is in general accompanied by chronic inflammation, which produces inflammation cytokines that contribute to DNA damage, and at the same time, aberrations occurred in the host DNA repair mechanisms, thus lead to HPV genomic integration into the host cells which propels cell immortalization. In this study, we reported the genome-wide expression profiles of both microRNAs (miRNAs) and mRNAs from 24 cervical samples with consecutive stages of normal, CIN I (mild dysplasia) and CIN III (severe dysplasia and carcinoma in situ), and presented the SIG++ algorithm which is founded on the evolution process of intermolecular regulation change during disease progression, to identify the significant change of miRNA-mRNA regulations rather than the expression change, across different disease stages, thereupon elucidating the molecular mechanisms of increasing host genomic instability as disease progresses. As reconstructing miRNA differential networks, we found that at each stage of CIN, there respectively exists specific miRNA regulations mediating chronic inflammation persistence, genome instability and cell survival, which coordinately carrys out the integration of HPV genomes into the host cell genomes, and finally results in cell immortalization. Beyond the specific implications for cervical carcinogenesis, this work establishes a new framework for studying the biology of miRNAs in pathogenesis from the perspective of miRNA differential regulation, and helps ensure the comprehensiveness of miRNA-mediated genetic regulatory pathways. There are totally 24 clinical samples in this study comprises three stages: 7 normal cervix samples (HPV-), 9 CIN I samples (HPV+) and CIN III samples (HPV+), where normal refers to the adjacent tissue of early lesions. For each sample, its total RNA was extracted and purified, then separately hybridized to Illumina HumanHT-12 V4.0 expression beadchip (gene symbol) and Illumina Human v2 MicroRNA Expression BeadChip, for examining the expression profiles of mRNAs and miRNAs, respectively.
2013-11-02 | E-GEOD-51993 | biostudies-arrayexpress
Project description:In most cases human papillomavirus (HPV) infections are cleared from the cervical cells by the immune system itself, but in a few cases, where there is persistent HPV infection, it can lead to cervical intraepithelial neoplasia (CIN) progression and ultimately invasive cervical carcinoma. The cytopathic effect is in general accompanied by chronic inflammation, which produces inflammation cytokines that contribute to DNA damage, and at the same time, aberrations occurred in the host DNA repair mechanisms, thus lead to HPV genomic integration into the host cells which propels cell immortalization. In this study, we reported the genome-wide expression profiles of both microRNAs (miRNAs) and mRNAs from 24 cervical samples with consecutive stages of normal, CIN I (mild dysplasia) and CIN III (severe dysplasia and carcinoma in situ), and presented the SIG++ algorithm which is founded on the evolution process of intermolecular regulation change during disease progression, to identify the significant change of miRNA-mRNA regulations rather than the expression change, across different disease stages, thereupon elucidating the molecular mechanisms of increasing host genomic instability as disease progresses. As reconstructing miRNA differential networks, we found that at each stage of CIN, there respectively exists specific miRNA regulations mediating chronic inflammation persistence, genome instability and cell survival, which coordinately carrys out the integration of HPV genomes into the host cell genomes, and finally results in cell immortalization. Beyond the specific implications for cervical carcinogenesis, this work establishes a new framework for studying the biology of miRNAs in pathogenesis from the perspective of miRNA differential regulation, and helps ensure the comprehensiveness of miRNA-mediated genetic regulatory pathways.
2013-11-02 | GSE51993 | GEO
Project description:We pursued the hypothesis that epigenetic regulators of transcription are involved in both the development and the progression of HPV-associated CIN. Using HELP-tagging, we performed the most comprehensive study to date of DNA methylation in HPV-associated cervical neoplasia, testing ~2 million loci throughout the human genome in biopsies from 78 HPV+ women, identifying changes starting in early CIN and maintained through carcinogenesis. We identified loci at which DNA methylation is consistently altered, beginning early in the course of neoplastic disease and progressing with disease advancement. DNA methylation profiles for cervical biopsies of 19 normals, 20 CIN1, 16 CIN2/3, and 23 cervical cancers.
2016-08-22 | E-GEOD-76986 | biostudies-arrayexpress
Project description:Identification of promoter methylation profile associated with cervical cancer progression. The Ilumina Infinium 27k Human DNA methylation Beadchip v1.2 was used to obtain DNA methylation profiles across approximately 27,000 CpGs from 19 cervical samples (including normal, CIN I-II, in situ and invasive cervical cancer tissues).
2013-01-01 | GSE41384 | GEO
Project description:Cervical intraepithelial neoplasia (CIN), also known as cervical dysplasia, is premalignant lesions of the cervical squamous cell carcinoma (CSCC) that shows abnormal growth of squamous cells in the cervix epithelium. Given the evidence suggesting that differences may exist between CIN and CSCC, we hypothesize that progression may be mediated by subpopulation selection or by acquisition of additional alterations, including gene mutations or chromosomal alterations. In this study, we analyzed cervical CIN, microinvasive carcinoma (MIC) and CSCC by whole-exome sequencing and array-comparative genomic hybridization (array-CGH) and found that CIN genomes harbored fewer mutations (especially fewer driver mutations) and copy number alterations (CNAs), suggesting that additional genomic alterations might burst onto the CIN genome at the final stage of CIN progression to CSCC or an early stage of CSCC.
2014-12-31 | GSE60067 | GEO
Project description:Cervical cancer results from the accumulation of (epi)genetic aberrations following persistent infection with high-risk human papillomavirus (HPV). In order to define genetic aberrations associated with cervical carcinogenesis, chromosomal profiles of high-grade cervical intraepithelial neoplasia (CIN) were generated. Common aberrations usually encompass large genomic regions and contain numerous genes, hampering identification of actual driver genes. Consequently, direct evidence of chromosomal alterations actively contributing to cervical carcinogenesis has been lacking so far. By analyzing 60 high-grade CIN with high resolution arrayCGH we identified focal chromosomal aberrations that each harbour only one or a few genes. In total 74 focal aberrations were identified encoding 305 genes. Analysis of genes located within these focal aberrations, using two independent expression microarray datasets, revealed concurrent altered expression in high-grade CIN and/or cervical carcinomas compared to normal cervical samples for 8 genes: ATP13A3, HES1, OPA1, HRASLS, EYA2, ZMYND8, APOBEC2 and NCR2. Gene silencing of EYA2, located within a focal gain at 20q13, significantly reduced viability and migratory capacity of HPV16-transformed keratinocytes. Interestingly, for hsa-miR-375, located within the most frequently identified focal loss at 2q35, a direct correlation between a (focal) loss and significantly reduced expression was found. Down-regulation of hsa-miR-375 expression during cervical carcinogenesis was confirmed in a second independent series of cervical tissues. Moreover, ectopic expression of hsa-miR-375 in 2 cervical carcinoma cell lines reduced cellular viability. In conclusion, our data provide a proof of concept that chromosomal aberrations are actively contributing to HPV-induced carcinogenesis and identify EYA2 and hsa-mir-375 as oncogene and tumor suppressor gene, respectively. DNA from microdissected tissues: 60 samples total. 11 high-grade CIN, <5yr preceding hrHPV infection, 43 high-grade CIN >5yr preceding hrHPV infection, 6 CIN3 adjacent to SCC
2012-12-31 | E-GEOD-34575 | biostudies-arrayexpress
Project description:Identification of promoter methylation profile associated with cervical cancer progression. The Ilumina Infinium 27k Human DNA methylation Beadchip v1.2 was used to obtain DNA methylation profiles across approximately 27,000 CpGs from 19 cervical samples (including normal, CIN I-II, in situ and invasive cervical cancer tissues). Bisulphite converted DNA from the 19 samples were hybridised to the Illumina Infinium 27k Human Methylation Beadchip v1.2
2013-01-01 | E-GEOD-41384 | biostudies-arrayexpress
Project description:We pursued the hypothesis that epigenetic regulators of transcription are involved in both the development and the progression of HPV-associated CIN. Using HELP-tagging, we performed the most comprehensive study to date of DNA methylation in HPV-associated cervical neoplasia, testing ~2 million loci throughout the human genome in biopsies from 78 HPV+ women, identifying changes starting in early CIN and maintained through carcinogenesis. We identified loci at which DNA methylation is consistently altered, beginning early in the course of neoplastic disease and progressing with disease advancement.
2016-08-22 | GSE76986 | GEO