CIN_Progression
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Manuela Ferracin
PROVIDER: E-MTAB-2019 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:Women persistently infected with human papillomavirus (HPV) type 16 are at high risk for development of cervical intraepithelial neoplasia grade 3 or cervical cancer (CIN3+). We aimed to identify biomarkers for progression to CIN3+ in women with persistent HPV16 infection. In this prospective study, 11,088 women aged 20–29 years were enrolled during 1991-1993, and re-invited for a second visit two years later. Cervical cytology samples obtained at both visits were tested for HPV DNA by Hybrid Capture 2 (HC2), and HC2-positive samples were genotyped by INNO-LiPA. The cohort was followed for up to 19 years via a national pathology register. To identify markers for progression to CIN3+, we performed microarray analysis on RNA extracted from cervical swabs of 30 women with persistent HPV16-infection and 11 HPV-negative women. After further validation, we found that high mRNA expression levels of TMEM45A, SERPINB5 and p16INK4a were associated with increased risk of CIN3+ in persistently HPV16-infected women.
2016-01-01 | GSE75132 | GEO
Project description:Women persistently infected with human papillomavirus (HPV) type 16 are at high risk for development of cervical intraepithelial neoplasia grade 3 or cervical cancer (CIN3+). We aimed to identify biomarkers for progression to CIN3+ in women with persistent HPV16 infection. In this prospective study, 11,088 women aged 20â29 years were enrolled during 1991-1993, and re-invited for a second visit two years later. Cervical cytology samples obtained at both visits were tested for HPV DNA by Hybrid Capture 2 (HC2), and HC2-positive samples were genotyped by INNO-LiPA. The cohort was followed for up to 19 years via a national pathology register. To identify markers for progression to CIN3+, we performed microarray analysis on RNA extracted from cervical swabs of 30 women with persistent HPV16-infection and 11 HPV-negative women. After further validation, we found that high mRNA expression levels of TMEM45A, SERPINB5 and p16INK4a were associated with increased risk of CIN3+ in persistently HPV16-infected women. We aimed at identifying genes differentially expressed in women with persistent HPV16 infection that either progressed to CIN3+ or not. As a test of principle we first compared HPV16 persistently infected women with HPV-negative women.
2016-07-03 | E-GEOD-75132 | biostudies-arrayexpress
Project description:Cervical cancer is characterized by a well-defined pre-malignant phase, cervical intraepithelial neoplasia (CIN). Identification of high grade CIN lesions by population-based screening programs and their subsequent treatment has led to a significant reduction of the incidence and mortality of cervical cancer. Cytology-based testing of cervical smears is the most widely used cervical cancer screening method, but is not ideal, as the sensitivity for detection of CIN2 and higher (CIN2+) is only ~55%. Therefore, more sensitive and specific biomarkers for cervical cancer and its precancerous stages are needed.
2018-05-03 | PXD008723 | Pride
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:High-grade cervical intraepithelial neoplasia (CIN2/3) represents a heterogeneous disease both with respect to clinical behaviour and chromosomal aberrations detected. We hypothesized that the extent of chromosomal aberrations reflects the duration of their existence. Chromosomal profiles were determined of CIN3 of women with a known 5 year history of high-risk human papillomavirus virus (hrHPV) infection, in which duration of prior hrHPV infection was considered a proxy for duration of CIN3 existence. Eleven women had a <5 year preceding hrHPV infection (CIN3<5yrPHI) and 24 had a PHI lasting ≥5 years (CIN3≥5yrPHI). For comparison, 6 CIN3 adjacent to squamous cell carcinomas (CIN3-SCC), the corresponding SCCs, and 6 CIN1 were included. Unsupervised hierarchical clustering analysis of the chromosomal profiles revealed two clusters. One was characterized by a low number of chromosomal aberrations and included all CIN1, 81.8% of CIN3<5yrPHI and 33.3% of CIN3≥5yrPHI. Samples in the second cluster, displaying multiple aberrations, included 18.2% of CIN3<5yrPHI, 66.7% CIN3≥5yrPHI, all except one CIN3-SCC and all SCCs. The number of genomic aberrations increased according to lesion grade and also with longer duration of PHI. The increase in aberrations in CIN3≥5yrPHI compared to <5yrPHI was highly significant (p=0.001), suggesting that CIN3≥5yrPHI represent more severe lesions. A longer duration of preceding hrHPV infection is associated with an increased number of chromosomal aberrations. Hence, CIN3 with a longer duration of existence are likely more prone to have an increased short-term risk of cervical cancer.
2012-01-25 | GSE30155 | 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:Cervical cancer develops from pre-cancerous high-grade cervical intraepithelial neoplasia (CIN) lesions harbouring a transforming infection with high-risk human papillomavirus (hrHPV), which is characterised by p16INK4a overexpression. Since it takes one or more decades for these pre-cancerous lesions to progress to invasive squamous cell carcinomas (SCCs), it is obvious that they are heterogeneous in terms of duration of existence and progression risk. We performed array-based comparative genomic hybridisation (array CGH) of 46 p16INK4a immuno-positive CIN2/3 lesions to determine whether this heterogeneity is reflected in their chromosomal profiles. Chromosomal profiles of CIN2/3 lesions were related to those of invasive cervical squamous cell carcinomas (SCCs) and promoter methylation of the CADM1 gene, a tumour suppressor gene known to be functionally involved in the tumorigenic phenotype of cervical cancer cells. Frequent alterations found in CIN2/3 lesions included gains located at chromosome 1, 3, 7 and 20 and losses located at 4, 11, 16, 17 and 19. Unsupervised hierarchical clustering identified two subsets of CIN2/3 lesions, chromosomal profiles of one of which closely resembled invasive SCCs. Gains of 1, 3q and 20 were characteristic for CIN2/3 lesions with chromosomal signatures resembling carcinomas. In addition, dense promoter methylation of the CADM1 gene was significantly more frequent in these CIN2/3 lesions (p=0.004). No chromosomal alterations were detected in one p16INK4a positive and five p16INK4a negative CIN1 lesions. These findings suggest that biomarkers associated with gains at chromosomes 1, 3q and 20 are potential hallmarks of advanced p16INK4a positive CIN2/3 lesions with a high short-term risk of progression.
2009-02-20 | GSE11573 | 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:The effect of preventive vaccination against Human Papillomavirus (HPV) in reducing the burden of cervical cancer (CC) will not be seen before 30 years. It is still necessary to improve the procedures of screening and treatment against CC. Current methods for screening have low sensitivity (Pap test) or specificity (HPV tests) to detect high-grade cervical intraepithelial neoplasias (CIN) and CC (CIN2+). The objective of this study was the identification and characterization of cellular targets present in most CC and absent in normal cervical tissue that can be considered as potential markers for screening or therapeutic targets. Methods and Findings. A pyramidal strategy was used. Initially the expression of 8,638 genes was compared between 43 HPV16-positive CC and 12 healthy cervical epitheliums using the HG-Focus microarray. The expression intensity of 8,370 genes was validated in 24 samples with a second microarray (HG-ST1.0). A total of 997 genes were deregulated in CC and the 21 best ranked were validated and confirmed by qRT-PCR in 67 CC and 25 controls. According to the ROC analysis and the fold change (FC), the best (AUC M-bM-^IM-% 0.97 and FC M-bM-^IM-% 10) six genes (CCNB2, CDC20, PRC1, SYCP2, NUSAP1, CDKN3) belong to the mitosis pathway. They were further explored by qRT-PCR in 29 CIN1 and 21 CIN2/3 lesions to investigate whether they could differentiate CIN2+ from CIN1 and healthy cervical epitheliums (CIN1-). Three of these genes were associated exclusively with invasive tumors (CCNB2, PRC1, SYCP2) and three (CDC20, NUSAP1, CDKN3) also with CIN2/3. The sensitivity and specificity of CDKN3 and NUSAP1, along with CDKN2A, to detect CIN2+ was around 90%. The protein codified by these genes was confirmed by immunohistochemistry in CC. The effect of these markers on the survival was investigated in 40 CC patients followed by 42 months. Only high-expression level of CDKN3 was associated with a poor survival (20%; p = 2 x 10-4, Long-rank test) and it was independent from FIGO staging. Conclusions. CDKN3 and NUSAP1, together with CDKN2A, may be potential targets for development of screening methods. However, further studies are needed from a screening population to define the optimal trade-off between sensitivity and specificity for detection of CIN2+. CDKN3 may be also considered as a survival marker. Inhibition of mitosis is a well-known strategy to combat cancers. Therefore, CDKN3 may be a potential therapeutic target in CC. However, itM-BM-4s still necessary to demonstrate whether itM-BM-4s indispensable for tumor growth. cervical cancer vs. healthy cervix
2013-03-31 | E-GEOD-39001 | biostudies-arrayexpress
Project description:The effect of preventive vaccination against Human Papillomavirus (HPV) in reducing the burden of cervical cancer (CC) will not be seen before 30 years. It is still necessary to improve the procedures of screening and treatment against CC. Current methods for screening have low sensitivity (Pap test) or specificity (HPV tests) to detect high-grade cervical intraepithelial neoplasias (CIN) and CC (CIN2+). The objective of this study was the identification and characterization of cellular targets present in most CC and absent in normal cervical tissue that can be considered as potential markers for screening or therapeutic targets. Methods and Findings. A pyramidal strategy was used. Initially the expression of 8,638 genes was compared between 43 HPV16-positive CC and 12 healthy cervical epitheliums using the HG-Focus microarray. The expression intensity of 8,370 genes was validated in 24 samples with a second microarray (HG-ST1.0). A total of 997 genes were deregulated in CC and the 21 best ranked were validated and confirmed by qRT-PCR in 67 CC and 25 controls. According to the ROC analysis and the fold change (FC), the best (AUC ≥ 0.97 and FC ≥ 10) six genes (CCNB2, CDC20, PRC1, SYCP2, NUSAP1, CDKN3) belong to the mitosis pathway. They were further explored by qRT-PCR in 29 CIN1 and 21 CIN2/3 lesions to investigate whether they could differentiate CIN2+ from CIN1 and healthy cervical epitheliums (CIN1-). Three of these genes were associated exclusively with invasive tumors (CCNB2, PRC1, SYCP2) and three (CDC20, NUSAP1, CDKN3) also with CIN2/3. The sensitivity and specificity of CDKN3 and NUSAP1, along with CDKN2A, to detect CIN2+ was around 90%. The protein codified by these genes was confirmed by immunohistochemistry in CC. The effect of these markers on the survival was investigated in 40 CC patients followed by 42 months. Only high-expression level of CDKN3 was associated with a poor survival (20%; p = 2 x 10-4, Long-rank test) and it was independent from FIGO staging. Conclusions. CDKN3 and NUSAP1, together with CDKN2A, may be potential targets for development of screening methods. However, further studies are needed from a screening population to define the optimal trade-off between sensitivity and specificity for detection of CIN2+. CDKN3 may be also considered as a survival marker. Inhibition of mitosis is a well-known strategy to combat cancers. Therefore, CDKN3 may be a potential therapeutic target in CC. However, it´s still necessary to demonstrate whether it´s indispensable for tumor growth.
2013-03-31 | GSE39001 | GEO