Dataset Information

Up regulation in gene expression of chromatin remodelling factors in cervical intraepithelial neoplasia.

ABSTRACT: The highest rates of cervical cancer are found in developing countries. Frontline monitoring has reduced these rates in developed countries and present day screening programs primarily identify precancerous lesions termed cervical intraepithelial neoplasias (CIN). CIN lesions described as mild dysplasia (CIN I) are likely to spontaneously regress while CIN III lesions (severe dysplasia) are likely to progress if untreated. Thoughtful consideration of gene expression changes paralleling the progressive pre invasive neoplastic development will yield insight into the key casual events involved in cervical cancer development.In this study, we have identified gene expression changes across 16 cervical cases (CIN I, CIN II, CIN III and normal cervical epithelium) using the unbiased long serial analysis of gene expression (L-SAGE) method. The 16 L-SAGE libraries were sequenced to the level of 2,481,387 tags, creating the largest SAGE data collection for cervical tissue worldwide. We have identified 222 genes differentially expressed between normal cervical tissue and CIN III. Many of these genes influence biological functions characteristic of cancer, such as cell death, cell growth/proliferation and cellular movement. Evaluation of these genes through network interactions identified multiple candidates that influence regulation of cellular transcription through chromatin remodelling (SMARCC1, NCOR1, MRFAP1 and MORF4L2). Further, these expression events are focused at the critical junction in disease development of moderate dysplasia (CIN II) indicating a role for chromatin remodelling as part of cervical cancer development.We have created a valuable publically available resource for the study of gene expression in precancerous cervical lesions. Our results indicate deregulation of the chromatin remodelling complex components and its influencing factors occur in the development of CIN lesions. The increase in SWI/SNF stabilizing molecule SMARCC1 and other novel genes has not been previously illustrated as events in the early stages of dysplasia development and thus not only provides novel candidate markers for screening but a biological function for targeting treatment.

SUBMITTER: Shadeo A

PROVIDER: S-EPMC2277413 | biostudies-literature | 2008 Feb

REPOSITORIES: biostudies-literature

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Up regulation in gene expression of chromatin remodelling factors in cervical intraepithelial neoplasia.

Shadeo Ashleen A Chari Raj R Lonergan Kim M KM Pusic Andrea A Miller Dianne D Ehlen Tom T Van Niekerk Dirk D Matisic Jasenka J Richards-Kortum Rebecca R Follen Michele M Guillaud Martial M Lam Wan L WL MacAulay Calum C

BMC genomics 20080204

<h4>Background</h4>The highest rates of cervical cancer are found in developing countries. Frontline monitoring has reduced these rates in developed countries and present day screening programs primarily identify precancerous lesions termed cervical intraepithelial neoplasias (CIN). CIN lesions described as mild dysplasia (CIN I) are likely to spontaneously regress while CIN III lesions (severe dysplasia) are likely to progress if untreated. Thoughtful consideration of gene expression changes pa ...[more]

PMID: 18248679

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Project description:The aim of the present study was to identify the differentially expressed genes between cervical intraepithelial neoplasias (CIN) and adjacent normal tissue, and to construct a protein-protein interaction (PPI) network. A CIN dataset was obtained from Gene Expression Omnibus, and data of gene expression in CIN and adjacent normal tissue were extracted from GSE64217. The differentially expressed genes were selected using software package and heat map was drawn using the 'pheatmap' package. The selected differentially expressed genes were subjected to PPI, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis using Cytoscape, Database for Annotation, Visualization and Integrated Discovery, STRING and KOBAS. In the present study, 287 genes were differentially expressed between CIN and adjacent normal tissue, of which 170 were significantly upregulated and 118 genes were significantly downregulated (P<0.00001, fold-change >6). A differential gene expression network map was constructed to show the interactions of 30 protein products encoded by differentially expressed genes using STRING software. In particular, the key gene, EGR1, was identified using Cytoscape software. The KEGG pathway analysis revealed that the differential genes were mainly involved in several pathways, including 'glutathione metabolism', 'arachidonic acid metabolism', and 'pentose phosphate pathway'. Results of the GO analysis showed that differential genes were enriched in different subsets. Specifically, small proline-rich protein 2E and 3, distal-less homeobox 5, epithelial membrane protein 1, cornifelin, periplakin, homeobox protein Hox-A13, estrogen receptor α, transglutaminase 1, small proline-rich protein 2A, Rh C glycoprotein, tumor protein p63, TGM3, homeobox B5 and small proline-rich protein 2D were enriched in 'epithelial cell differentiation', which affected the differentiation of epithelial cells. In conclusion, 287 differentially expressed genes were identified successfully. The key gene was identified based on the results of PPI, GO and KEGG analyses, and functional annotation and pathway analysis were also performed. Our study provides the basis for further studies on the interaction among differentially expressed genes.

Project description:PURPOSE:Ligand-dependent corepressor (LCoR) and receptor-interacting protein 140 (RIP140/NRIP1) play an important role in the regulation of multiple oncogenic signaling pathways and the development of cancer. LCoR and RIP140 form a nuclear complex in breast cancer cells and are of prognostic value in further prostate and cervical cancer. The purpose of this study was to analyze the regulation of these proteins in the development of cervical intraepithelial neoplasia (CIN I-III). METHODS:Immunohistochemical analysis was obtained to quantify RIP140 and LCoR expression in formalin-fixed paraffin embedded tissue sections of cervical intraepithelial neoplasia samples. Tissue (n?=?94) was collected from patients treated in the Department of Gynecology and Obstetrics, Ludwig-Maximilians-University of Munich, Germany, between 2002 and 2014. Correlations of expression levels with clinical outcome were carried out to assess for prognostic relevance in patients with CIN2 progression. Kruskal-Wallis test and Mann-Whitney U test were used for data analysis. RESULTS:Nuclear LCoR overexpression correlates significantly with CIN II progression. Nuclear RIP140 expression significantly increases and nuclear LCoR expression decreases with higher grading of cervical intraepithelial neoplasia. Cytoplasmic RIP140 expression is significantly higher in CIN III than in CIN I or CIN II. CONCLUSION:A decrease of nuclear LCoR expression in line with an increase of dedifferentiation of CIN can be observed. Nuclear LCoR overexpression correlates with CIN II progression indicating a prognostic value of LCoR in cervical intraepithelial neoplasia. Nuclear and cytoplasmic RIP140 expression increases significantly with higher grading of cervical intraepithelial neoplasia underlining its potential role in the development of pre-cancerous lesions. These findings support the relevance of LCoR and RIP140 in the tumorigenesis indicating a possible role of LCoR and RIP140 as targets for novel therapeutic approaches in cervical intraepithelial neoplasia and cervical cancer.

Project description:ObjectiveTo compare the risk of cervical cancer in women with histologically confirmed cervical intraepithelial neoplasia who returned to routine screening after having completed post-treatment follow-up with consecutive normal smear test results with women with a normal primary smear test result.DesignPopulation based cohort study using data from a nationwide pathology register.SettingThe Netherlands, 1994 to 2006.Population38,956 women with histologically confirmed intraepithelial neoplasia grades 1 to 3 with completed follow-up after treatment.InterventionRoutine post-treatment follow-up of cervical intraepithelial neoplasia, recommending smear tests at six, 12, and 24 months.Main outcome measureIncidence of cervical cancer in the period from completed follow-up with negative test results after cervical intraepithelial neoplasia to the next primary test. 10-year hazard ratios were compared with periods after normal results for the primary smear test, adjusted for year in follow-up.Results20 cervical cancers were diagnosed during 56,956 woman years after completed follow-up of cervical intraepithelial neoplasia, whereas 1613 cervical cancers were diagnosed during 25,020,697 woman years after a normal primary smear test result. The incidence of 35.1 (95% confidence interval 21.4 to 54.2) per 100,000 woman years and 6.4 (6.1 to 6.8) per 100,000 woman years, respectively, led to an adjusted hazard ratio of 4.2 (95% confidence interval 2.7 to 6.5) for periods after completed follow-up compared with periods after normal primary smear test results. This hazard ratio was increased for all ages. No significant difference in risk of cervical cancer was observed by grade of cervical intraepithelial neoplasia.ConclusionsAn excess risk of cervical cancer previously observed for women treated for cervical intraepithelial neoplasia was also observed in the subgroup of women who completed their post-treatment follow-up with three consecutive normal smear test results. The overall corrected risk of cervical cancer in these women was increased fourfold 35 cases per 100,000 woman years) compared with women with normal primary smear test results (6 per 100,000 woman years).

Project description:BackgroundInformation on the long-term risk of cervical intraepithelial neoplasia (CIN) recurrence among women treated for CIN is limited yet critical for evidence-based surveillance recommendations.MethodsWe retrospectively identified 37,142 women treated for CIN 1, 2, or 3 from January 1, 1986, through December 31, 2000 (CIN cohort), from the British Columbia Cancer Agency cytology database and linked their records with cancer registry and vital statistics data. Treatment included cryotherapy, loop electrosurgical excision procedure, cone biopsy, and laser vaporization or excision. A comparison cohort contained 71,213 women with normal cytology and no previous CIN diagnosis. Follow-up continued through December 31, 2004. Among women in both cohorts under active surveillance, we compared rates of CIN 2 or 3 (CIN 2/3) and cervical cancer. Cumulative incidence rates of CIN 2/3 and 95% confidence intervals (CIs) were estimated by a life table approach by using annual rates. Cumulative rates of invasive cancer were examined by the person-years method.ResultsOverall observed cumulative rates of CIN 2/3 in the first 6 years after treatment were 14.0% (95% CI = 13.84% to 14.15%) for women originally treated for CIN 3, 9.3% (95% CI = 9.09% to 9.42%) for CIN 2, and 5.6% (95% CI = 4.91% to 5.21%) for CIN 1. Annual rates of CIN 2/3 were less than 1% after 6 years. Initial diagnosis, age, and treatment type were associated with a diagnosis of CIN 2/3 after treatment, with 6-year adjusted rates for women aged 40-49 years ranging from 2.6% (95% CI = 1.9% to 3.4%) for treatment of CIN 1 with the loop electrosurgical excision procedure to 34.0% (95% CI = 30.9% to 37.1%) for treatment of CIN 3 with cryotherapy. Overall incidence of invasive cancer (per 100,000 woman-years) was higher in the CIN cohort (37 invasive cancers, 95% CI = 30.6 to 42.5 cancers) than in the comparison cohort (six cancers, 95% CI = 4.3 to 7.7 cancers). Cryotherapy, compared with other treatments, was associated with the highest rate of subsequent disease (adjusted odds ratio for invasive cancer = 2.98, 95% CI = 2.09 to 4.60).ConclusionRisk of CIN 2/3 after treatment was associated with initial CIN grade, treatment type, and age. Long-term risk of invasive cancer remained higher among women treated for CIN, particularly those treated with cryotherapy.

Dataset Information

Up regulation in gene expression of chromatin remodelling factors in cervical intraepithelial neoplasia.

Publications

Up regulation in gene expression of chromatin remodelling factors in cervical intraepithelial neoplasia.

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