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Programmed death-1 (PD-1) expression in cervical intraepithelial neoplasia and its relationship with recurrence after conization.

ABSTRACT: OBJECTIVE:Impaired local cellular immunity contributes to persistent human papillomavirus (HPV) infection and development of cervical intraepithelial neoplasia (CIN). Programmed death-1 (PD-1) and its ligands PD-ligand-1 (L1) and PD-L2 are negative regulators of T cell activity in various cancers, but few studies exist. The aim of this study was to determine the clinicopathologic and immunologic parameters (PD-1, PD-L1, and PD-L2) related to the persistence/recurrence of CIN after conization. METHODS:Medical records of 652 patients diagnosed with CIN and underwent conization were reviewed. The associations between clinicopathologic parameters (e.g., age, parity, initial HPV load, etc.) and persistence/recurrence of CIN were analyzed. Expression of PD-1, PD-L1, and PD-L2 was assessed on 100 conization specimens by immunohistochemistry (IHC) in women matched for propensity-score (50 with persistence/recurrence and 50 without). RESULTS:Initial HPV load (>1,000 relative light unit) and positive margin were shown to be significantly associated with CIN persistence/recurrence (p=0.012 and p<0.001, respectively). Multivariate analysis showed that margin status was an independent predictor of persistence/recurrence (hazard ratio=8.86; 95% confidence interval=1.67-16.81; p<0.001). On IHC analysis, none of the patients expressed PD-L1. PD-1+ T cells were observed in 25 of 100 patients. Also, PD-1+ T cells were significantly correlated with increasing grade of CIN (p=0.031). In addition, patients with persistence/recurrence had increased expression of PD-1 compared with those without (36% vs. 14%, respectively; p=0.020). Although PD-L2 expression did not differ between 2 groups, it was significantly higher in patients with high-grade CIN compared to low-grade (34.7% vs. 12%, respectively; p=0.041). CONCLUSION:Positive surgical margin and expression of PD-1+ T cells were associated with CIN persistence/recurrence after conization.

SUBMITTER: Chang H

PROVIDER: S-EPMC5920214 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Programmed death-1 (PD-1) expression in cervical intraepithelial neoplasia and its relationship with recurrence after conization.

Chang Hyeyoon H Hong Jin Hwa JH Lee Jae Kwan JK Cho Hyun Woong HW Cho Hyun Woong HW Ouh Yung Taek YT Min Kyung Jin KJ So Kyeong A KA

Journal of gynecologic oncology 20180129 3

<h4>Objective</h4>Impaired local cellular immunity contributes to persistent human papillomavirus (HPV) infection and development of cervical intraepithelial neoplasia (CIN). Programmed death-1 (PD-1) and its ligands PD-ligand-1 (L1) and PD-L2 are negative regulators of T cell activity in various cancers, but few studies exist. The aim of this study was to determine the clinicopathologic and immunologic parameters (PD-1, PD-L1, and PD-L2) related to the persistence/recurrence of CIN after coniza ...[more]

PMID: 29400020

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Project description: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.

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.

Dataset Information

Programmed death-1 (PD-1) expression in cervical intraepithelial neoplasia and its relationship with recurrence after conization.

Publications

Programmed death-1 (PD-1) expression in cervical intraepithelial neoplasia and its relationship with recurrence after conization.

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