RESUMO
In developing countries, cervical cancer is still the major cause of cancer-related death among women. To better understand the correlation between tumor microenvironment (TME) and prognosis of cervical cancer, we screened 1367 differentially expressed genes (DEGs) of cervical cancer samples in The Cancer Genome Atlas (TCGA) database using Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) algorithm-derived immune scores. Then, we extracted 401 tumor immune microenvironment (TIME)-related DEGs that related to patients' survival outcomes. Protein-protein interaction (PPI) network and functional enrichment analysis revealed that the prognostic genes mainly participated in myeloid leukocyte activation, adaptive immune response regulation, and receptor signaling pathways. A total of 79 key prognostic DEGs were obtained through PPI network. A TF-lncRNA-miRNA-mRNA regulatory network was constructed to explore the potential regulatory mechanism. 4 genes (CCR7, PD-1, ZAP70, and CD28) were validated in another independent cohort of cervical cancer from the Gene Expression Omnibus (GEO) database. Finally, potential drugs for key prognostics DEGs were predicted using DrugBank. In conclusion, we obtained a list of potential prognostic TIME-related genes and potential predicted drugs by integrative bioinformatics approaches. A comprehensive understanding of prognostic genes within the TIME may provide new strategies for cervical cancer treatment.
RESUMO
In 2015, the American Society for Colposcopy and Cervical Pathology and the Society of Gynecologic Oncology issued interim guidance for the use of a human papillomavirus (HPV) test for primary screening, suggesting triage of women positive for high-risk human papillomavirus (hrHPV) by HPV-16/18 genotyping and cytology for women positive for non-16/18 hrHPV. The design of the present study was based on this interim guidance and analysis of the methylation status of specific candidate genes, which has been proposed as a tool to reduce unnecessary referral following primary HPV screening for cervical cancer. We performed a hospital-based case-control study including 312 hrHPV-positive women. hrHPV genotyping was performed by nested multiplex PCR assay with type-specific primers.Residual cervical cells from liquid-based cytology were used for extraction of genomic DNA for assessment of the methylation status of PAX1, ZNF582, SOX1, and NKX6-1 and HPV genotyping. Combined with HPV-16/18 genotyping, both a dual methylation test for PAX1/ZNF582 and testing for ZNF582 methylation demonstrated 100% association of methylation with pathology results, indicating carcinoma in situ or squamous cell carcinoma. The sensitivity and specificity of the dual methylation test for PAX1/ZNF582 as a reflex test for identification of CIN3+ lesions were 78.85% and 73.55% (odds ratio = 10.37, 95% confidence interval = 4.76-22.58), respectively. This strategy could reduce the number of patients referred for colposcopic examination by 31.3% compared with cytology, and thus provide a feasible follow-up solution in regions where colposcopy is not readily available. This strategy could also prevent unnecessary anxiety in women with hrHPV infection.