The Exploration Of The Construction Of An M6A RNA Methylation Genes-based Prognostic Model For Cervical Cancer

Background Cervical cancer,one of the gynecological tumors with the highest risk of dying in the world,poses a serious threat to women’s health.The m6A methylation is widely involved in various biological processes of tumorigenesis and metastassis,and plays an important role in prognosis of cancer.The purpose of this study was to develop an m6A methylation gene-based molecular biomarker and prognostic model for cervical cancer.Methods RNA sequencing data and clinical data of patients with cervical cancer were downloaded from The Cancer Genome Atlas(TCGA)database.We standardized the types of transcriptome data from the original counts to the TPM types(Trans Per Million).Clinical data included age,T stage,N stage,M stage,FIGO(International Federation of Gynecology and Obstetrics)stage and survival status.Based on the m6A methylation-related genes reported in the previous literature,the expression of 13 genes(FTO,YTHDC1,YTHDC2,YTHDF1,YTHDF2,METTL3,METTL14,HNRNPC,ALKBH5,WTAP,RBM15,ZC3H13,KIAA1429)in tumor tissues and normal tissues were identified.According to the differential expression level of m6A gene,patients with cervical cancer were divided into two groups by consensus clustering.Then,the difference of clinicopathological characteristics in the two groups were compared.Kaplan-Meier method was used to compare the survival difference in different groups.LASSO COX regression analysis was performed for developing a prognostic model for patients with cervical cancer.The prognostic model was validated by the way of univariate and multivariate Cox regression analyses.The genes related to prognosis were selected from the m6A genes differentially expressed in cervical cancer for immunohistochemical experiments.The relationship between the selected genes,clinicopathologic features and survival was analyzed.Results Compared with normal tissues,the expression levels of YTHDF2(p=0.002),METTL3(p=0.007)and RBM15(p=0.001)were increased in cervical cancer tissues,while the expression levels of FTO(p=0.009)and ZC3H13(p=0.042)were decreased.There was no significant difference in the expression of other m6A methylated genes.The patients with cervical cancer were divided into two groups and the FIGO stage,immune cell infiltration and immune score in the two groups were significantly different(all p<0.05).The results of Kaplan-Meier survival analysis showed that the patients with high expression levels of YTHDF2(p=0.004),ZC3H13(p=0.005),HNRNPC(p=0.0099).KIAA1429(p=0.013),METTL14(p=0.017),WTAP(p=0.025)had poor survival.A prognostic model including ZC3H13 and YTHDF1 was developed.The high-risk group had a worse survival than the low-risk group(p=0.0039).The results of multivariate Cox regression analysis showed that it was an independent prognostic factor.The results of Immunohistochemical method associated with clinical data showed that the degree of muscle infiltration in the YTHDF2 high expression group was significantly higher than that in the low expression group.Patients with high expression of METTL3 had advanced FIGO stage and worse treatment response.High expression levels of METTL3 implicated worse disease-free survival(p=0.036).Conclusion There is a correlation between the expression of m6A methylation gene and the clinicopathological features,response to treatment and survival.The m6A genes have the potential to become molecular biomarker for cervical cancer.According to the expression of m6A gene,patients with cervical cancer were divided into two groups and a prognostic model was developed.FIGO stage,immune cell infiltration and immune microenvironment in the two groups were significantly different.And patients evaluated high risk score are at a high risk for dying.This study could provide a reference for the individualized treatment and prognosis of cervical cancer,and provide a basis for the exploration of the mechanism of m6A and treatment sensitivity in cervical cancer.