Abstract
N6-Methyladenosine (m6A) is one of the most prominent modification regulating RNA processing and metabolism. Increasing studies have illuminated the vital role of m6A methylation in carcinogenesis. However, little is known about the interaction between m6A-related genes and survival of ovarian cancer (OC) patients. The purpose of this study was to obtain more reliable m6A-related genes that could be used as prognostic markers of OC using bioinformatics analysis performed on the RNA-seq data of OC. Gene expression datasets of all m6A-related genes as well as corresponding clinical data were obtained from the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) databases. We detected differential expressed m6A-related candidate genes as well as their relationship and interaction. m6A RNA methylation regulator ALKBH5 and 35 m6A-related genes are dysregulated in OC. A gene set that could be used as a potential independent prognostic risk feature was further screened including NEBL, PDGFRA, WDR91, and ZBTB4. The results of mRNA expression analysis by PCR were consistent with those of bioinformatics analysis. We applied consensus clustering analysis on the expression of the four prognostic genes and obtained four OC subgroups TM1-TM4. There were significant differences in age, stage and grade among the subgroups, and the overall survival (OS) as well as Disease-free survival (DFS) of TM2 group were shorter than those of the other three groups. Further GO and KEGG enrichment analysis indicated that these differential genes were closely related to biological processes and key signaling pathways involved in OC. In summary, our study has indicated that m6A-related genes are key factors in the progression of OC and have potential effects on the prognostic stratification of OC and the development of treatment strategies.
Highlights
Ovarian cancer (OC) ranks the seventh most common cancer worldwide, with a total incidence of 239,000 each year (Bray et al, 2018)
Through univariate analysis of m6A-related genes related to ovarian cancer (OC) in samples with different stages, a total of 36 candidate m6A-Related Genes in Ovarian Cancer genes with significant differences in expression between different stages were selected from 267 m6A-related genes related to OC (p ≤ 0.05), of which 1 was an m6A methylation regulator ALKBH5 (Supplementary Figure 1)
In order to study the prognostic role of genes related to m6A RNA methylation regulation in OC, we used 306 samples with survival information in the The Cancer Genome Atlas (TCGA) dataset as the training data set, and all 36 related candidate genes were preliminarily screened for prognostic risk characteristics using Cox univariate regression analysis
Summary
Ovarian cancer (OC) ranks the seventh most common cancer worldwide, with a total incidence of 239,000 each year (Bray et al, 2018). It is the leading cause of gynecologic cancer-related deaths among women, causing 152,000 deaths yearly (Torre et al, 2018). M6A modification on RNAs was labeled by methyltransferases (writers), preferentially recognized and transmitted by binding proteins (readers), and erased by demethylases (erasers) (Zhao et al, 2020; Jiang et al, 2021). FTO and ALKBH5, considered as erasers, can remove the methyl group from target RNAs to achieve the dynamics and reversibility of the m6A modification process (Livneh et al, 2020)
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