Predictive value of DNA methylation in the efficacy of chemotherapy for gastric cancer.

Abstract

Gastric cancer (GC) is one of the most common causes of cancer-related death. Drug resistance in chemotherapy often occurs in patients with GC, leading to tumor recurrence and poor survival. DNA methylation is closely related to the development of cancer. To investigate the role of DNA methylation in chemotherapy resistance in GC patients, we conducted a comprehensive analysis using DNA methylation data and survival information obtained from The Cancer Genome Atlas. Univariate Cox analysis was performed to screen for differential DNA methylation of chemotherapy response in patients who did and did not receive chemotherapy. Multivariate Cox analysis was then performed to identify the independent prognostic genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were used to explore the biological function of the signature genes. Patients receiving adjuvant chemotherapy for GC survived longer. 308 differentially methylated genes were demonstrated to be associated with prognosis. Six genes were optimally chosed for establisehing the risk model, including C6orf222, CCNL1, CREBZF, GCKR, TFCP2, and VIPR2. It was constructed based on the DNA methylation levels of these six genes: risk score = 0.47123374*C6orf222 + 9.53554803*CCNL1 + 10.40234138* CREBZF + 0.07611856* GCKR + 18.87661557*TFCP2 - 0.46396254* VIPR2. According to the risk score, patients receiving chemotherapy were divided into high- and low-risk groups, and the prognosis of the two groups was compared. The high-risk group had a shorter survival; however, this association was not present in patients without chemotherapy. The accuracy and predictive efficacy of the risk score in predicting the 1-, 3-, and 5-year survival of patients was evaluated with the receiver operating characteristic curve. In patients receiving chemotherapy, the area under the curve of the risk score for 1-, 3-, and 5-year survival was 0.841, 0.72, and 0.734, respectively. In patients who did not receive chemotherapy, the area under the curve was 0.406, 0.585, and 0.585, respectively. A nomogram model was constructed based on the risk score and clinical indicators. The model showed good consistency in the predicted probabilities and actual probabilities. Gene Ontology functional enrichment of these candidate methylated genes showed the following molecular functions: RNA binding, protein binding, mRNA binding, and nucleic acid binding; that they were mediated mainly through the following cell components: nuclear speck, nucleoplasm, nucleus, catalytic step 2 spliceosome, and the transcription factor AP-1 complex; and that they were involved in the following biological processes: mRNA processing, mRNA splicing, and RNA polymerase II promoter transcription. The Kyoto Encyclopedia of Genes and Genomes pathway enrichment results revealed that the signaling pathways mainly enriched were transcriptional misregulation in cancer, spliceosome, and the IL-17 signaling pathway. Our work identifies a six DNA methylated expression signature as a promising biomarker of chemo-resistance in GC, which provides new insights into the development of new strategies to overcome chemo-resistance in GC.