Genome‐wide identification of CpG island methylator phenotype related gene signature as a novel prognostic biomarker of gastric cancer

Abstract

Background Gastric cancer (GC) is one of the most fatal cancers in the world. Results of previous studies on the association of the CpG island methylator phenotype (CIMP) with GC prognosis are conflicting and mainly based on selected CIMP markers. The current study attempted to comprehensively assess the association between CIMP status and GC survival and to develop a CIMP-related prognostic gene signature of GC. Methods We used a hierarchical clustering method based on 2,082 GC-related methylation sites to stratify GC patients from the cancer genome atlas into three different CIMP subgroups according to the CIMP status. Gene set enrichment analysis, tumor-infiltrating immune cells, and DNA somatic mutations analysis were conducted to reveal the genomic characteristics in different CIMP-related patients. Cox regression analysis and the least absolute shrinkage and selection operator were performed to develop a CIMP-related prognostic signature. Analyses involving a time-dependent receiver operating characteristic (ROC) curve and calibration plot were adopted to assess the performance of the prognostic signature. Results We found a positive relationship between CIMP and prognosis in GC. Gene set enrichment analysis indicated that cancer-progression-related pathways were enriched in the CIMP-L group. High abundances of CD8+ T cells and M1 macrophages were found in the CIMP-H group, meanwhile more plasma cells, regulatory T cells and CD4+ memory resting T cells were detected in the CIMP-L group. The CIMP-H group showed higher tumor mutation burden, more microsatellite instability-H, less lymph node metastasis, and more somatic mutations favoring survival. We then established a CIMP-related prognostic gene signature comprising six genes (CST6, SLC7A2, RAB3B, IGFBP1, VSTM2L and EVX2). The signature was capable of classifying patients into high‐and low‐risk groups with significant difference in overall survival (OS; p < 0.0001). To assess performance of the prognostic signature, the area under the ROC curve (AUC) for OS was calculated as 0.664 at 1 year, 0.704 at 3 years and 0.667 at 5 years. When compared with previously published gene-based signatures, our CIMP-related signature was comparable or better at predicting prognosis. A multivariate Cox regression analysis indicated the CIMP-related prognostic gene signature was an independent prognostic indicator of GC. In addition, Gene ontology analysis indicated that keratinocyte differentiation and epidermis development were enriched in the high-risk group. Conclusion Collectively, we described a positive association between CIMP status and prognosis in GC and proposed a CIMP-related gene signature as a promising prognostic biomarker for GC.

High Expression of VSTM2L Induced Resistance to Chemoradiotherapy in Rectal Cancer through Downstream IL-4 Signaling

“…VSTM2L is a novel molecule described as an uncharacterized function gene in cancer. Although a few studies have been reported about its gene expression and clinical relevance in gastric cancer [ 16 , 17 ], there is still lack of researches on the functional role and potential molecular mechanism of VSTM2L in cancer. In our study, we used GEO dataset analysis and considered VSTM2L high expression as a biomarker for prediction of poor tumor response and survival prognosis of rectal cancer patients receiving pCRT.…”

“…In recent years, there are a few studies that described the expression and clinical relevance of VSTM2L in cancer; the mRNA level of VSTM2L is lower in gastric cancer tissues than in adjacent normal tissues and was downregulated in the H. pylori-positive gastric cancer [ 16 ]. Moreover, the VSTM2L gene was considered a novel CIMP-related prognostic marker to classify gastric cancer patients into high- and low-risk groups with significant difference in overall survival time [ 17 ]. In this study, we have found that high expression of VSTM2L could be significantly identified to predict poor tumor response and survival prognosis of rectal cancer patients receiving pCRT and described its important functional roles and potential mechanism of VSTM2L in rectal cancer with CRT based on the experimental evidences of patient-derived tumor organoid model and cell line.…”

A hypoxia risk signature for the tumor immune microenvironment evaluation and prognosis prediction in acute myeloid leukemia

“…An analytical tool, CIBERSORT, uses gene expression data to estimate the abundances of cell types in a mixed cell population. A leukocyte gene signature matrix known as LM22 in CIBERSORT, which contains 547 genes, was utilized to identify 22 types of immune cells 73 , which mainly includes tumor-associated macrophages (TAMs), resting dendritic cells, neutrophils and so on. The fractions of immune cell types between two groups with different hypoxia risk scores were estimated using CIBERSORT.…”

Cystatin M/E (Cystatin 6): A Janus-Faced Cysteine Protease Inhibitor with Both Tumor-Suppressing and Tumor-Promoting Functions

“…Moreover, patients with hypermethylated CST6 had a significantly shorter survival time than those with hypomethylated promoter [ 110 ]. In a close way, a CpG island methylator phenotype-related prognostic gene signature, including CST6 , may allow the classification of patients with gastric cancer into high-and low-risk groups with a significant OS difference [ 111 ].…”