Methylation analysis of Gasdermin E shows great promise as a biomarker for colorectal cancer

Abstract

In addition to its implication in hereditary hearing loss, the Gasdermin E ( GSDME ) gene is also a tumor suppressor involved in cancer progression through programmed cell death. GSDME epigenetic silencing through methylation has been shown in some cancer types, but studies are yet to fully explore its diagnostic/prognostic potential in colorectal cancer on a large‐scale. We used public data from The Cancer Genome Atlas (TCGA) to investigate differences in GSDME methylation and expression between colorectal cancer and normal colorectal tissue, and between left‐ and right‐sided colorectal cancers in 432 samples. We also explored GSDME 's diagnostic capacity as a biomarker for colorectal cancer. We observed differential methylation in all 22 GSDME CpGs between tumor and normal tissues, and in 18 CpGs between the left‐ and right‐sided groups. In the cancer tissue, putative promoter probes were hypermethylated and gene body probes were hypomethylated, while this pattern was inversed in normal tissues. Both putative promoter and gene body CpGs correlated well together but formed distinct methylation patterns with the putative promoter exhibiting the most pronounced methylation differences between tumor and normal tissues. Clinicopathological parameters, excluding age, did not show any effect on CpG methylation. Although the methylation of 5 distinct probes was a good predictor of gene expression, we could not identify an association between GSDME methylation and expression in general. Survival analysis showed no association between GSDME methylation and expression on 5‐year patient survival. Through logistic regression, we identified a combination of 2 CpGs, that can discriminate between cancer and normal tissue with high accuracy (AUC = 0.95) irrespective of age and tumor stage. We also validated our model in 3 external methylation datasets, from the Gene Expression Omnibus database, and similar results were reached. Our results suggest that GSDME is a promising biomarker for the detection of colorectal cancer.

The role of pyroptosis in cancer: pro-cancer or pro-“host”?

“…However, methods for preventing excessive inflammation responses by downregulating GSDMD to avoid endotoxin shock still need further study. The methylation of DFNA5/GSDME mRNA results in lower DFNA5/GSDME expression in many types of tumor cells than in normal cells 62,74,87–89,131 , which makes activating pyroptosis difficult in most tumor cells. In the chemotherapeutic treatment of malignant tumors, appropriate chemotherapeutic drugs can be selected according to the level of DFNA5/GSDME expression, which can be upregulated in tumor cells, thereby enhancing chemotherapeutic drug sensitivity and reducing drug resistance.…”

“…Therefore, Gsdmc is an oncogene that may act as a new therapeutic target for CRC treatment with the Tgfbr2 mutation 73 . Recently, Ibrahim et al identified two combinations of CpGs that can accurately distinguish between CRC and normal tissues regardless of age and stage, suggesting that GSDME may be a promising biomarker for CRC detection 74 (Table 1).…”

Determination of the Potential Tumor-Suppressive Effects of Gsdme in a Chemically Induced and in a Genetically Modified Intestinal Cancer Mouse Model

“…Since its discovery in 1998, a number of studies on GSDME have been published, pointing towards a possible involvement in cancer [2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17]. Moreover, genomic methylation screens unveiled GSDME as a possible tumor suppressor gene [11,13,14].…”

“…Moreover, genomic methylation screens unveiled GSDME as a possible tumor suppressor gene [11,13,14]. Furthermore, epigenetic silencing through GSDME methylation was previously shown in primary gastric [14], breast [6,7,12], and colorectal cancer [5,9,13]. In addition, GSDME expression was significantly downregulated, both in colon cancer samples and in colorectal cancer cell lines [13].…”

“…In this study, we aimed to determine the potential tumor-suppressive effects of Gsdme both in a chemically induced and in a genetically modified intestinal cancer mouse model, given the strong evidence that GSDME plays a role in human colorectal cancer [5,9,13] and good, representative mouse models for intestinal cancer are available [18,19,20,21,22,23,24,25,26]. To mimic the silencing of GSDME by methylation, as observed in human cancers, a Gsdme knockout (KO) mouse model was developed.…”