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.
Highlights
Colorectal cancer is the third most common cancer worldwide with 746 000 cases in men, 614 000 cases in women, and 694 000 deaths globally in 2012.1 incidence and mortality rates have been settling in several developed countries, the universal burden of colorectal cancer is projected to increase by more than 2.2 million cases and 1.1 million deaths by the year 2030.1 Its pathogenesis originates from epithelial cells lining the colon or rectum, which accumulate mutations in key cell signaling pathways such as Wnt signaling and, most commonly, in the APC tumor suppressor gene.[2]
Discovered in our lab as a gene responsible for autosomal hearing loss, Gasdermin E (GSDME) was identified as a target of epigenetic silencing in several cancer types.[13,14,15,16,17]
In this analysis of The Cancer Genome Atlas (TCGA) methylation data, we provide evidence that GSDME DNA methylation is a promising biomarker for the diagnosis of colorectal cancer
Summary
Colorectal cancer is the third most common cancer worldwide with 746 000 cases in men, 614 000 cases in women, and 694 000 deaths globally in 2012.1 incidence and mortality rates have been settling in several developed countries, the universal burden of colorectal cancer is projected to increase by more than 2.2 million cases and 1.1 million deaths by the year 2030.1 Its pathogenesis originates from epithelial cells lining the colon or rectum, which accumulate mutations in key cell signaling pathways such as Wnt signaling and, most commonly, in the APC tumor suppressor gene.[2]. In addition to its role in hearing loss, GSDME is a tumor suppressor gene capable of inducing programmed cell death as a result of a caspase‐3 cleavage.[12] Given its role in cancer, epigenetic silencing through methylation has been shown in 52% and 65% of primary gastric tumors[13] and colorectal adenocarcinomas[14,15] respectively. These studies were performed on a small number of tumors and only included a few CpGs from the putative promoter.
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