Dataset Information

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.

SUBMITTER: Ibrahim J

PROVIDER: S-EPMC6536921 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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

Ibrahim Joe J Op de Beeck Ken K Fransen Erik E Croes Lieselot L Beyens Matthias M Suls Arvid A Vanden Berghe Wim W Peeters Marc M Van Camp Guy G

Cancer medicine 20190416 5

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 ...[more]

PMID: 30993897

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Project description:BackgroundLong interspersed nucleotide element 1 (LINE-1) hypomethylation is suggested to play a role in the progression of colorectal cancer (CRC). To assess intra-patient heterogeneity of LINE-1 methylation in CRC and to understand its biological relevance in invasion and metastasis, we evaluated the LINE-1 methylation at multiple tumor sites. In addition, the influence of stromal cell content on the measurement of LINE-1 methylation in tumor tissue was analyzed.MethodsFormalin-fixed paraffin-embedded primary tumor tissue was obtained from 48 CRC patients. Matched adjacent normal colon tissue, lymph node metastases and distant metastases were obtained from 12, 18 and 7 of these patients, respectively. Three different areas were microdissected from each primary tumor and included the tumor center and invasive front. Normal mucosal and stromal cells were also microdissected for comparison with the tumor cells. The microdissected samples were compared in LINE-1 methylation level measured by multicolor MethyLight assay. The assay results were also compared between microdissected and macrodissected tissue samples.ResultsLINE-1 methylation within primary tumors showed no significant intra-tumoral heterogeneity, with the tumor center and invasive front showing identical methylation levels. Moreover, no difference in LINE-1 methylation was observed between the primary tumor and lymph node and distant metastases from the same patient. Tumor cells showed significantly less LINE-1 methylation compared to adjacent stromal and normal mucosal epithelial cells. Consequently, LINE-1 methylation was significantly lower in microdissected samples compared to macrodissected samples. A trend for less LINE-1 methylation was also observed in more advanced stages of CRC.ConclusionsLINE-1 methylation shows little intra-patient tumor heterogeneity, indicating the suitability of its use for molecular diagnosis in CRC. The methylation is relatively stable during CRC progression, leading us to propose a new concept for the association between LINE-1 methylation and disease stage.

Project description:BackgroundEpigenetic alternation is a common contributing factor to neoplastic transformation. Although previous studies have reported a cluster of aberrant promoter methylation changes associated with silencing of tumor suppressor genes, little is known concerning their sequential DNA methylation changes during the carcinogenetic process. The aim of the present study was to address a genome-wide search for identifying potentially important methylated changes and investigate the onset and pattern of methylation changes during the progression of colorectal neoplasia.MethodsA three-phase design was employed in this study. In the screening phase, DNA methylation profile of 12 pairs of colorectal cancer (CRC) and adjacent normal tissues was analyzed by using the Illumina MethylationEPIC BeadChip. Significant CpG sites were selected based on a cross-validation analysis from The Cancer Genome Atlas (TCGA) database. Methylation levels of candidate CpGs were assessed using pyrosequencing in the training dataset (tumor lesions and adjacent normal tissues from 46 CRCs) and the validation dataset (tumor lesions and paired normal tissues from 13 hyperplastic polyps, 129 adenomas, and 256 CRCs). A linear mixed-effects model was used to examine the incremental changes of DNA methylation during the progression of colorectal neoplasia.ResultsThe comparisons between normal and tumor samples in the screening phase revealed an extensive CRC-specific methylomic pattern with 174,006 (21%) methylated CpG sites, of which 22,232 (13%) were hyermethylated and 151,774 (87%) were hypomethylated. Hypermethylation mostly occurred in CpG islands with an overlap of gene promoters, while hypomethylation tended to be mapped far away from functional regions. Further cross validation analysis from TCGA dataset confirmed 265 hypermethylated promoters coupling with downregulated gene expression. Among which, hypermethylated changes in MEEPD2 promoter was successfully replicated in both training and validation phase. Significant hypermethylation appeared since precursor lesions with an extensive modification in CRCs. The linear mixed-effects modeling analysis found that a cumulative pattern of MPPED2 methylation changes from normal mucosa to hyperplastic polyp to adenoma, and to carcinoma (P < 0.001).ConclusionsOur findings indicate that epigenetic alterations of MPPED2 promoter region appear sequentially during the colorectal neoplastic progression. It might be able to serve as a promising biomarker for early diagnosis and stage surveillance of colorectal tumorigenesis.

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

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

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