Genome-wide DNA methylation analysis of colorectal adenomas with and without recurrence reveals an association between CpG methylation and histological subtypes.
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ABSTRACT:
PROVIDER: PRJNA531024 | ENA |
REPOSITORIES: ENA
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Project description:Aberrant methylation of DNA is supposed to be a major and early driver of colonic adenoma development and may also lead to colorectal cancer (CRC) formation. While gene methylation assays are used already for CRC screening, differential epigenetic alterations of recurring and non-recurring colorectal adenomas have yet not been systematically investigated. Here, we collected a sample set (n=72) of formalin-fixed paraffin-embedded (FFPE) primary colorectal adenomas without recurrence (n=30), primary adenomas with recurrence at the same location (n=19), so-called “matched pair samples” (n=10; comprising the primary adenoma and the recurrent adenoma) and normal mucosa specimens (n=3). We aimed to unveil differentially methylated CpG positions (DMPs) across the methylome of the selected samples using the Illumina HumanMethylation 450K BeadChip array. Unsupervised hierarchical clustering exhibited a significant association of methylation patterns with the histological subtypes. No significant DMPs were identified comparing primary adenomas with and without recurrence. Despite that, a total of 5,094 DMPs (FDR<0.05, fold change>10%) were identified in the comparisons of recurrent adenomas vs. (non-) matched primary adenomas with recurrence (674; 98% hypermethylated), recurrent adenomas vs. primary adenomas with and without recurrence (241; 99% hypermethylated) and adenomas vs. normal mucosae (4,179; 46% hypermethylated). DMPs in CpG islands were frequently hypermethylated whereas open sea and shelves exhibited hypomethylation. Gene ontological analysis demonstrated enrichment of genes associated with the immune system, inflammatory processes, and cancer-pathways. We conclude that methylation data is helpful to contribute to a more stable and reproducible histological adenoma classification which is a prerequisite to establishing profound surveillance guidelines
2019-06-01 | GSE129364 | GEO
Project description:Colorectal adenomas are common precancerous lesions with the potential for malignant transformation to colorectal adenocarcinoma. Endoscopic polypectomy provides an opportunity for cancer prevention, however, recurrence rates are high. We collected formalin-fixed paraffin-embedded tissue of fourteen primary adenomas with recurrence, fourteen primary adenomas without recurrence, and fourteen matched pair samples (primary adenoma and the corresponding recurrent adenoma). These samples were analysed by array-based comparative genomic hybridisation (aCGH) to understand the dynamics of copy number alterations (CNAs) and to identify molecular markers to predict recurrence. ACGH analysis confirmed the genetic landscape specific for colorectal tumorigenesis, i.e., CNAs of chromosomes 7 (13.7%), 13q (13.7%), 18 (5.8%) and 20q (13.7%). CNAs were detected in 41/51 (80.4%) of colorectal adenomas (2N). Focal aberrations (≤10 Mbp) were mapped to chromosome bands 6p22.1-p21.33 (33.3%), 7q22.1 (31.4%) and 16q21 (29.4%). Gains of CDX2 were exclusively seen in adenomas with recurrence compared to adenomas without recurrence. However, the average number of copy alterations failed to discriminate primary adenomas with recurrence from primary adenomas without recurrence.
2018-04-01 | GSE110221 | GEO
Project description:Aberrant methylation of DNA is supposed to be a major and early driver of colonic adenoma development, which may result in colorectal cancer (CRC). Although gene methylation assays are used already for CRC screening, differential epigenetic alterations of recurring and nonrecurring colorectal adenomas have yet not been systematically investigated. Here, we collected a sample set of formalin-fixed paraffin-embedded colorectal low-grade adenomas (n = 72) consisting of primary adenomas without and with recurrence (n = 59), recurrent adenomas (n = 10), and normal mucosa specimens (n = 3). We aimed to unveil differentially methylated CpG positions (DMPs) across the methylome comparing not only primary adenomas without recurrence vs primary adenomas with recurrence but also primary adenomas vs recurrent adenomas using the Illumina Human Methylation 450K BeadChip array. Unsupervised hierarchical clustering exhibited a significant association of methylation patterns with histological adenoma subtypes. No significant DMPs were identified comparing primary adenomas with and without recurrence. Despite that, a total of 5094 DMPs (false discovery rate <0.05; fold change >10%) were identified in the comparisons of recurrent adenomas vs primary adenomas with recurrence (674; 98% hypermethylated), recurrent adenomas vs primary adenomas with and without recurrence (241; 99% hypermethylated) and colorectal adenomas vs normal mucosa (4179; 46% hypermethylated). DMPs in cytosine-phosphate-guanine (CpG) islands were frequently hypermethylated, whereas open sea- and shelf-regions exhibited hypomethylation. Gene ontology analysis revealed enrichment of genes associated with the immune system, inflammatory processes, and cancer pathways. In conclusion, our methylation data could assist in establishing a more robust and reproducible histological adenoma classification, which is a prerequisite for improving surveillance guidelines.
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Project description:The DNA methylation value in early-stage hepatocellular carcinoma was undetermined. The Illumina Infinium 450k Human DNA methylation Beadchip was used to identify recurrence-related abbrent CpG methylation. This study was performed in a total of 66 early-stage HCC samples, including 29 recurrence samples and 37 recurrence-free samples
2017-04-30 | E-GEOD-75041 | biostudies-arrayexpress
Project description:We aimed to identify epigenetic alterations associated with the development of traditional serrated adenomas (TSAs). Through DNA methylation analysis with HumanMethylation450 BeadChip in TSAs and sessile serrated adenoma/polyp (SSA/Ps), we identified DNA methylation specifically associated with TSA development.
2018-01-01 | GSE96540 | GEO
Project description:Recurrent single-nucleotide and small indel somatic mutations were infrequent among the three adenoma subtypes. However, somatic copy-number alterations (SCNA) were identified in all three pituitary adenoma subtypes. Methylation analysis revealed adenoma subtype-specific DNA methylation profiles, with GHsecreting adenomas being dominated by hypomethylated sites. Likewise, gene-expression patterns revealed adenoma subtype-specific profiles. Integrating DNA methylation and gene-expression data revealed that hypomethylation of promoter regions are related with increased expression of GH1 and SSTR5 genes in GH-secreting adenomas and POMC gene in ACTH secreting adenomas. Finally, multispectral IHC staining of immune-related proteins showed abundant expression of PD-L1 among all three adenoma subtypes.
2020-03-26 | GSE147548 | GEO
Project description:The DNA methylation value in early-stage hepatocellular carcinoma was undetermined. The Illumina Infinium 450k Human DNA methylation Beadchip was used to identify recurrence-related abbrent CpG methylation.
2017-04-30 | GSE75041 | GEO
Project description:Aberrant DNA methylation is frequent in colorectal cancer (CRC), but the underlying mechanisms and pathological consequences are poorly understood. Ten-Eleven Translocation (TET) dioxygenases and Thymine DNA Glycosylase (TDG) mediate active DNA demethylation by generating and removing oxidized cytosine species. TET1 and TDG mutations, and altered levels of oxidized cytosines have been identified in human CRC. To investigate the TET-TDG demethylation axis in intestinal tumorigenesis, we generated ApcMin mice that are devoid of Tet1 and/or Tdg, and characterized the methylome and transcriptome of intestinal adenomas. There were increased numbers (>30) of adenomas in ApcMin mice expressing the dominant-negative TdgN151A allele, whereas Tet1-deficient and Tet1/Tdg-double heterozygous ApcMin adenomas were larger and displayed features of erosion and invasion. Methylome analysis revealed reduction in global DNA hypomethylation in colonic adenomas from Tet1- and Tdg-mutant ApcMin mice, and hypermethylation of CpG islands in Tet1-mutant ApcMin mice. In addition, RNA sequencing showed upregulation of inflammatory, immune and interferon response genes in Tet1- and Tdg-mutant colonic adenomas compared to control ApcMin adenomas. The corresponding 127-gene inflammatory signature separated human colonic adenocarcinomas in four groups, closely aligned with their microsatellite or chromosomal instability, and characterized by different levels of DNA methylation and DNMT1 expression that anti-correlated with TET1 expression. These findings demonstrate a novel mechanism of epigenetic regulation during intestinal tumorigenesis by which TET1-TDG-mediated DNA demethylation may decrease methylation levels and inflammatory/interferon/immune responses, and is linked to the type of genomic instability.
2024-07-01 | GSE179313 | GEO
Project description:The CpG island methylator phenotype is common in both BRAF mutant colorectal cancer and their precursors, the sessile serrated adenoma (SSA). SSAs acquire dysplasia immediate prior to progressing to invasive cancer. Here we examine the methylome of the remnant non-dysplastic portion of dysplastic sessile serrated adenomas to identify changes that occur immediately prior to the development of overt histological dysplasia.
2019-07-11 | E-MTAB-7854 | biostudies-arrayexpress