Cooperative participation of epigenomic and genomic alterations in the clinicopathological diversity of gastric adenocarcinomas: significance of cell adhesion and epithelial–mesenchymal transition-related signaling pathways

Abstract

The present study was conducted to clarify the cooperative significance of epigenomic and genomic abnormalities during gastric carcinogenesis. Using 21 samples of normal control gastric mucosa (C), 109 samples of non-cancerous gastric mucosa (N) and 105 samples of cancerous tissue (T) from 109 patients with primary gastric adenocarcinomas, genome-wide DNA methylation analysis was performed using Infinium assay. Among these samples, 66 paired N and corresponding T samples were subjected to whole-exome and single nucleotide polymorphism array analyses. As had been shown in our previous study, 109 patients were clustered clinicopathologically into least aggressive Cluster A (n=20), most aggressive Cluster B1 (n=20), and Cluster B2 (n=69). Most DNA methylation alterations in each cluster had already occurred even in N samples compared to C samples, and DNA methylation alterations at the precancerous N stage were inherited by the established cancers themselves. Recurrent single-nucleotide variants and insertions/deletions resulting in functional disruption of the proteins encoded by the ABCA10, BNC2, CDH1, CTNNB1, SMAD4 and VAV2 genes were specific to Cluster B1, whereas those of the APC, EGFR, ERBB2, ERBB3, MLH1 and MUC6 genes were specific to Cluster A. MetaCore pathway analysis revealed that the epigenomically affected TWIST1 gene and genomically affected CDH1, CTNNB1, MMP9, TLN2, ROCK1 and SMAD4 genes were accumulated in signaling pathways related to cell adhesion, cytoskeleton remodeling and epithelial-mesenchymal transition in Cluster B1. These data indicate that epigenomic alterations at the precancerous stage are important in gastric carcinogenesis and that epigenomic and genomic alterations cooperatively underlie the aggressiveness of gastric adenocarcinomas.

Genotoxic Potential of Nanoparticles: Structural and Functional Modifications in DNA

“…The alterations or “un-balance” in epigenome leads to several diseases like cancer and others ( Wu et al, 2020 ; Yang et al, 2020 ) in the respective individual. However, how these epigenetic alterations are restored in a cell remains unanswered.…”

Quantification of DNA methylation for carcinogenic risk estimation in patients with non-alcoholic steatohepatitis

“…It is well known that not only genomic but also epigenomic alterations participate in carcinogenesis in various human organs [6,7]. DNA methylation alterations are one of the most important epigenomic changes resulting in chromosomal instability and aberrant expression of tumorrelated genes [8][9][10]. In fact, our previous genome-wide DNA methylation analysis using the Infinium assay with pathological tissue specimens has revealed that NASH-specific DNA methylation alterations, which differ from such alterations occurring during viral hepatitis, are inherited by or strengthened in NASH-related HCCs [11].…”

Genetic Clonality as the Hallmark Driving Evolution of Non-Small Cell Lung Cancer

“…Elucidation of this processes is clinically important as metastatic disease causes the majority of cancer deaths [ 17 , 19 , 32 ]. It was shown that genetic background may play an important role in supporting the movement of cancer cells to the specific organs where they form metastases [ 12 , 78 , 95 ]. Primary tumors accumulate most of the alterations vital to metastatic spread, thus NSCLC dissemination may arise from metastatic stem cells (MetSCs) [ 53 , 54 , 72 ] that phylogenetically evolve from the CSCs through tumor progression, sharing with them many genetic similarities [ 72 , 80 , 96 ].…”

“…EMT phenomenon posits that cancer cells partially or completely lose their epithelial properties, detach and travel as single cells, and form clonal or subclonal metastases [ 12 , 78 , 98 , 99 , 100 , 101 ]. However, studies indicate that MetSCs, which have undergone EMT, still exhibit a CSCs phenotype [ 73 , 99 ], suggesting that genes involved in EMT may be key targets in eradicating the CSCs population [ 95 , 98 , 99 ]. This might lead to reduction of cancer dissemination [ 73 ].…”

“…It is postulated that all cancer cells carry a lineage of specific alterations that may play a role in their evolution [ 95 ]. In many somatic CNAs or SNVs (single nucleotide variations) minor subclones in the primary tumors of NSCLC may become fully clonal in distant metastasis [ 13 , 41 ].…”