BACKGROUND AND AIMFusobacterium enrichment has been associated with colorectal cancer development. Ulcerative colitis (UC) associated tumorigenesis is characterized as high degree of methylation accumulation through continuous colonic inflammation. The aim of this study was to investigate a potential link between Fusobacterium enrichment and DNA methylation accumulation in the inflammatory colonic mucosa in UC.METHODSIn the candidate analysis, inflamed colonic mucosa from 86 UC patients were characterized the methylation status of colorectal a panel of cancer related 24 genes. In the genome-wide analysis, an Infinium HumanMethylation450 BeadChip array was utilized to characterize the methylation status of >450,000 CpG sites for fourteen UC patients. Results were correlated with Fusobacterium status.RESULTSUC with Fusobacterium enrichment (FB-high) was characterized as high degree of type C (for cancer-specific) methylation compared to other (FB-low/neg) samples (P<0.01). Genes hypermethylated in FB-high samples included well-known type C genes in colorectal cancer, such as MINT2 and 31, P16 and NEUROG1. Multivariate analysis demonstrated that the FB high status held an increased likelihood for methylation high as an independent factor (odds ratio: 16.18, 95% confidence interval: 1.94-135.2, P=0.01). Genome-wide methylation analysis demonstrated a unique methylome signature of FB-high cases irrespective of promoter, outside promoter, CpG and non-CpG sites. Group of promoter CpG sites that were exclusively hypermethylated in FB-high cases significantly codified the genes related to the catalytic activity (P=0.039).CONCLUSIONOur findings suggest that Fusobacterium accelerates DNA methylation in specific groups of genes in the inflammatory colonic mucosa in UC.
Molecular irreversibleness with Helicobacter pylori (H. pylori) infection might have a role in gastric tumorigenesis after H. pylori eradication. We performed comprehensive DNA methylation profiling of gastric mucosa after H. pylori eradication with or without gastric cancer. Using four different groups of biopsies obtained from gastric body without history of H. pylori infection (Hp-), gastric body without cancer after H. pylori eradication (cancer-free body), gastric body with early gastric cancer diagnosed after H. pylori eradication (EGC body) and their paired samples from adjacent mucosa of cancer (EGC ADJ), methylation status of five candidate genes (MYOD1, SLC16A12, IGF2, RORA and PRDM5) was examined by the bisulfite pyrosequencing. An Infinium Methylation EPIC BeadChip array was also used to characterize the methylation status of greater than 850,000 CpG sites. The EGC ADJ group showed highest methylation levels of five candidate genes among the four groups of biopsies. In the gastric body (cancer-free body + EGC body), methylation levels were significantly decreased in patients with longer period after eradication, while such association was not observed in EGC ADJ group. Hyper methylated samples were associated with shorter telomere, an indicator for rapid cell turnover, and higher DNMT1 protein expression, an enzyme related to methyl transfer reaction. The genome-wide methylation analysis demonstrated strikingly higher methylation levels especially at CpG islands in the EGC ADJ group. Exclusively hypermethylated promoter CpG islands in the same group frequently coded zinc finger proteins. Our data show that DNA methylation accumulation is associated with molecular irreversibleness and gastric carcinogenesis after H. pylori eradication.
Both genetic and epigenetic abnormalities play important roles in gastric cancer (GC) development. We investigated whether the molecular subtypes of gastric cancer by combining genetic and epigenetic anomalies define its clinicopathological features and prognosis. The CpG island methylator phenotype (CIMP), MLH1 methylation, TP53, and KRAS mutation statuses were characterized in 214 GCs in relation to their clinicopathological features and prognosis. The molecular subtypes based on CIMP and TP53 hot spot mutation status (R175, G245, R248, R273, and R282) best predicted prognosis of GC. These subtypes contained 120 CIMP‐positive (CIMP+) TP53 hot spot mutation‐negative (TP53 hot spot–) cases, 81 CIMP‐negative (CIMP–) TP53 hot spot– cases, 8 CIMP+TP53 hot spot mutation‐positive (TP53 hot spot+) cases, and 5 CIMP– TP53 hot spot+ cases. The CIMP–TP53 hot spot+ group presented the worst overall survival (OS) and progression‐free survival (PFS), followed by the CIMP+TP53 hot spot+, CIMP–TP53 hot spot– and CIMP+TP53 hot spot– groups (both P < 0.0001). These subtypes also correlated well with several aggressive clinicopathological features in that order. The molecular subtypes were independent factors for predicting overall survival (hazard ratio = 1.66, 95% CI = 1.07–2.57, P = 0.006). The molecular subtypes combining the CIMP and TP53 hot spot mutation status provide distinct clinicopathological features and prognostic impacts in GC.
Rationale:Pneumatosis intestinalis (PI) and hepatic portal venous gas (HPVG) are rare but potentially lethal conditions in which gas pathologically accumulates in the portal vein and intestinal wall, respectively. Proposed mechanisms include flatus escaping through an injured intestinal mucosa into the submucosa and thence into the portal venous system, or bacterial translocation (BT) of gas-forming enteric microorganisms from the gut into and through the intestinal wall to other organs. However, there has been no clear histopathological evidence to support these hypotheses.Patient concerns:A 61-year-old man underwent sigmoidectomy for colonic adenocarcinoma. Postoperatively, he developed paralytic ileus and then had a sudden cardiopulmonary arrest.Diagnoses:PI and HPVG were found at autopsy, presumably caused by the postoperative paralytic ileus and associated with BT of gas-forming organisms.Interventions:Cardiopulmonary resuscitation was unsuccessful.Outcomes:Postmortem imaging indicated the presence of massive PI and HPVG. At autopsy, there was marked intestinal emphysema with diffuse ischemic mucosal necrosis and severe pneumatosis in the stomach and intestine and marked gaseous dilation of the intrahepatic portal veins. Postmortem bacterial cultures revealed enteric bacteria in the peripheral blood and liver tissue.Lessons:Postoperative ileus leading to intestinal mucosal damage may be associated with BT of gas-forming enteric bacteria and the rapid onset of PI and HPVG with a lethal outcome.
Magnifying the NBI pattern well correlates with pathological status of gastric mucosa after H. pylori eradication and may predict gastric cancer occurrence.
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