Methylation status of IGF2 DMR and LINE1 in leukocyte DNA provides distinct clinicopathological features of gastric cancer patients.

DNA methylation of leukocyte DNA has been proposed to be a biomarker for cancer that can be used to target patients for appropriate clinical implementation. We investigated IGF2 DMR and LINE1 methylation in the leukocyte DNA and their association with clinicopathological features and prognosis of gastric cancer (GC) patients. Methylation status of IGF2 DMR and LINE1 in the leukocyte DNA was quantified using bisulfite pyrosequencing in 207 GC patients. Methylation of both IGF2 DMR and the LINE1 was significantly higher in the undifferentiated histologic type compared to the differentiated histologic type (both P = 0.0002). Hypermethylation of both the IGF2 DMR and the LINE1 was associated with more aggressive features of GC such as advanced stage (IGF2 DMR, P = 0.0002; LINE1, P < 0.0001), lymphatic invasion positive (IGF2 DMR, P = 0.004; LINE1, P = 0.002), venous invasion positive (IGF2 DMR, LINE1, both P = 0.03), lymph node metastasis positive (IGF2 DMR, P = 0.01; LINE1, P = 0.001), peritoneal dissemination positive (IGF2 DMR, P = 0.04; LINE1, P = 0.002), liver metastasis positive (IGF2 DMR, P = 0.008; LINE1, P = 0.001), and other distant metastasis positive (IGF2 DMR, P = 0.04). Our data suggest that high LINE1 and IGF2 DMR methylation status would be a phenomenon that is observed with the progression of GC, supporting their potential utility as a biomarker in GC patients.

Erratum to 'Jejunal GI tumor using probe-based confocal laser endomicroscopy': [VideoGIE 2018;3:220-2].

[This corrects the article DOI: 10.1016/j.vgie.2018.04.010.].

Potential link between Fusobacterium enrichment and DNA methylation accumulation in the inflammatory colonic mucosa in ulcerative colitis.

BACKGROUND AND AIM: Fusobacterium 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. METHODS: In 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. RESULTS: UC 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). CONCLUSION: Our findings suggest that Fusobacterium accelerates DNA methylation in specific groups of genes in the inflammatory colonic mucosa in UC.

Telomere Length in Leukocyte DNA in Gastric Cancer Patients and its Association with Clinicopathological Features and Prognosis.

BACKGROUND/AIM: Telomere shortening in leukocytes has been thought to be associated with reduced immune response capacity and increased chromosome instability. Several studies indicate that telomere length in the peripheral blood leukocyte DNA can predict clinical outcome of several cancers. We evaluated the potential association between telomere shortening in the leukocyte DNA and clinicopathological features and prognosis of gastric cancer (GC) in Japanese patients. MATERIALS AND METHODS: Telomere length in leukocyte DNA was measured using quantitative real-time polymerase chain reaction (PCR) in 207 GC patients. The association between telomere length and clinicopathological features and prognosis was evaluated. RESULTS: These short-telomere group was significantly associated with advanced stage (p=0.015), worse overall survival (OS) and progression-free survival (PFS) (p=0.046 and 0.026, respectively). The same group was also weakly associated with overall and peritoneal recurrences (p=0.052 and 0.059, respectively). CONCLUSION: Telomere shortening in leukocyte DNA is associated with advanced stage and poor prognosis of GC, which may reflect their reduced immune response capacity or increased chromosome instability.

Relationship between expression of onco-related miRNAs and the endoscopic appearance of colorectal tumors.

Accumulating data indicates that certain microRNAs (miRNAs or miRs) are differently expressed in samples of tumors and paired non-tumorous samples taken from the same patients with colorectal tumors. We examined the expression of onco-related miRNAs in 131 sporadic exophytic adenomas or early cancers and in 52 sporadic flat elevated adenomas or early cancers to clarify the relationship between the expression of the miRNAs and the endoscopic morphological appearance of the colorectal tumors. The expression levels of miR-143, -145, and -34a were significantly reduced in most of the exophytic tumors compared with those in the flat elevated ones. In type 2 cancers, the miRNA expression profile was very similar to that of the exophytic tumors. The expression levels of miR-7 and -21 were significantly up-regulated in some flat elevated adenomas compared with those in exophytic adenomas. In contrast, in most of the miR-143 and -145 down-regulated cases of the adenoma-carcinoma sequence and in some of the de novo types of carcinoma, the up-regulation of oncogenic miR-7 and/or -21 contributed to the triggering mechanism leading to the carcinogenetic process. These findings indicated that the expression of onco-related miRNA was associated with the morphological appearance of colorectal tumors.

The loss of HBeAg without precore mutation results in lower HBV DNA levels and ALT levels in chronic hepatitis B virus infection.

BACKGROUND: The aim of this study was to investigate the correlation between precore (PC)/basal core promoter (BCP) mutations and the viral loads or activity of hepatitis in patients with chronic hepatitis B virus (HBV) infection. METHODS: HBV genotypes, PC mutations, BCP mutations, HBV DNA levels, and serological markers of HBV were analyzed in all the patients with chronic HBV infection seen in Fujita Health University Hospital from June 2004 to November 2008 (n=215). RESULTS: HBV genotype was C in 169 patients, B in 16, A in 3, F in 1, and unclassifiable in 5. Among the patients with genotype C, the prevalence of PC wild type was significantly lower in hepatitis B envelope antigen (HBeAg)(-) patients than in HBeAg(+) patients (9.5% versus 49.0%, P<0.0001). Among HBeAg(-) patients, the patients with PC wild type had significantly lower serum viral loads and alanine aminotransferase (ALT) levels compared with those with PC mutant (P<0.001). Among HBeAg(-) patients, the patients with genotype B had lower serum viral loads compared with those with genotype C (3.6+/-0.9 versus 4.6+/-1.6, P<0.05), and the prevalence of BCP wild type was significantly higher in those with genotype B than in those with genotype C (58.3% versus 10.8%, P<0.05). CONCLUSIONS: Among HBeAg(-) patients with genotype C, the patients with PC wild type had significantly lower viral loads and ALT levels than those with PC mutant. This suggests that the patients with PC wild type may have better prognosis than those with PC mutant among HBeAg(-) patients with genotype C.

Liver stiffness measured by transient elastography correlates with fibrosis area in liver biopsy in patients with chronic hepatitis C.

AIM: Liver stiffness (LS) measured by transient elastography (TE) has been reported to correlate with liver fibrosis, which is usually semiquantitatively assessed. In the present study, the fibrosis area was measured by image analysis software in liver biopsy specimens and its correlation with LS was assessed. METHODS: LS was measured by TE in all 165 patients with chronic hepatitis C virus (HCV) infection who underwent liver biopsy consecutively in Fujita Health University Hospital from July 2004 to September 2007. RESULTS: Fibrosis area was significantly correlated with fibrosis stage as assessed by the Metavir score (rho = 0.733, P < 0.0001). The optimal cut-off value of fibrosis area was 1.6% for F > or = 2, 3.1% for F > or = 3, and 3.8-6.4% for F4. LS was significantly correlated with fibrosis stage (rho = 0.734, P < 0.0001). The optimal cut-off value of LS was 7.1 kPa for F > or = 2, 9.6 kPa for F > or = 3 and 11.6-16.9 kPa for F4. Multiple linear regression analysis selected fibrosis area (P = 0.0002), alanine aminotransferase (ALT) (P = 0.0237), gamma-glutamyltransferase (gamma-GTP) (P = 0.0114), prothrombin time (P = 0.0114) and hyaluronic acid (P < 0.0001) as factors correlating with LS. CONCLUSION: The correlation between LS and liver fibrosis was confirmed by the objective measurement of fibrosis area. ALT was significantly correlated with LS, suggesting that inflammatory activity also affects LS values. Despite some limitation, LS measurement is a useful method for the diagnosis of liver fibrosis.

Assessment of nutritional status of patients with hepatitis C virus-related liver cirrhosis.

AIM: Nutrition support for patients with liver cirrhosis, such as late evening snacks and branched-chain amino acids, has been demonstrated to be effective. However, the assessment of the malnutrition of liver cirrhosis is still a problem. The aim of this study was to assess the nutritional status of patients with liver cirrhosis due to hepatitis C virus by six methods and to test the sensitivity and specificity of these methods. METHODS: In total, 86 patients with liver cirrhosis due to hepatitis C virus were assessed for nutritional status by triceps skinfold thickness (TSF), arm muscle circumference (AMC), subjective global assessment (SGA), nutritional risk index (NRI), Maastricht index (MI), and instant nutritional assessment (INA). RESULTS: Malnutrition was found in 11 (12.8%) patients by TSF, 15 (17.4%) by AMC, 22 (25.6%) by SGA, 52 (60.5%) by the NRI, 66 (76.7%) by the MI, and in 54 (62.8%) by INA. The MI detected malnutrition at a significantly higher rate compared with the other five methods. Sixty-two patients were diagnosed as malnourished by the combined index, which defines the patients as malnourished when any two of the NRI, MI, and INA also define them as malnourished. The misclassification rate compared with the combined indexes was significantly lower in the MI (4.7%) than in any of the TSF (59.3%), AMC (59.3%), SGA (46.5%), NRI (16.3%), and INA (14.0%). CONCLUSION: The MI was the best single score to identify the patients who had malnutrition, including early stage, and may benefit from nutrition support.