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Background: Epstein–Barr virus (EBV)-associated gastric cancer (EBVaGC) has been reported to account for approximately 5–16% of all GCs with good prognosis compared to EBV-negative GC. We evaluated the clinicopathological characteristics of EBVaGC including survival rate in South Korea. Methods: A total of 4,587 patients with GC who underwent EBV in situ hybridization (EBV–ISH) were prospectively enrolled at the Seoul National University Bundang Hospital from 2003 to 2021. Age, sex, smoking status, cancer type and stage, tumor size and location, histological type, molecular features and survival information were analyzed. Results: A total of 456 patients with GC (9.9%) were positive for EBV. The EBVaGC group displayed a higher proportion of males (P < 0.001), a predominant presence in the proximal stomach (P < 0.001), a higher proportion of undifferentiated cancer (P < 0.001), and a lower cancer stage (P = 0.004) than the EBV-negative group. Cox multivariate analyses revealed age (hazard ratio [HR] = 1.025, P < 0.001), tumor size (HR = 1.109, P < 0.001), and cancer stage (stage2 HR = 4.761, P < 0.001; stage3 HR = 13.286, P < 0.001; stage4 HR = 42.528, P < 0.001) as significant risk factors for GC-specific mortality, whereas EBV positivity was inversely correlated (HR = 0.620, P = 0.022). Furthermore, the EBVaGC group displayed statistically significant survival advantages over the EBV-negative cancer group in terms of both overall (P = 0.021) and GC-specific survival (P = 0.007) on the Kaplan–Meier survival curve. However, this effect was evident only in males. Conclusions: EBVaGC patients showed better prognoses despite their association with proximal location and poorly differentiated histology in male, probably due to the difference in immunity between males and females. [ABSTRACT FROM AUTHOR]

Background: Inactivation of TP53, a tumor suppressor gene, is associated with the development of several malignancies, including gastric cancer (GC). The present study aimed to evaluate the correlation between the overexpression of p53 and survival in different Lauren-type GCs. Methods: From May 2003 to December 2019, 3608 GC patients treated endoscopically or surgically at the Seoul National University Bundang Hospital were enrolled for the study. Immunohistochemical staining for p53 was performed on all endoscopic and surgical gastric specimens. Clinicopathologic characteristics with Lauren classification, survival rate, and cancer recurrence were analyzed according to p53 overexpression. Results: Among 3608 GC patients, p53 overexpression was seen in 1334 patients (37%). p53 overexpression was associated with lower depth of invasion (P = 0.026) and Early gastric cancer (P = 0.044) in intestinal-type GC, and with advanced TNM stage (P < 0.001) and Advanced gastric cancer (P < 0.001) in diffuse-type GC. The overall survival (OS) and GC-specific survival (GCSS) were significantly lower in p53 overexpression positive patients. This significance was more pronounced and enhanced in the diffuse-type GC and was absent in the intestinal-type GC. In multivariate analyses, p53 overexpression was associated with poor OS in both subtypes of GC and cancer recurrence in diffuse-type GC. (OS in intestinal-type: adjusted hazard ratio [aHR] = 1.423, P = 0.022; OS in diffuse-type: aHR = 1.401 P = 0.035; cancer recurrence in diffuse-type: aHR = 1.502, P = 0.039). Conclusion: p53 overexpression was associated with poor prognosis in GC, especially in diffuse-type. In addition, p53 overexpression was associated with early stage disease in intestinal-type GC and with advanced stage disease in diffuse-type GC. [ABSTRACT FROM AUTHOR]

Objective: It remains unknown whether individuals with a family history (FH) of gastric cancer (GC) are associated with aberrant DNA methylation. The aim of this study was to investigate the association between aberrant DNA methylation and FH of GC. Design: Using quantitative MethyLight assay, MOS, miR124a-3, NKX6-1, EMX1, CDH1, and TWIST1 methylation levels in the noncancerous gastric mucosa was compared between subjects with and without FH based on GC and Helicobacter pylori (Hp) infection. Changes in the methylation levels were evaluated over time after Hp eradication. Results: In Hp-positive GC patients, MOS (P < 0.001), CDH1 (P < 0.001), and TWIST1 (P = 0.004) methylation were decreased in subjects with FH (n = 64) than in those without FH (n = 58). In Hp-positive controls, MOS methylation was lower in subjects with FH (n = 73) than in those without FH (n = 50) (P = 0.042), while miR124a-3 (P = 0.006), NKX6-1 (P < 0.001), and CDH1 (P < 0.001) methylation were higher in subjects with FH. CDH1 methylation constantly decreased from 2 years in GC patients and 3–4 years in controls after Hp eradication (all P < 0.001). A persistent decrease in methylation over time was not observed in other genes after eradication. Conclusion: The methylation of MOS and CDH1 provided an association between aberrant DNA methylation and gastric carcinogenesis in FH of GC, a useful marker for GC risk in individuals with FH. Furthermore, CDH1 methylation decreased after Hp eradication. [ABSTRACT FROM AUTHOR]

Objective: Helicobacter pylori (HP) is known to play an important role in the development of gastric cancer (GC). The aim of this study was to analyze the effect of HP eradication on the survival rate and cancer recurrence in patients who underwent subtotal gastrectomy for GC. Design: Totally 1,031 patients diagnosed with gastric adenocarcinoma who received surgical treatment at the Seoul National University Bundang Hospital from 2003 to 2017 and positive for HP infection were analyzed. The overall and GC-related survival according to HP eradication were compared; risk factors for GC-specific death and cancer recurrence were analyzed, and propensity score matching (PSM) was performed. Results: Statistically significant benefits of overall and GC-specific survival were observed in the eradicated group compared to the non-eradicated group (P < 0.001), and these benefits were maintained after PSM (P < 0.001) in both of early and advance stage. In Cox proportional hazards multivariate analyses, cancer stage (stage II, adjusted hazard ratio [aHR] = 9.33, P < 0.001; stage III or IV, aHR = 26.17, P < 0.001), and HP positivity (aHR = 3.41, P = 0.001) were independent risk factors for GC-specific death; cancer stage (cancer stage II, aHR = 7.08, P < 0.001; cancer stage III or IV, aHR = 19.64, P < 0.001) and HP positivity (aHR = 2.70; P = 0.005) were independent risk factors for cancer recurrence. Conclusion: Our results suggest that HP needed to be conducted more intensively in patients who are surgically treated for GC, regardless of cancer stage. [ABSTRACT FROM AUTHOR]

The role of macrophage migration inhibitory factor (MIF) and autophagy in gastric cancer is not clear. We determined H. pylori infection status of the subjects and investigated the expression of MIF and autophagy markers (Atg5, LC3A and LC3B) in human gastric tissue at baseline. Then H. pylori eradication was done for H. pylori positive patients and MIF and Atg5 levels were investigated on each follow-up for both H. pylori-eradicated and H. pylori negative patients. Baseline tissue mRNA expression of MIF, Atg5, LC3A and LC3B was measured by real-time PCR in 453 patients (control 165, gastric dysplasia 82, and gastric cancer 206). Three hundred three patients (66.9%) had H. pylori infection at the time of enrollment. Only within H. pylori-positive group, MIF level was significantly elevated in patients with cancer than in control or dysplasia groups (P<0.05). LC3A and LC3B levels also showed significant differences within H. pylori-positive subgroups. H. pylori-positive dysplasia subgroup showed significantly lower (LC3A) (P<0.05) and higher (LC3B) mRNA levels (P<0.05) than in other subgroups. On follow-up, within H. pylori-eradicated group, Atg5 expression increased sequentially from control to dysplasia and cancer subgroups. Multiple linear regression showed autophagy markers (LC3A, LC3B, and Atg5) directly predicted MIF level (adjusted R2 = 0.492, P<0.001). Serial follow-up showed longitudinal increase in Atg5 level in general, with constantly higher levels in H. pylori-eradicated group than in -negative group. Intestinal metaplasia (IM) group initially showed higher Atg5 expression than the IM-negative group. However, it was reversed between the groups eventually because of the lower rate of increase in IM group. These results suggest a role of MIF and autophagy markers and their interaction in H. pylori-associated gastric carcinogenesis. [ABSTRACT FROM AUTHOR]

Background: A large-scale study was performed to identify the risk factors for developing synchronous and metachronous colorectal cancer (CRC) in gastric cancer (GC) patients, including microsatellite instability (MSI) and p53 overexpression. Methods: A total of 1041 GC patients who underwent endoscopic resection or surgery and underwent colonoscopy simultaneously or during surveillance for GC were consecutively enrolled. Clinicopathologic characteristics, MSI, and p53 overexpression were compared between the GC patients with and those without synchronous and metachronous CRC. Results: Of the 1041 patients, CRCs were detected in 67 (6.4 %) patients with GC. Forty-six (4.4 %) had synchronous CRC and 21 (2.0 %) had metachronous CRC. Univariate analysis indicated that age ≥63 years ( P < 0.001), male sex ( P = 0.005), and p53 overexpression ( P = 0.040) were significantly associated with a higher incidence of CRC. However, body mass index, smoking, tumor location, tumor multiplicity, tumor histology, TNM stage, and MSI were not significantly associated with the incidence of CRC. Age ≥63 years (OR: 5.881; 95 % CI: 3.083-11.221; P < 0.001) and male sex (OR: 2.933; 95 % CI: 1.307-6.584; P = 0.009) were risk factors for CRC in GC patients according to multivariate analysis. Conclusions: GC patients who are male and/or ≥63 years old are recommended to receive colonoscopy to detect CRC. MSI and p53 overexpression were not useful molecular markers for predicting CRC in GC. [ABSTRACT FROM AUTHOR]

Background: Obesity is known to be associated with an increased risk of gastric cardia cancer but not with noncardia cancer. In terms of gastric dysplasia, few studies have evaluated its relationship with obesity. In addition, no study on the relationship between obesity and the risk of gastric cancer has analyzed the status of Helicobacter pylori infection. Methods: A case-control study was designed to investigate the relationship between obesity and the risk of gastric cancer and dysplasia adjusted for the status of H. pylori infection in Koreans. Nine hundred ninety-eight gastric cancer patients, 313 gastric dysplasia patients, and 1,288 subjects with normal endoscopic findings were included. Results: As gender differences could be the largest confounding factor, the risk of gastric cancer and dysplasia with an increasing body mass index (BMI) was analyzed in men and women, separately, and was adjusted for age, smoking, drinking, family history of gastric cancer, H. pylori infection, atrophic gastritis, intestinal metaplasia, and serum pepsinogen I/pepsinogen II ratio. Obesity (BMI 25 kg/m or greater but less than 30 kg/m) was associated with increased risk of early gastric cancer [adjusted odds ratio (aOR) 1.657; 95 % confidence interval (CI) 1.086-2.528; P = 0.019] and well or moderately differentiated adenocarcinoma (aOR 1.566; 95 % CI 1.011-2.424; P = 0.044) compared with normal BMI status (BMI < 23 kg/m) in men. Obesity was related to gastric dysplasia (aOR 2.086; 95 % CI 1.011-4.302; P = 0.047) in women. Conclusions: The effect of obesity on gastric cancer showed a gender difference. That is, in men it was related to increased risk of early gastric cancer and well or moderately differentiated adenocarcinoma, but it was associated with gastric dysplasia in women regardless of H. pylori infection in Korea. Further research into this difference is necessary. [ABSTRACT FROM AUTHOR]

Background: Transforming growth factor-β1 (TGF-β1) has dual roles inhibiting and promoting carcinogenesis. Although many researchers have conducted association studies between TGFB1 C-509T polymorphism and the risk of developing gastric cancer, the results are not uniform. Methods: We genotyped 1028 gastric cancer patients and 958 controls by the polymerase chain reaction-restriction fragment length polymorphism method. Immunohistochemistry was performed to assess the expression of TGF-β1 in the cancer and noncancerous tissues of 120 gastric cancer patients. mRNA expression was also measured in noncancerous gastric mucosa by qRT-PCR in the 282 subjects. Results: The CT genotype in the TGFB1 C-509T polymorphism was associated with an increased risk of gastric cancer development (adjusted OR 1.35, 95 % CI 1.07-1.71, P = 0.013), especially for intestinal-type cancer (adjusted OR 1.43, 95 % CI 1.08-1.90, P = 0.014). More frequent TGF-β1 expression was found in the center of cancer tissue in the TGFB1-509T carrier group than in the others (90.5 % vs. 72.2 %, P = 0.010). T-carriers also presented higher expression level of gastric TGF-β1 mRNA than non T-carriers (median 1.29 vs. 0.80, P = 0.004) when they were infected by H. pylori. Cancer patients showed elevated gastric TGFB1gene expression compared to the control group (median 1.22 vs. 0.89, P = 0.009). Conclusions: The carcinogenic effect of TGF-β1 might be associated with increased gastric TGF-β1 expression in subjects with the T allele of TGFB1-509. [ABSTRACT FROM AUTHOR]

Background: The relationship between alcohol intake and the risk for gastric cancer is not fully understood. The association between alcohol consumption and the risk for gastric cancer was investigated in the Korean population with the ALDH2 genotype. Methods: From 2003 to 2008, 445 patients with gastric cancer and 370 control subjects ≥ 50 years of age were included in the analysis. Logistic regression models including age, gender, education, smoking and drinking status, Helicobacter pylori infection and ALDH2 genotype were evaluated to estimate the adjusted odds ratios (ORs) for the development of gastric cancer. Results: For all subjects, the risk for gastric cancer was increased in ex-drinkers [OR 1.68, 95% confidence interval (CI) 1.07-2.64], but not in current drinkers. Subjects with inactive ALDH2 *2 allele(s) showed a lower level of alcohol consumption than ALDH2 *1/*1 homozygotes (P < 0.001). Among the ALDH2 *1/*2 carriers (n = 243), current/ex-drinkers had a significantly increased risk for gastric cancer compared with never/rare drinkers (OR 2.80, 95% CI 1.51-5.19). Among heavy drinkers (n = 115), ALDH2 *1/*2 heterozygotes had a 4-fold increased risk for gastric cancer compared with *1/*1 homozygotes (OR 4.26, 95% CI 1.10-16.47); however, no risk increase was seen among never/rare drinkers. Conclusions: A dose-response association between alcohol intake and the risk for gastric cancer was not observed. However, ALDH2 polymorphisms were found to modify the susceptibility to the development of gastric cancer associated with alcohol intake, especially in case of ALDH2 *1/*2 genotype. The findings suggest an alcohol-ALDH2 genotype interaction in gastric carcinogenesis. [ABSTRACT FROM AUTHOR]

Objective: To identify genetic variations which is associated with gastric cancer (GC) risk according to Helicobacter pylori infection. Methods: This study incorporated 527 GC patients and 441 controls from a cohort at Seoul National University Bundang Hospital. The associations between GC risk and single nucleotide polymorphisms were calculated, stratified by H. pylori status, adjusting for age, sex, and smoking. mRNA expression from non-cancerous gastric mucosae was evaluated using reverse transcription quantitative polymerase chain reaction. Results: In the entire cohort, genome-wide association study showed no significant variants reached the genome-wide significance level. In the H. pylori–positive group, rs2671655 (chr17:47,468,020;hg19, GH17J049387 enhancer region) was identified at a genome-wide significance level, which was more pronounced in diffuse type GC. There was no significant variant in the H. pylori–negative group, indicating the effect modification of rs2671655 by H. pylori. Among the target genes of GH17J049387 enhancer (PHB1, ZNF652 and SPOP), PHB1 mRNA was expressed more in cases than in controls, who were not affected by H. pylori. By contrast, an increase in ZNF652 and SPOP in GC was observed only in the H. pylori–negative group (P < 0.05). Mediation analysis showed that PHB1 (P = 0.0238) and SPOP (P = 0.0328) mediated the effect of rs2671655 on GC risk. The polygenic risk score was associated with the number of rs2671655 risk alleles only in the H. pylori–positive group (P = 0.0112). Conclusion: After H. pylori infection, rs2671655 may increase GC risk, especially in diffuse-type GC, by regulating the expression of several genes that consequently modify susceptibility to GC. [ABSTRACT FROM AUTHOR]

There have been only a few reports investigating the clinical efficacy of follow-up endoscopy for detection of recurrent gastric cancer after total gastrectomy (TG). We reviewed the records of 747 patients undergoing TG from 2003 to 2012 and enrolled 267 patients (70 with early gastric cancer (EGC) and 197 with advanced gastric cancer (AGC)), who received one or more follow-up endoscopy and contrast abdominal computed tomography (CT) scan. We found no tumor recurrence in the 70 EGC patients during the mean follow-up periods of 42.1 ± 18 and 43.2 ± 19 months by endoscopy and contrast abdominal CT scan. In 197 AGC patients, 59 patients (29.8%) had confirmed tumor recurrence during mean follow-up periods of 40.5 ± 21 and 45.3 ± 22 months. The most common pattern of tumor recurrence was distant metastasis (n = 35) followed by peritoneal metastasis (n = 11). Among the other 13 cases with loco-regional recurrence, seven cases were regional lymph node metastases, four were anastomosis site recurrences, and two were duodenal stump and jejunal loop site recurrences. Three of the four cases of anastomosis site recurrence were found by both endoscopy and contrast abdominal CT scan; one case was missed by contrast abdominal CT scan. However, the two cases with duodenal stump and jejunal loop recurrences were detected by contrast abdominal CT scan only. An annual follow-up endoscopy for gastric cancer after TG might have a limited role in the detection of tumor recurrence, especially in patients with EGC. Contrast abdominal CT scan may be sufficient as a follow-up method for recurrent gastric cancer after TG. [ABSTRACT FROM AUTHOR]