Upper gastrointestinal neoplasia in the esophagus, stomach and pancreas is associated with the formation of pre-neoplastic metaplasias. We have previously reported the up-regulation of Human epididymis protein 4 (HE4) in all metaplasias in the stomach of humans and mice. We have now sought to evaluate the expression of HE4 in metaplasias/pre-neoplastic precursors and cancers of the human stomach, pancreas and esophagus. Tissue microarrays for gastric cancers, pancreatic cancers and esophageal adenocarcinoma were stained with antibodies against HE4. Immunostaining was quantified by digital imaging and the results were evaluated to assess expression in metaplasias, expression in cancer pathological subtypes and the effects of expression on survival in cancer patients. In gastric cancer patients from Korea, HE4 was detected in 74% of intestinal and 90% of diffuse cancers, while in a gastric cancer cohort from Johns Hopkins HE4 was detected 74% of intestinal type and 92% of diffuse cancers. Nevertheless, in both cohorts there was no impact of HE4 expression on overall survival. In the esophagus, we observed expression of HE4 in scattered endocrine cells within Barrett’s esophagus samples, but Barrett’s columnar metaplasias and HE4 was detected in only 2% of esophageal adenocarcinomas. Finally, in the pancreas, HE4 expression was not observed in pancreatic intraepithelial neoplasia (PanIN) lesions, but 46.8% of pancreatic adenocarcinomas expressed HE4 expression. Still, we did not observe any influence of HE4 expression on survival. The results suggest that HE4 is up-regulated during gastric and pancreatic carcinogenesis.

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Background: Growth differentiation factor- 15 (GDF-15) is positively associated with the risk of mortality from acute coronary syndrome and chronic heart failure. A prior study reported decreased methylation at four promising GDF-15 related CpG sites tended to be associated with myocardial infarction, however, little is known of the association of methylation levels at these sites with the risk for cardiovascular disease (CVD) death. Objective: To evaluate whether methylation levels at the four GDF-15 CpG sites (site A: cg13033585, site B: cg16936953, site C: cg17150809, and site D: cg18608055) are associated with death from CVD, independent of genes and shared environmental factors. Method: We included 19 male monozygotic twin pairs discordant for death from CVD through December 31, 2014 from the National Heart, Lung, and Blood Institute (NHLBI) Twin Study initiated in 1969-1973. Buffy coat DNA samples were collected in exam 3 (1986-87). The vital status was followed up through December 31, 2014. Genome wide DNA methylation levels were quantified using the Illumina Infinium HumanMethylation450 (450K) BeadChip. Conditional logistic models were used to estimate hazard ratio (HR). Known baseline CVD risk factors were adjusted. Results: The twins’ mean baseline age was 50.4 years with standard deviation of 2.4. The crude HR was 0.01 (95% CI: 0.00, 2854.46), 2038.89 (95%CI: 0.01, 3.84 X 10 8 ), 0.12 (95% CI: 0.00, 55.99), and 2.08 (95% CI: 0.00, 1.26 X 10 6 ) for sites A, B, C, and D, respectively, suggesting that our sample size was small to test these sites. After adjustment for body mass index, years of education, and Framingham risk scores, HR was 0.03 (95% CI: 0.00, 45281.06) for site A, 700.96 (95% CI: 0.00, 2.32 X10 8 ) for site B, 0.00 (95% CI: 0.00, 7.35) for site C, and 0.81 (95% CI: 0.00, 1.44 X 10 6 ) for site D. Further adjustment for white blood cell subtypes dramatically changed HRs and/or largely widened 95% CIs, suggesting potential overadjustment bias: 0.01 (95% CI:0.00, 1.89 X 10 10 ) for site A, 2.78 X 10 8 (95% CI: 0.00, 7.84 X 10 21 ) for site B, 0.00 (95% CI: 0.00, 620.94) for site C, and 1.69 (95% CI: 0.00, 4.18 X 10 13 ) for site D. Conclusion: DNA methylation levels at the GDF-15 CpG sites are not associated with death risk from cardiovascular disease independent of genes and shared environment.