Xiangzhu Zhu

Background: Esophageal and gastric cancers have a high incidence and mortality in the US. Understanding the risk factors and trends associated with these cancers is crucial for developing effective prevention strategies.Objective: This descriptive study analyzed time trends for esophageal and gastric cancer incidence and related modifiable risk factors.Methods: Data from the Surveillance, Epidemiology, and End Results Survey Program (1975-2020), and the National Health and Nutrition Examination Survey (1988-2018) were used. Temporal trends in incidence rates and risk factor prevalence were determined, including for groups defined by sex, race, and subtype.Results: Esophageal squamous cell carcinoma rates declined, particularly among Black males (from 16.1 to 1.5 per 100,000), while esophageal adenocarcinoma rates increased among White males (from 0.7 to 4.3 per 100,000). Cardia gastric cancer rates remained stable, with higher incidence among males (average 3.1 per 100,000 compared to 0.7 per 100,000), whereas non-cardia gastric cancer incidence decreased for all. The percentage of the population that was overweight/obese increased from 52.4% to 73.8%. In contrast, prevalence of heavy alcohol drinking and current smoking decreased while the prevalence of inadequate intakes of nutrients such as calcium, particularly folate, significantly improved. Recently, inactivity prevalence has decreased, but >50% of the population remains physically inactive.Conclusion: Trends in modifiable lifestyle factors, such as increased obesity, reduced heavy alcohol consumption, and changing dietary habits, could explain some of the observed trends in esophageal and gastric cancer rates. Therefore, continued public health efforts are needed to address modifiable risk factors and reduce cancer incidence..

Supplementary Figure S3: Differential expression of biomarkers in rectal biopsy samples

Supplementary Table S1: Adjusted odds ratios with 95% confidence interval for the expression of biomarkers and risk of metachronous polyp, results from the PPCCT

Supplementary Methods S1: FFPE protocol for cultured cell lines

Supplementary Figure S2: Validation and optimization of TUNEL staining

Supplementary Figure S4: The potential mechanisms for the interaction of necroptosis, apoptosis, and inflammation in colorectal carcinogenesis

FFPE protocol for cultured cell lines

Necroptosis triggers an inflammatory cascade associated with antimicrobial defense. No prospective human study has yet explored the role of necroptosis in colorectal cancer development. We conducted quantitative analysis of biomarkers for necroptosis [transient receptor potential cation channel subfamily M member 7 (TRPM7) and phosphorylated mixed lineage kinase domain-like protein], inflammation [cyclooxygenase-2 (COX-2)], apoptosis [BCL2-associated X (BAX) and terminal deoxynucleotidyl transferase dUTP nick end labeling], and cell proliferation (Ki67). This was done using tissue microarray biospecimens from the Cooperative Human Tissue Network and rectal biopsies from a longitudinal study within the Personalized Prevention of Colorectal Cancer Trial. In the human colorectal adenoma–carcinoma sequence, we observed an inverse expression trend between BAX and TRPM7; TRPM7 decreased from normal mucosa to small and large adenomas but significantly increased in early colorectal cancer stages (Ptrend = 0.004). It maintained high levels through all cancer stages. An increased COX-2 intensity in the epithelium was noted during tumorigenesis (Ptrend = 0.02) and was significantly associated with an elevated risk of metachronous polyps (odds ratio = 3.04; 95% confidence interval, 1.07–8.61; Ptrend = 0.02). The combined composite index scores of TRPM7 and COX-2 were strongly linked to 6- to 47-fold increased risks for metachronous adenoma/serrated polyps, whereas combined scores of phosphorylated mixed lineage kinase domain-like protein or TRPM7 with BAX were associated with an 11.5- or 13.3-fold elevated risk for metachronous serrated polyps. In conclusion, our findings suggest that COX-2 expression within normal-looking colorectal mucosa is significantly associated with an increased risk of metachronous colorectal polyp. Furthermore, our results propose the hypothesis that synergistic interactions among necroptosis, inflammation, and apoptosis could play a pivotal role in human colorectal tumorigenesis.Prevention Relevance:Our findings suggest that COX-2 expression and combined scores of COX-2, TRPM7, and BAX hold promise for predicting the risk of metachronous polyps and could potentially serve as a tool for assessing the effectiveness of chemopreventive agents in preventing colorectal cancer during intervention trials.

INTRODUCTION: Esophageal adenocarcinoma (EAC) develops through histopathological stages, including Barrett's esophagus (BE). We analyzed the associations between plasma levels of one-carbon metabolism factors and risks of long-segment BE or EAC. METHODS: Plasma levels were measured from an Irish population-based case-control study (Factors INfluencing the Barrett Adenocarcinoma Relationship study; 204 long-segment BE cases, 211 EAC cases, and 251 controls). A “methyl replete score” was derived by assigning a score of 0 (median) to the levels of 3 dietary methyl donors (methionine, choline, and betaine) and summing across the metabolites. Multinomial logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between EAC or BE and sex-specific quartiles or score using the lowest level as the reference category and adjusted for potential confounders. RESULTS: Highest methionine, betaine, vitamin B6, and choline levels were all associated with 62%–82% reduced risks of EAC ( P _trends < 0.001). Conversely, S-adenosylmethionine, S-adenosylmethionine/S-adenosylhomocysteine ratio, total homocysteine, and cystathionine were associated with a greater than 2-fold increased EAC risk. A higher methyl replete score was associated with reduced EAC risk (OR 0.33; 95% CI 0.16–0.66). The highest vs lowest plasma methionine levels were borderline statistically significantly associated with long-segment BE (OR 0.55; 95% CI 0.28–1.07), but all other associations were null. DISCUSSION: Several biomarkers of one-carbon metabolism are associated with EAC risk, particularly markers of dietary methyl group donors. Future studies to replicate and prospectively evaluate these markers are warranted.

Table S8 Comparisons of pre- (Week 0) to post-treatment (Week 9) changes in endpoint biomarkers for continuous aspirin vs. intermittent aspirin arm