UCLA

Background

Stomach cancer (SC) is the fifth most commonly diagnosed cancer and the third leading cause of cancer deaths worldwide. China is one of the countries with the highest incidence and mortality of stomach cancer. Different environmental factors are involved in the development of stomach cancer, including Helicobacter (H.) pylori infection, tobacco smoking, alcohol consumption, sodium intake, and dietary factors. The roles of various dietary factors on the development of stomach cancer are still an open question. Moreover, there is an increasing interest in studying gene-diet interactions that might explain variations in stomach cancer across different populations.

Methods

A population-based case-control study, Jiangsu Four Cancers (JFC) study, was conducted in four counties (Dafeng, Ganyu, Chuzhou, and Tongshan) in Jiangsu Province, China, from 2003 to 2010, to gather epidemiologic data to study both environmental and genetic factors on the development of four top cancers in a Chinese population, including stomach cancer. Epidemiologic data were collected by in-person interviews using a structured questionnaire. After the personal interview, blood samples were collected and separated in a local laboratory. H. pylori infection and genetic susceptibility markers were assayed. In specific aim 1, we evaluated the roles of total and subtypes of fatty acids, total cholesterol, and flavonoids on the development of stomach cancer. These nutrients were estimated based on the Food Frequency Questionnaire (FFQ) and China Food Composition (CFC) Tables. Missing data were imputed by multiple imputation methods. Adjusted odds ratios (ORs) and their 95% confidence intervals (CIs) were estimated using multiple unconditional logistic regression models, energy-adjusted method, and semi-Bayes shrinkage method. Multiplicative and additive interactions between dietary factors and the known risk factors and their joint effects on the development of stomach cancer were assessed. Natural direct effect (NDE) and natural indirect effect (NIE) of mediation analysis were also estimated. In specific aim 2, we studied the impact of adherence to both modified Chinese Healthy Eating Index (mCHEI) and Healthy Eating Index-2015 (HEI-2015) in relation to stomach cancer. Multiple unconditional logistic regression analyses were applied to examine relationships between mCHEI, HEI-2015, and stomach cancer while adjusting for potential confounders. The possible interactions between mCHEI and HEI-2015 and established risk factors were investigated. In specific aim 3, we assessed the potential effects of genetic susceptibility markers, single nucleotide polymorphisms (SNPs) and their interplay with nutritional factors on stomach cancer. Adjusted odds ratios and their 95% CIs for candidate SNPs were estimated for stomach cancer using multiple unconditional logistic models and semi-Bayes shrinkage method. Log-additive, dominant, and recessive genetic models were employed for the evaluation of each SNP. Stratified analyses and gene-diet interaction analysis (multiplicative and additive scales) were performed by using dichotomous variables of total fatty acids, cholesterol, and flavonoids. Genetic risk scores (GRS) were applied to estimate the cumulative contributions of genetic factors on stomach cancer. All analyses were conducted using SAS, version 9.4.

Results

A total of 2,216 stomach cancer cases and 8,019 controls were recruited. In specific aim 1, 1,900 SC cases and 6,532 controls were included in the analyses, excluding individuals with incomplete data of FFQs. Dietary saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), and total cholesterol were positively associated with the development of SC comparing the highest versus lowest quarters. Higher intakes of dietary SFAs (p-trend = 0.005; adjusted odds ratio (aOR), 1.11; 95% CI, 1.01-1.22 with a 7 g/day increase as a continuous variable) and total cholesterol (p-trend < 0.001; aOR, 1.13; 95% CI, 1.06-1.22 with a 250 mg/day increase as a continuous variable) were monotonically associated with elevated odds of developing SC. In specific aim 2, a higher score of sodium, reflecting less intake per day and better adherence to the guidelines, was inversely associated with stomach cancer (OR, 0.95; 95%CI, 0.91-0.99 for mCHEI; OR, 0.97; 95%CI, 0.94-0.99 for HEI-2015). There were null associations for total scores of HEI-2015 (p-trend = 0.98; OR, 0.98; 95% CI, 0.87-1.10 with a 10-point increase) and mCHEI (p-trend =0.22; OR, 1.05; 95% CI, 0.94-1.17 with a 10-point increase) in relation to stomach cancer. However, multiplicative interaction was identified between mCHEI and body mass index on stomach cancer (p for interaction=0.02). In specific aim 3, a total of 788 stomach cancer cases and 2,398 controls from Dafeng and Ganyu County were included because of the availability of SNP measurements. Associations with stomach cancer were observed for miR-300 rs12894467, IKBKAP rs2230793, PLCE1 rs2274223, R267S rs12934922, TERT rs2736100, CHEK2 rs738722, WWOX rs12828, E2F2 rs2075993, HEY2 rs3734637, WNT8A rs4835761, Gemin3 rs197412, FTO rs8050136, SEMA5B rs9868873. There was a dose-response relationship between increased genetic risk scores (polygenic risk score and weighted multi-genetic index) and stomach cancer. Potential interactions were observed between dietary fatty acids and TERT rs2736100, as well as GKN2 -GKN1 rs4254535 on SC; and between dietary cholesterol and R267S rs12934922, E2F2 rs2075993, and Notch4 rs915894 on SC. Possible interaction was also observed between IKBKAP rs1538660 with dietary flavonoids on SC.

Conclusions

Our results confirm the associations between high intakes of dietary SFAs, MUFAs, total cholesterol, and the development of stomach cancer with a dose-response pattern. mCHEI is more sensitive to identify specific food components associated with stomach cancer compared with HEI-2015. Dietary total fatty acids, cholesterol, and flavonoids may modify the associations between some SNPs and stomach cancer. The findings might shed some light on the potential etiological roles of dietary factors on stomach cancer. A better understanding of genetic and dietary factors for stomach cancer would help to identify high-risk individuals in personalized risk prediction and dietary intervention.