The incidence of gastric cancer has gradually declined over the past few decades. Nevertheless, gastric cancer is the fifth most common type of cancer following lung, breast, colorectal and prostate cancer, and it was the third leading cause of cancer death worldwide in 2012. No studies have comprehensively examined the genetic effects of one-carbon metabolism-related genes or their interactive effects with folate intake in terms of gastric cancer. Given the complexity of the one-carbon metabolism pathway, it is worth considering genetic polymorphisms involved in one-carbon metabolism other than MTHFR, MTR and MTRR to understand the biological mechanisms of gastric carcinogenesis. Moreover, gene-folate interactions may not only explain the current conflicting results but also contribute to personalized dietary prevention of gastric cancer through identifying a genetically susceptible population. Therefore, this study aimed to evaluate the interactive effects between polymorphisms in one-carbon metabolism-related genes (i.e., MTHFR, MTR, MTRR, SHMT1 and SLC19A1) and dietary folate intake on gastric cancer risk in the Korean population in a hospital-based case-control study. A total of 542 controls and 271 cases were included. Genotype data were selected from data produced by the Affymetrix Axiom® Exome 319 Array. We considered seven single nucleotide polymorphisms (SNPs) of five genes whose SNPs are located in the coding region with a minor allele frequency > 5%: MTHFR (G1793A, A1298C, C677T), MTR A2756G, MTRR A66G, SHMT1 C1420T and SLC19A1 G80A. Our study found MTR A2756G was associated with a decreased gastric cancer risk. MTR A2756G was found to be significantly associated with a decreased risk of gastric cancer, exhibiting an OR (95% CI) of 0.60 (0.41-0.86) for the GA/GG genotype compared to the AA genotype. Significant associations between folate intake and gastric cancer were observed; high group of folate intake was inversely associated with gastric cancer compared to low group with OR (95% CI) of 0.70 (0.53-0.95). After adjusting for potential risk factors, the estimated risk was slightly decreased to 0.69 (0.49-0.96) compared high group to low group of folate intake. Folate intake as a continuous scale was also significantly associated with gastric cancer (Pcrude=0.032, Padjusted=0.004). Individuals in the high folate intake group with major homozygote were considered as the reference group. Only MTHFR G1793A showed a statistically significant interaction with folate intake (p=0.03). The polymorphism was significantly associated with an increased gastric cancer risk in the low folate intake group with AG/AA genotype (OR (95% CI): 2.79 (1.51-5.18). MTHFR A1298C was significantly associated with an increased risk of gastric cancer among individuals in the low folate intake group with CA/CC genotype (OR (95% CI): ):2.35 (1.40-3.94). MTR A2756G and SHMT1 C1420T were associated with an increased gastric cancer risk in the low folate intake group with major homozygotes, yielding OR (95% CI) of 1.79 (1.19-2.71) and 1.79 (1.18-2.71), respectively. SLC19A1 G80A was associated with an increased risk of gastric cancer in the low folate intake with AA and GA genotype, yielding OR (95% CI) of 2.08 (1.08-4.03) and 1.89 (1.04-3.43), respectively. These significant associations seem to be from the effect of folate intake rather than from the effect modification. Our results suggest that MTR A2756G is not only associated with gastric cancer risk but also interacts with dietary folate intake on the risk of gastric cancer, and MTHFR G1793A statistically interacts with dietary folate intake. Our findings indicate that gene-folate interactions may contribute to gastric cancer risk.

Citation Format: Jeongseon Kim, Woori Kim, Hae Dong Woo, Jeonghee Lee, Il Ju Choi, Young Woo Kim, Joohon Sung. Dietary folate, one-carbon metabolism-related genes, and gastric cancer risk in Korea. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr A10.