Jimi Kim1, Jeonghee Lee1, Jae Hwan Oh2, Dae Kyung Sohn2, Aesun Shin3,4, Jeongseon Kim5, Hee Jin Chang6. 1. Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang-si, 10408, Gyeonggi-do, South Korea. 2. Center for Colorectal Cancer, National Cancer Center Hospital, National Cancer Center, Goyang-si, 10408, Gyeonggi-do, South Korea. 3. Department of Preventive Medicine, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, 03080, Seoul, South Korea. 4. Cancer Research Institute, Seoul National University, 103 Daehak-ro, Jongno-gu, 03080, Seoul, South Korea. 5. Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang-si, 10408, Gyeonggi-do, South Korea. jskim@ncc.re.kr. 6. Division of Precision Medicine, Research Institute, and Department of Pathology, National Cancer Center Hospital, National Cancer Center, Goyang-si, 10408, Gyeonggi-do, South Korea. heejincmd@ncc.re.kr.
Abstract
PURPOSE: Colorectal cancer (CRC) is a heterogeneous disease caused by complex interplay among the diet, the environment, and genetics involving numerous molecules and pathological pathways. This study aimed to determine whether methyl donor nutrients are associated with CRC and how these associations are altered by DNA mismatch repair (MMR) genes. METHODS: In total, 626 cases and 838 age- and sex-matched controls were recruited for this case-control study. A validated food frequency questionnaire was used to assess seven methyl donor nutrients (vitamin B2, niacin, B6, folate, B12, methionine, and choline). MMR polymorphisms were genotyped using an Illumina MEGA-Expanded Array. For the 626 patients, the microsatellite instability status and immunohistochemical expression of MMR proteins were analyzed. Multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Among the methyl donor nutrients, B2, niacin, B6, folate, and methionine were inversely associated with CRC risk, while a high intake of choline increased CRC. Regarding MMR genes, three hMSH3 polymorphisms (rs32952 A > C, rs41097 A > G, and rs245404 C > G) reduced CRC risk. Regarding gene-diet interactions, a stronger interaction effect was observed in G allele carriers of hMSH3 rs41097 with high niacin intake than in AA carriers with low niacin intake (OR, 95% CI = 0.49, 0.33-0.72, P for interaction = 0.02) in subgroups of patients with distal colon cancer (P for interaction = 0.008) and MMR proficiency with microsatellite stability (P for interaction = 0.021). CONCLUSIONS: Methyl donor nutrients may affect CRC risk leading to a balance in the MMR machinery.
PURPOSE: Colorectal cancer (CRC) is a heterogeneous disease caused by complex interplay among the diet, the environment, and genetics involving numerous molecules and pathological pathways. This study aimed to determine whether methyl donor nutrients are associated with CRC and how these associations are altered by DNA mismatch repair (MMR) genes. METHODS: In total, 626 cases and 838 age- and sex-matched controls were recruited for this case-control study. A validated food frequency questionnaire was used to assess seven methyl donor nutrients (vitamin B2, niacin, B6, folate, B12, methionine, and choline). MMR polymorphisms were genotyped using an Illumina MEGA-Expanded Array. For the 626 patients, the microsatellite instability status and immunohistochemical expression of MMR proteins were analyzed. Multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Among the methyl donor nutrients, B2, niacin, B6, folate, and methionine were inversely associated with CRC risk, while a high intake of choline increased CRC. Regarding MMR genes, three hMSH3 polymorphisms (rs32952 A > C, rs41097 A > G, and rs245404 C > G) reduced CRC risk. Regarding gene-diet interactions, a stronger interaction effect was observed in G allele carriers of hMSH3 rs41097 with high niacin intake than in AA carriers with low niacin intake (OR, 95% CI = 0.49, 0.33-0.72, P for interaction = 0.02) in subgroups of patients with distal colon cancer (P for interaction = 0.008) and MMR proficiency with microsatellite stability (P for interaction = 0.021). CONCLUSIONS: Methyl donor nutrients may affect CRC risk leading to a balance in the MMR machinery.
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