Case Control Study
Copyright ©2014 Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Aug 28, 2014; 20(32): 11313-11320
Published online Aug 28, 2014. doi: 10.3748/wjg.v20.i32.11313
Lower serum folate is associated with development and invasiveness of gastric cancer
Teng-Yu Lee, En-Pei Chiang, Yin-Ting Shih, Hsien-Yuan Lane, Jaw-Town Lin, Chun-Ying Wu
Teng-Yu Lee, Hsien-Yuan Lane, Chun-Ying Wu, Graduate Institute of Clinical Medical Science, China Medical University, Taichung 407, Taiwan
Teng-Yu Lee, Department of Medicine, Chung Shan Medical University, Taichung 407, Taiwan
Teng-Yu Lee, Chun-Ying Wu, Division of Gastroenterology and Hepatology, Taichung Veterans General Hospital, Taichung 407, Taiwan
En-Pei Chiang, Yin-Ting Shih, Department of Food Science and Biotechnology, National Chung Hsing University, Taichung 402, Taiwan
En-Pei Chiang, Agricultural Biotechnology Center, National Chung-Hsing University, Taichung 402, Taiwan
Hsien-Yuan Lane, Department of Psychiatry, China Medical University Hospital, Taichung 404, Taiwan
Jaw-Town Lin, School of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan
Chun-Ying Wu, Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan
Chun-Ying Wu, Department of Life Sciences, National Chung Hsing University, Taichung 402, Taiwan
Chun-Ying Wu, Department of Public Health, China Medical University, Taichung 404, Taiwan
Author contributions: Lee TY, Chiang EP and Wu CY designed this study; Shih YT and Chiang EP performed experimental studies; Lee TY, Lane HY and Wu CY collected and analyzed clinical data; Lin JT, Chiang EP and Wu CY provided executive support for this work; Lee TY and Wu CY wrote the manuscript; Chiang EP and Wu CY equally contributed to this study.
Supported by National Science Council, Executive Yuan, No. NSC-96-2314-B-075A-007, No. NSC100-2628-B005-002MY4, No. NSC101-2320-B-005-006-MY3 and No. NSC 101-2911-I​-005-301; and the ATU plan of the Ministry of Education, Taiwan
Correspondence to: Chun-Ying Wu, Professor, Faculty of Medicine, School of Medicine, National Yang-Ming University, 155, Sec. 2, Linong Street, Taipei 112, Taiwan. chun@vghtc.gov.tw
Telephone: +886-4-23592525 Fax: +886-4-2374133
Received: January 23, 2014
Revised: March 26, 2014
Accepted: April 30, 2014
Published online: August 28, 2014
Abstract

AIM: To evaluate the associations of serum folate level with development, invasiveness and patient survival of gastric cancer.

METHODS: In this nested case-control study, patients with newly diagnosed gastric cancer undergoing gastrectomy were enrolled, and patients receiving chemotherapy prior to surgery, with other concurrent malignancy, or of the aboriginal and alien populations were excluded. In total, 155 gastric cancer patients and 149 healthy controls were enrolled for determination of serum folate levels and their correlation with gastric cancer. Using the median value of serum folate computed among the overall population as the cutoff value, the associations between serum folate and gastric cancer in all cases and different age and gender subgroups were analyzed by multivariate logistic regression analysis. In the patient cohort of gastric cancer, receiver-operating characteristic analyses were performed to calculate the best cutoff values of serum folate, and the associations between serum folate levels and clinicopathological features were further analyzed by multivariate regression analysis. Survival analyses were conducted using the Cox proportional hazards model.

RESULTS: The mean serum folate level was significantly lower in gastric cancer patients than that in controls (3.71 ± 0.30 ng/mL vs 8.00 ± 0.54 ng/mL, P < 0.01), and folate levels were consistently lower in gastric cancer patients regardless of age and gender (all P < 0.01). Using the median serum folate value as the cutoff value, low serum folate was significantly associated with gastric cancer risk in the whole population (OR = 19.77, 95%CI: 10.54-37.06, P < 0.001) and all strata (age < 60 years OR = 17.39, 95%CI: 7.28-41.54, age ≥ 60 years (OR = 21.67, 95%CI: 8.27-56.80), males (OR = 17.95, 95%CI: 7.93-40.62), and females (OR = 20.95, 95%CI: 7.66-57.31); all P < 0.001. In the patient cohort of gastric cancer, the respective cutoff values showed that low serum folate levels were significantly associated with serosal invasion (OR = 2.54, 95%CI: 1.23-5.23), lymphatic invasion (OR = 2.23, 95%CI: 1.17-4.26), and liver metastasis (OR = 6.67, 95%CI: 1.28-34.91) of gastric cancer (all P < 0.05). Serum folate level below 1.90 ng/mL was associated with poor patient survival (HR = 1.84, 95%CI: 1.04-3.27, P < 0.05) in univariate analysis.

CONCLUSION: Lower serum folate levels were significantly associated with gastric cancer development and invasive phenotypes. The role of folate depletion in gastric cancer invasion warrants further study.

Keywords: Folic acid, Folate, Plasma, Metastasis, Invasion

Core tip: Low folate status is involved in the development of gastric cancer, but the role of folate in invasiveness of gastric cancer remains unclear. In addition, although folate levels in blood may reflect the degree of folate depletion, an association between blood folate status and gastric cancer has not been established. In this case-control study, we found lower serum folate was significantly associated with gastric cancer development. Besides, in the patient cohort of gastric cancer, lower serum folate was significantly associated with invasive phenotypes such as serosal invasion, lymphatic invasion and liver metastasis. These findings warrant further study.