Association between folate metabolism-related polymorphisms and colorectal cancer risk

Kim,Jong  Woo; Jeon,Young  Joo; Jang,Moon  Ju; Kim,Jung  O; Chong,So  Young; Ko,Kwang  Hyun; Hwang,Seong  Gyu; Oh,Doyeun; Oh,Jisu; Kim,Nam  Keun

doi:10.3892/mco.2015.520

Association between folate metabolism-related polymorphisms and colorectal cancer risk

Authors:
- Jong Woo Kim
- Young Joo Jeon
- Moon Ju Jang
- Jung O Kim
- So Young Chong
- Kwang Hyun Ko
- Seong Gyu Hwang
- Doyeun Oh
- Jisu Oh
- Nam Keun Kim
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Affiliations: Department of Surgery, CHA Bundang Medical Center, CHA University, Seongnam, Gyeonggi 463‑712, Republic of Korea, Institute for Clinical Research, School of Medicine, CHA University, Seongnam, Gyeonggi 463‑712, Republic of Korea, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Gyeonggi 463‑712, Republic of Korea
Published online on: February 27, 2015 https://doi.org/10.3892/mco.2015.520
Pages: 639-648

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Abstract

Folate has essential roles in DNA synthesis, repair and methylation. Folate metabolism‑related gene variants may modulate the levels of this vitamin and affect the cancer risk. Thus, whether these polymorphisms play an important role in carcinogenesis, particularly colorectal cancer (CRC) development, has been a subject interest. The present study investigated the association between polymorphisms in the methylenetetrahydrofolate reductase (MTHFR), thymidylate synthase (TS) and the reduced folate carrier 1 (RFC1) genes and CRC risk. Polymorphisms in MTHFR (677C>T and 1298A>C), TS [1494del6 and the TS enhancer region (TSER)] and RFC1 (‑43T>C, 80G>A and 696C>T) were characterized using polymerase chain reaction‑restriction fragment length polymorphism in 477 CRC cases and 514 controls. Although no polymorphisms were significantly associated with the CRC risk in the overall sample, significant associations between folate metabolism‑related polymorphisms and CRC risk were identified in the stratified analyses. The MTHFR 677CT/1298AC and MTHFR 1298AC+CC/TSER 2R3R genotypes in the presence of plasma folate levels ≤4.12 ng/ml were associated with significantly increased CRC risk. In addition, individuals with the MTHFR 677TT/TSER 3R3R or MTHFR 677/TSER 3R3R/TS 1494 0bp6bp+6bp6bp genotypes and diabetes mellitus (DM) were at an increased risk for CRC. Therefore, the data suggest that i) MTHFR polymorphisms combined with low plasma folate levels and ii) polymorphisms in folate metabolism‑related genes combined with metabolic syndrome risk factors (hypertension and DM) increase the odds of developing CRC.

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1	Slattery ML, Potter JD, Samowitz W, Schaffer D and Leppert M: Methylenetetrahydrofolate reductase, diet and risk of colon cancer. Cancer Epidemiol Biomarkers Prev. 8:513–518. 1999.PubMed/NCBI
2	Frosst P, Blom HJ, Milos R, et al: A candidate genetic risk factor for vascular disease: A common mutation in methylenetetrahydrofolate reductase. Nat Genet. 10:111–113. 1995. View Article : Google Scholar : PubMed/NCBI
3	Rozen R: Genetic predisposition to hyperhomocysteinemia: Deficiency of methylenetetrahydrofolate reductase (MTHFR). Thromb Haemost. 78:523–526. 1997.PubMed/NCBI
4	Kono S and Chen K: Genetic polymorphisms of methylenetetrahydrofolate reductase and colorectal cancer and adenoma. Cancer Sci. 96:535–542. 2005. View Article : Google Scholar : PubMed/NCBI
5	Keku T, Millikan R, Worley K, Winkel S, Eaton A, Biscocho L, Martin C and Sandler R: 5,10-Methylenetetrahydrofolate reductase codon 677 and 1298 polymorphisms and colon cancer in African Americans and whites. Cancer Epidemiol Biomarkers Prev. 11:1611–1621. 2002.PubMed/NCBI
6	Kawakami K, Omura K, Kanehira E and Watanabe Y: Polymorphic tandem repeats in the thymidylate synthase gene is associated with its protein expression in human gastrointestinal cancers. Anticancer Res. 19:3249–3252. 1999.PubMed/NCBI
7	Mandola MV, Stoehlmacher J, Zhang W, Groshen S, Yu MC, Iqbal S, Lenz HJ and Ladner RD: A 6 bp polymorphism in the thymidylate synthase gene causes message instability and is associated with decreased intratumoral TS mRNA levels. Pharmacogenetics. 14:319–327. 2004. View Article : Google Scholar : PubMed/NCBI
8	Chango A, Emery-Fillon N, de Courcy GP, Lambert D, Pfister M, Rosenblatt DS and Nicolas JP: A polymorphism (80G->A) in the reduced folate carrier gene and its associations with folate status and homocysteinemia. Mol Genet Metab. 70:310–315. 2000. View Article : Google Scholar : PubMed/NCBI
9	Kim JW, Park HM, Choi YK, Chong SY, Oh D and Kim NK: Polymorphisms in genes involved in folate metabolism and plasma DNA methylation in colorectal cancer patients. Oncol Rep. 25:167–172. 2011.PubMed/NCBI
10	Rah H, Choi YS, Jeon YJ, Choi Y, Cha SH, Choi DH, Ko JJ, Shim SH and Kim NK: Solute Carrier Family 19, member 1 (SLC19A1) polymorphisms (−43T>C, 80G>A and 696C>T) and haplotypes in idiopathic recurrent spontaneous abortion in a Korean population. Reprod Sci. 19:513–519. 2012. View Article : Google Scholar : PubMed/NCBI
11	Yim DJ, Kim OJ, An HJ, Kang H, Ahn DH, Hwang SG, Oh D and Kim NK: Polymorphisms of thymidylate synthase gene 5′- and 3′-untranslated region and risk of gastric cancer in Koreans. Anticancer Res. 30:2325–2330. 2010.PubMed/NCBI
12	Chung YS, Jeon YJ, Shin DE, Min KT, Shin YS, Won KS, Koh YC, Hong SH and Kim NK: Methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthase (TS) polymorphisms with osteoporotic vertebral compression fracture (OVCF) in postmenopausal Korean women. Genes Genom. 34:257–263. 2012. View Article : Google Scholar
13	Sheng X, Zhang Y, Zhao E, Lu S, Zheng X, Ge H and Lu W: MTHFR C677T polymorphism contributes to colorectal cancer susceptibility: Evidence from 61 case-control studies. Mol Biol Rep. 39:9669–9679. 2012. View Article : Google Scholar : PubMed/NCBI
14	Yang Z, Zhang XF, Liu HX, Hao YS and Zhao CL: MTHFR C677T polymorphism and colorectal cancer risk in Asians, a meta-analysis of 21 studies. Asian Pac J Cancer Prev. 13:1203–1208. 2012. View Article : Google Scholar : PubMed/NCBI
15	Ma J, Stampfer MJ, Giovannucci E, Artigas C, Hunter DJ, Fuchs C, Willett WC, Selhub J, Hennekens CH and Rozen R: Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer. Cancer Res. 57:1098–1102. 1997.PubMed/NCBI
16	van der Put NM, Gabreëls F, Stevens EM, Smeitink JA, Trijbels FJ, Eskes TK, van den Heuvel LP and Blom HJ: A second common mutation in the methylenetetrahydrofolate reductase gene: An additional risk factor for neural-tube defects? Am J Hum Genet. 62:1044–1051. 1998. View Article : Google Scholar : PubMed/NCBI
17	Kawakami K and Watanabe G: Identification and functional analysis of single nucleotide polymorphism in the tandem repeat sequence of thymidylate synthase gene. Cancer Res. 63:6004–6007. 2003.PubMed/NCBI
18	Mandola MV, Stoehlmacher J, Muller-Weeks S, Cesarone G, Yu MC, Lenz HJ and Ladner RD: A novel single nucleotide polymorphism within the 5′tandem repeat polymorphism of the thymidylate synthase gene abolishes USF-1 binding and alters transcriptional activity. Cancer Res. 63:2898–2904. 2003.PubMed/NCBI
19	Zhou JY, Shi R, Yu HL, Zeng Y, Zheng WL and Ma WL: The association between two polymorphisms in the TS gene and risk of cancer: A systematic review and pooled analysis. Int J Cancer. 131:2103–2116. 2012. View Article : Google Scholar : PubMed/NCBI
20	Chen J, Hunter DJ, Stampfer MJ, Kyte C, Chan W, Wetmur JG, Mosig R, Selhub J and Ma J: Polymorphism in the thymidylate synthase promoter enhancer region modifies the risk and survival of colorectal cancer. Cancer Epidemiol Biomarkers Prev. 12:958–962. 2003.PubMed/NCBI
21	Marsh S, Collie-Duguid ES, Li T, Liu X and McLeod HL: Ethnic variation in the thymidylate synthase enhancer region polymorphism among Caucasian and Asian populations. Genomics. 58:310–312. 1999. View Article : Google Scholar : PubMed/NCBI
22	Marsh S, McKay JA, Cassidy J and McLeod HL: Polymorphism in the thymidylate synthase promoter enhancer region in colorectal cancer. Int J Oncol. 19:383–386. 2001.PubMed/NCBI
23	Ulrich CM, Curtin K, Potter JD, Bigler J, Caan B and Slattery ML: Polymorphisms in the reduced folate carrier, thymidylate synthase, or methionine synthase and risk of colon cancer. Cancer Epidemiol Biomarkers Prev. 14:2509–2516. 2005. View Article : Google Scholar : PubMed/NCBI
24	de Jonge R, Tissing WJ, Hooijberg JH, Jansen G, Kaspers GJ, Lindemans J, Peters GJ and Pieters R: Polymorphisms in folate-related genes and risk of pediatric acute lymphoblastic leukemia. Blood. 113:2284–2289. 2009. View Article : Google Scholar : PubMed/NCBI
25	Wang L, Chen W, Wang J, Tan Y, Zhou Y, Ding W, Hua Z, Shen J, Xu Y and Shen H: Reduced folate carrier gene G80A polymorphism is associated with an increased risk of gastroesophageal cancers in a Chinese population. Eur J Cancer. 42:3206–3211. 2006. View Article : Google Scholar : PubMed/NCBI
26	Eklöf V, Van Guelpen B, Hultdin J, Johansson I, Hallmans G and Palmqvist R: The reduced folate carrier (RFC1) 80G>A and folate hydrolase 1 (FOLH1) 1561C>T polymorphisms and the risk of colorectal cancer: A nested case-referent study. Scand J Clin Lab Invest. 68:393–401. 2008. View Article : Google Scholar : PubMed/NCBI
27	Jokić M, Brčić-Kostić K, Stefulj J, Catela Ivković T, Božo L, Gamulin M and Kapitanović S: Association of MTHFR, MTR, MTRR, RFC1, and DHFR gene polymorphisms with susceptibility to sporadic colon cancer. DNA Cell Biol. 30:771–776. 2011. View Article : Google Scholar : PubMed/NCBI
28	Antony AC: The biological chemistry of folate receptors. Blood. 79:2807–2820. 1992.PubMed/NCBI
29	Duthie SJ: Folate and cancer: How DNA damage, repair and methylation impact on colon carcinogenesis. J Inherit Metab Dis. 34:101–109. 2011. View Article : Google Scholar : PubMed/NCBI
30	Giovannucci E: Metabolic syndrome, hyperinsulinemia, and colon cancer: A review. Am J Clin Nutr. 86:s836–s842. 2007.PubMed/NCBI