Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
World Journal of Surgical Oncology
Published in: World Journal of Surgical Oncology 1/2016

Open Access 01-12-2016 | Research

Association between MTHFR gene 1298A>C polymorphism and breast cancer susceptibility: a meta-analysis based on 38 case-control studies with 40,985 subjects

Authors: Jinghong Zhang, Lijun Zhang, Guangming Li

Published in: World Journal of Surgical Oncology | Issue 1/2016

Login to get access

Abstract

Background

Studies investigating the association between the methylenetetrahydrofolate reductase (MTHFR) gene 1298A>C polymorphism and the risk of breast cancer have reported inconsistent results. So, we performed this updated meta-analysis and tried to give a more precise estimation of association between MTHFR gene 1298A>C polymorphism and breast cancer susceptibility.

Methods

Relevant studies published before 1 January 2016 were identified by searching PubMed and EMBASE. The strength of relationship between the MTHFR gene 1298A>C polymorphism and breast cancer susceptibility was assessed using odds ratio (OR) and corresponding 95 % confidence interval (95 % CI). The meta-analysis was performed using Stata 11.0 software.

Results

A total number of 38 case-control studies including 18,686 cases and 22,299 controls were identified. No association was found in five genetic models (dominant model: OR = 0.99, 95 % CI 0.99–1.00, P = 0.218; recessive model: OR = 1.00, 95 % CI 0.97–1.02, P = 0.880; homozygote genetic model: OR = 0.99, 95 % CI 0.98–1.01, P = 0.390; heterozygote genetic model: OR = 0.99, 95 % CI 0.97–1.00, P = 0.138; and allele contrast genetic model: OR = 0.99, 95 % CI 0.98–1.01) for MTHFR gene 1298 A>C polymorphism and breast cancer susceptibility. In the subgroup analysis stratified by source of control, decreased risk of breast cancer was found in studies with hospital-based controls in dominant model (OR = 0.98, 95 % CI 0.96–1.00, P = 0.037).

Conclusions

Our meta-analysis suggested that there is no significant association between MTHFR gene 1298A>C polymorphism and breast cancer susceptibility for overall population.
Literature
1.
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.CrossRefPubMed
2.
3.
4.
5.
Hankinson SE, Colditz GA, Willett WC. Towards an integrated model for breast cancer etiology: the lifelong interplay of genes, lifestyle, and hormones. Breast Cancer Research: BCR. 2004;6(5):213–8.CrossRefPubMedPubMedCentral
6.
Dumitrescu RG, Cotarla I. Understanding breast cancer risk—where do we stand in 2005? J Cell Mol Med. 2005;9(1):208–21.CrossRefPubMed
7.
Weber BL, Abel KJ, Couch FJ, Merajver SD, Chandrasekharappa SC, Castilla L, et al. Progress toward isolation of a breast cancer susceptibility gene, BRCA1. Cold Spring Harb Symp Quant Biol. 1994;59:531–6.CrossRefPubMed
8.
Xu X, Gammon MD, Zeisel SH, Lee YL, Wetmur JG, Teitelbaum SL, et al. Choline metabolism and risk of breast cancer in a population-based study. FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology. 2008;22(6):2045–52.CrossRef
9.
Wei LK, Sutherland H, Au A, Camilleri E, Haupt LM, Gan SH, et al. A potential epigenetic marker mediating serum folate and vitamin B12 levels contributes to the risk of ischemic stroke. BioMed Research International. 2015;2015:167976.PubMed
10.
Xu X, Chen J. One-carbon metabolism and breast cancer: an epidemiological perspective. Journal of Genetics and Genomics = Yi chuan xue bao. 2009;36(4):203–14.CrossRefPubMedPubMedCentral
11.
Weisberg I, Tran P, Christensen B, Sibani S, Rozen R. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab. 1998;64(3):169–72.CrossRefPubMed
12.
Lee YS, Han DH, Jeon CM, Lyoo IK, Na C, Chae SL, et al. Serum homocysteine, folate level and methylenetetrahydrofolate reductase 677, 1298 gene polymorphism in Korean schizophrenic patients. Neuroreport. 2006;17(7):743–6.CrossRefPubMed
13.
Ergul E, Sazci A, Utkan Z, Canturk NZ. Polymorphisms in the MTHFR gene are associated with breast cancer. Tumour Biology: The Journal of the International Society for Oncodevelopmental Biology and Medicine. 2003;24(6):286–90.CrossRef
14.
Stevens VL, McCullough ML, Pavluck AL, Talbot JT, Feigelson HS, Thun MJ, et al. Association of polymorphisms in one-carbon metabolism genes and postmenopausal breast cancer incidence. Cancer Epidemiology, Biomarkers & Prevention: A Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. 2007;16(6):1140–7.CrossRef
15.
Ericson U, Sonestedt E, Ivarsson MI, Gullberg B, Carlson J, Olsson H, et al. Folate intake, methylenetetrahydrofolate reductase polymorphisms, and breast cancer risk in women from the Malmo Diet and Cancer cohort. Cancer Epidemiology, Biomarkers & Prevention: A Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. 2009;18(4):1101–10.CrossRef
16.
Justenhoven C, Hamann U, Pierl CB, Rabstein S, Pesch B, Harth V, et al. One-carbon metabolism and breast cancer risk: no association of MTHFR, MTR, and TYMS polymorphisms in the GENICA study from Germany. Cancer Epidemiology, Biomarkers & Prevention: A Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. 2005;14(12):3015–8.CrossRef
17.
Li K, Li W, Dong X. Association of 677 C>T (rs1801133) and 1298 A>C (rs1801131) polymorphisms in the MTHFR gene and breast cancer susceptibility: a meta-analysis based on 57 individual studies. PLoS One. 2014;9(6):e71290.CrossRefPubMedPubMedCentral
18.
Zhang XF, Liu T, Li Y, Li S. Association between MTHFR 677C/T and 1298A/C gene polymorphisms and breast cancer risk. Genetics and Molecular Research: GMR. 2015;14(4):16425–30.CrossRefPubMed
19.
Lu Q, Jiang K, Li Q, Ji YJ, Chen WL, Xue XH. Polymorphisms in the MTHFR gene are associated with breast cancer risk and prognosis in a Chinese population. Tumour Biology: The Journal of the International Society for Oncodevelopmental Biology and Medicine. 2015;36(5):3757–62.CrossRef
20.
Awwad N, Yousef AM, Abuhaliema A, Abdalla I, Yousef M. Relationship between genetic polymorphisms in MTHFR (C677T, A1298C and their Haplotypes) and the incidence of breast cancer among Jordanian females—case-control study. Asian Pacific Journal of Cancer Prevention: APJCP. 2015;16(12):5007–11.CrossRefPubMed
21.
Little J, Bradley L, Bray MS, Clyne M, Dorman J, Ellsworth DL, et al. Reporting, appraising, and integrating data on genotype prevalence and gene-disease associations. Am J Epidemiol. 2002;156(4):300–10.CrossRefPubMed
22.
23.
Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539–58.CrossRefPubMed
24.
25.
Akram M, Malik FA, Kayani MA. Mutational analysis of the MTHFR gene in breast cancer patients of Pakistani population. Asian Pacific Journal of Cancer Prevention: APJCP. 2012;13(4):1599–603.CrossRefPubMed
26.
Carvalho Barbosa Rde C, Menezes DC, Freire TF, Sales DC, Alencar VH, Rabenhorst SH. Associations of polymorphisms of folate cycle enzymes and risk of breast cancer in a Brazilian population are age dependent. Mol Biol Rep. 2012;39(4):4899–907.CrossRefPubMed
27.
Chen J, Gammon MD, Chan W, Palomeque C, Wetmur JG, Kabat GC, et al. One-carbon metabolism, MTHFR polymorphisms, and risk of breast cancer. Cancer Res. 2005;65(4):1606–14.CrossRefPubMed
28.
Cheng CW, Yu JC, Huang CS, Shieh JC, Fu YP, Wang HW, et al. Polymorphism of cytosolic serine hydroxymethyltransferase, estrogen and breast cancer risk among Chinese women in Taiwan. Breast Cancer Res Treat. 2008;111(1):145–55.CrossRefPubMed
29.
Chou YC, Wu MH, Yu JC, Lee MS, Yang T, Shih HL, et al. Genetic polymorphisms of the methylenetetrahydrofolate reductase gene, plasma folate levels and breast cancer susceptibility: a case-control study in Taiwan. Carcinogenesis. 2006;27(11):2295–300.CrossRefPubMed
30.
Forsti A, Angelini S, Festa F, Sanyal S, Zhang Z, Grzybowska E, et al. Single nucleotide polymorphisms in breast cancer. Oncol Rep. 2004;11(4):917–22.PubMed
31.
Gao CM, Tang JH, Cao HX, Ding JH, Wu JZ, Wang J, et al. MTHFR polymorphisms, dietary folate intake and breast cancer risk in Chinese women. J Hum Genet. 2009;54(7):414–8.CrossRefPubMed
32.
He JM, Pu YD, Wu YJ, Qin R, Zhang QJ, Sun YS, et al. Association between dietary intake of folate and MTHFR and MTR genotype with risk of breast cancer. Genetics and Molecular Research: GMR. 2014;13(4):8925–31.CrossRefPubMed
33.
34.
Inoue M, Robien K, Wang R, Van Den Berg DJ, Koh WP, Yu MC. Green tea intake, MTHFR/TYMS genotype and breast cancer risk: the Singapore Chinese Health Study. Carcinogenesis. 2008;29(10):1967–72.CrossRefPubMedPubMedCentral
35.
Kakkoura MG, Demetriou CA, Loizidou MA, Loucaides G, Neophytou I, Marcou Y, et al. Single-nucleotide polymorphisms in one-carbon metabolism genes, Mediterranean diet and breast cancer risk: a case-control study in the Greek-Cypriot female population. Genes & Nutrition. 2015;10(2):453.CrossRef
36.
Kotsopoulos J, Zhang WW, Zhang S, McCready D, Trudeau M, Zhang P, et al. Polymorphisms in folate metabolizing enzymes and transport proteins and the risk of breast cancer. Breast Cancer Res Treat. 2008;112(3):585–93.CrossRefPubMed
37.
Lajin B, Alhaj Sakur A, Ghabreau L, Alachkar A. Association of polymorphisms in one-carbon metabolizing genes with breast cancer risk in Syrian women. Tumour Biology: The Journal of the International Society for Oncodevelopmental Biology and Medicine. 2012;33(4):1133–9.CrossRef
38.
Le Marchand L, Haiman CA, Wilkens LR, Kolonel LN, Henderson BE. MTHFR polymorphisms, diet, HRT, and breast cancer risk: the multiethnic cohort study. Cancer Epidemiology, Biomarkers & Prevention: A Publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2004;13(12):2071–7.
39.
Lissowska J, Gaudet MM, Brinton LA, Chanock SJ, Peplonska B, Welch R, et al. Genetic polymorphisms in the one-carbon metabolism pathway and breast cancer risk: a population-based case-control study and meta-analyses. International Journal of Cancer Journal International du cancer. 2007;120(12):2696–703.CrossRefPubMed
40.
Liu Y, Zhou LS, Xu XM, Deng LQ, Xiao QK. Association of dietary intake of folate, vitamin B6 and B12 and MTHFR genotype with breast cancer risk. Asian Pacific Journal of Cancer Prevention: APJCP. 2013;14(9):5189–92.CrossRefPubMed
41.
Lopez-Cortes A, Echeverria C, Ona-Cisneros F, Sanchez ME, Herrera C, Cabrera-Andrade A, et al. Breast cancer risk associated with gene expression and genotype polymorphisms of the folate-metabolizing MTHFR gene: a case-control study in a high altitude Ecuadorian mestizo population. Tumour Biology: The Journal of the International Society for Oncodevelopmental Biology and Medicine. 2015;36(8):6451–61.CrossRef
42.
Ma E, Iwasaki M, Junko I, Hamada GS, Nishimoto IN, Carvalho SM, et al. Dietary intake of folate, vitamin B6, and vitamin B12, genetic polymorphism of related enzymes, and risk of breast cancer: a case-control study in Brazilian women. BMC Cancer. 2009;9:122.CrossRefPubMedPubMedCentral
43.
Mir MM, Dar JA, Dar NA, Dar MS, Salam I, Lone MM, et al. Combined impact of polymorphism of folate metabolism genes; glutamate carboxypeptidase, methylene tetrahydrofolate reductase and methionine synthase reductase on breast cancer susceptibility in Kashmiri women. International Journal of Health Sciences. 2008;2(1):3–14.PubMedPubMedCentral
44.
Ozen F, Erdis E, Sik E, Silan F, Uludag A, Ozdemir O. Germ-line MTHFR C677T, FV H1299R and PAI-1 5G/4G variations in breast carcinoma. Asian Pacific Journal of Cancer Prevention: APJCP. 2013;14(5):2903–8.CrossRefPubMed
45.
Papandreou CN, Doxani C, Zdoukopoulos N, Vlachostergios PJ, Hatzidaki E, Bakalos G, et al. Evidence of association between methylenetetrahydrofolate reductase gene and susceptibility to breast cancer: a candidate-gene association study in a South-eastern European population. DNA Cell Biol. 2012;31(2):193–8.CrossRefPubMed
46.
Platek ME, Shields PG, Marian C, McCann SE, Bonner MR, Nie J, et al. Alcohol consumption and genetic variation in methylenetetrahydrofolate reductase and 5-methyltetrahydrofolate-homocysteine methyltransferase in relation to breast cancer risk. Cancer Epidemiology, Biomarkers & Prevention: A Publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2009;18(9):2453–9.CrossRef
47.
Qi J, Miao XP, Tan W, Yu CY, Liang G, Lu WF, et al. Association between genetic polymorphisms in methylenetetrahydrofolate reductase and risk of breast cancer. Zhonghua zhong liu za zhi (Chinese Journal of Oncology). 2004;26(5):287–9.
48.
Sangrajrang S, Sato Y, Sakamoto H, Ohnami S, Khuhaprema T, Yoshida T. Genetic polymorphisms in folate and alcohol metabolism and breast cancer risk: a case-control study in Thai women. Breast Cancer Res Treat. 2010;123(3):885–93.CrossRefPubMed
49.
Sharp L, Little J, Schofield AC, Pavlidou E, Cotton SC, Miedzybrodzka Z, et al. Folate and breast cancer: the role of polymorphisms in methylenetetrahydrofolate reductase (MTHFR). Cancer Lett. 2002;181(1):65–71.CrossRefPubMed
50.
Shrubsole MJ, Gao YT, Cai Q, Shu XO, Dai Q, Hebert JR, et al. MTHFR polymorphisms, dietary folate intake, and breast cancer risk: results from the Shanghai breast cancer study. Cancer Epidemiology, Biomarkers & Prevention: A Publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2004;13(2):190–6.CrossRef
51.
Vainer AS, Boiarskikh UA, Voronina EN, Selezneva IA, Sinkina TV, Lazarev AF, et al. Polymorphic variants of folate metabolizing genes (C677T and A1298C MTHFR, C1420T SHMT1 and G1958A MTHFD) are not associated with the risk of breast cancer in West Siberian Region of Russia. Mol Biol. 2010;44(5):816–23.
52.
Weiwei Z, Liping C, Dequan L. Association between dietary intake of folate, vitamin B6, B12 & MTHFR, MTR genotype and breast cancer risk. Pakistan Journal of Medical Sciences. 2014;30(1):106–10.PubMedPubMedCentral
53.
Wu XY, Ni J, Xu WJ, Zhou T, Wang X. Interactions between MTHFR C677T-A1298C variants and folic acid deficiency affect breast cancer risk in a Chinese population. Asian Pacific Journal of Cancer Prevention: APJCP. 2012;13(5):2199–206.CrossRefPubMed
54.
Xu X, Gammon MD, Zhang H, Wetmur JG, Rao M, Teitelbaum SL, et al. Polymorphisms of one-carbon-metabolizing genes and risk of breast cancer in a population-based study. Carcinogenesis. 2007;28(7):1504–9.CrossRefPubMed
55.
Ziva Cerne J, Stegel V, Gersak K, Novakovic S. Lack of association between methylenetetrahydrofolate reductase genetic polymorphisms and postmenopausal breast cancer risk. Mol Med Rep. 2011;4(1):175–9.PubMed
56.
Guo LN. Methylenetetrahydrofolate reductase C677T polymorphism and cervical cancer risk: a meta-analysis. Asian Pacific Journal of Cancer Prevention: APJCP. 2012;13(5):2193–7.CrossRefPubMed
57.
Larsson SC, Giovannucci E, Wolk A. Folate intake, MTHFR polymorphisms, and risk of esophageal, gastric, and pancreatic cancer: a meta-analysis. Gastroenterology. 2006;131(4):1271–83.CrossRefPubMed
58.
Hou XH, Huang YM, Mi YY. Methylenetetrahydrofolate reductase gene C677T polymorphism and lung cancer: an updated meta-analysis. Asian Pacific Journal of Cancer Prevention: APJCP. 2012;13(5):2025–9.CrossRefPubMed
59.
Ma C, Liu Y, Zhang W, Liu P. The association between MTHFR C677T polymorphism and ovarian cancer risk: a meta-analysis of 18,628 individuals. Mol Biol Rep. 2013;40(3):2061–8.CrossRefPubMed
60.
Qi X, Sun X, Xu J, Wang Z, Zhang J, Peng Z. Associations between methylenetetrahydrofolate reductase polymorphisms and hepatocellular carcinoma risk in Chinese population. Tumour Biology: The Journal of the International Society for Oncodevelopmental Biology and Medicine. 2014;35(3):1757–62.CrossRef
61.
Gao Y, Huang YB, Liu XO, Chen C, Dai HJ, Song FJ, et al. Tea consumption, alcohol drinking and physical activity associations with breast cancer risk among Chinese females: a systematic review and meta-analysis. Asian Pacific Journal of Cancer Prevention: APJCP. 2013;14(12):7543–50.CrossRefPubMed
62.
Lajous M, Lazcano-Ponce E, Hernandez-Avila M, Willett W, Romieu I. Folate, vitamin B(6), and vitamin B(12) intake and the risk of breast cancer among Mexican women. Cancer Epidemiology, Biomarkers & Prevention: A Publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2006;15(3):443–8.CrossRef
63.
Pizot C, Boniol M, Mullie P, Koechlin A, Boniol M, Boyle P, et al. Physical activity, hormone replacement therapy and breast cancer risk: a meta-analysis of prospective studies. Eur J Cancer. 2016;52:138–54.CrossRefPubMed
64.
Zhu H, Lei X, Feng J, Wang Y. Oral contraceptive use and risk of breast cancer: a meta-analysis of prospective cohort studies. The European Journal of Contraception & Reproductive Health Care: The Official Journal of the European Society of Contraception. 2012;17(6):402–14.CrossRef
65.
Sillero-Arenas M, Delgado-Rodriguez M, Rodigues-Canteras R, Bueno-Cavanillas A, Galvez-Vargas R. Menopausal hormone replacement therapy and breast cancer: a meta-analysis. Obstet Gynecol. 1992;79(2):286–94.PubMed
66.
Langsenlehner T, Renner W, Yazdani-Biuki B, Langsenlehner U. Methylenetetrahydrofolate reductase (MTHFR) and breast cancer risk: a nested-case-control study and a pooled meta-analysis. Breast Cancer Res Treat. 2008;107(3):459–60.CrossRefPubMed
67.
Macis D, Maisonneuve P, Johansson H, Bonanni B, Botteri E, Iodice S, et al. Methylenetetrahydrofolate reductase (MTHFR) and breast cancer risk: a nested-case-control study and a pooled meta-analysis. Breast Cancer Res Treat. 2007;106(2):263–71.CrossRefPubMed
68.
Yu L, Chen J. Association of MTHFR Ala222Val (rs1801133) polymorphism and breast cancer susceptibility: an update meta-analysis based on 51 research studies. Diagn Pathol. 2012;7:171.CrossRefPubMedPubMedCentral
69.
Zhang J, Qiu LX, Wang ZH, Wu XH, Liu XJ, Wang BY, et al. MTHFR C677T polymorphism associated with breast cancer susceptibility: a meta-analysis involving 15,260 cases and 20,411 controls. Breast Cancer Res Treat. 2010;123(2):549–55.CrossRefPubMed
70.
Rai V. Methylenetetrahydrofolate reductase A1298C polymorphism and breast cancer risk: a meta-analysis of 33 studies. Annals of Medical and Health Sciences Research. 2014;4(6):841–51.CrossRefPubMed
Metadata
Title
Association between MTHFR gene 1298A>C polymorphism and breast cancer susceptibility: a meta-analysis based on 38 case-control studies with 40,985 subjects
Authors
Jinghong Zhang
Lijun Zhang
Guangming Li
Publication date
01-12-2016
Publisher
BioMed Central
Published in
World Journal of Surgical Oncology / Issue 1/2016
Electronic ISSN: 1477-7819
DOI
https://doi.org/10.1186/s12957-016-0978-2

Other articles of this Issue 1/2016

World Journal of Surgical Oncology 1/2016 Go to the issue

Research

Surgical outcomes of robotic thyroidectomy vs. conventional open thyroidectomy for papillary thyroid carcinoma

Case report

A case of disseminated carcinomatosis of the bone marrow originating from gastric cancer 3 years after intraperitoneal chemotherapy against peritoneal carcinomatosis

Case report

Synchronous malignancies of the gall bladder and common bile duct: a case report

Erratum

Erratum to: Surgical spacer placement prior carbon ion radiotherapy (CIRT): an effective feasible strategy to improve the treatment for sacral chordoma

Research

Nephrometry score-guided off-clamp laparoscopic partial nephrectomy: patient selection and short-time functional results

Case report

Mucosa-associated lymphoid tissue (MALT) lymphoma as an unusual cause of malignant hilar biliary stricture: a case report with literature review