CEBP Susan G. Komen for the Cure-AACR Outstanding Investigator Award for Breast Cancer Research 2008 Conference on Cancer Prevention - Washington, D.C.
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Cell Growth & Differentiation
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Semmler, A.
Right arrow Articles by Linnebank, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Semmler, A.
Right arrow Articles by Linnebank, M.
Cancer Epidemiology Biomarkers & Prevention Vol. 15, 2314-2316, November 2006
© 2006 American Association for Cancer Research

Short Communication

The Methionine Synthase Polymorphism c.2756A>G Alters Susceptibility to Glioblastoma Multiforme

Alexander Semmler1, Matthias Simon2, Susanna Moskau1 and Michael Linnebank1

Departments of 1 Neurology and 2 Neurosurgery, University Hospital Bonn, Bonn, Germany

Requests for reprints: Michael Linnebank, Department of Neurology, University Hospital Bonn, Sigmund-Freud-Straße, 25, 53105 Bonn, Germany. Phone: 49-228-287-5712; Fax: 49-228-287-5024. E-mail: Michael.Linnebank{at}ukb.uni-bonn.de


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Genetic polymorphisms of methionine metabolism, in particular methionine synthase (MTR) c.2756A>G (D919G) and methylenetetrahydrofolate reductase (MTHFR) c.677C>T (A222V), have been associated with various human cancers. We investigated MTR c.2756A>G, MTHFR c.677C>T, and a third polymorphism, transcobalamin 2 c.776C>G (P259R), for a potential association with the formation of glioblastoma multiforme. The MTR c.2756G allele was significantly underrepresented among 328 glioblastoma multiforme patients of Caucasian origin when compared with 400 population controls [patients AA/AG/GG: 0.72/0.26/0.02 and controls AA/AG/GG: 0.57/0.38/0.05, degrees of freedom = 2; {chi}2 = 17.86 (Pearson); P < 0.001]. No association between glioblastoma multiforme and the two other polymorphisms was observed. (Cancer Epidemiol Biomarkers Prev 2006;15(11):2314–6)


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Glioblastoma multiforme is the most common glial tumor. The annual incidence of malignant astrocytomas (i.e., anaplastic astrocytoma and glioblastoma multiforme) is 3 to 4 per 100,000 (1). Glioblastoma multiformes account for up to 80% of malignant gliomas (2). Patients diagnosed with glioblastoma multiforme typically undergo microsurgical resection of their tumor followed by radiation. Adjuvant chemotherapy confers a modest survival benefit. However, median survival usually does not exceed 12 to 15 months even in selected patient series (3).

Great progress has been made in delineating characteristic patterns of somatic mutations in glioblastoma multiformes (4). However, relatively little is known with respect to germ-line genetic factors influencing an individual's risk to develop a malignant glioma. The genetic pathways involved in glioblastoma multiforme formation may vary with ethnicity (5). Well-characterized cancer predisposition syndromes such as the Li-Fraumeni syndrome or Turcot syndrome are rarely diagnosed in glioblastoma patients (6, 7). Some studies suggested that polymorphisms of the p53 gene and of genes coding for DNA repair enzymes, glutathione S-transferase and CYP2E1, may be associated with glioblastoma multiforme formation (8-10). Genetic variants associated with asthma may protect against glioblastoma multiforme and gliomas in general (11).

The 5-methyltetrahydrofolate-homocysteine S-methyltransferase (MTR; also called methionine synthase) catalyzes the remethylation of homocysteine to methionine and has influence on DNA methylation as well as on nucleic acid synthesis (12). The missense polymorphism MTR c.2756A>G (D919G) has been reported to alter the susceptibility to various cancers (12-17). Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate, a cofactor for MTR. Some evidence suggests that the MTHFR c.677C>T (A222V) polymorphism as well might be associated with a variety of cancers (18). Transcobalamin 2 (Tc2) is the transporter of a vitamin B12 derivate, which serves as the second cofactor for MTR. Synergistic effects between the Tc2 c.776C>G (P259R) and MTR c.2756A>G polymorphisms on the development of white matter in patients with primary central nervous system lymphoma treated with methotrexate have been described (19).

In the present study, we investigated the three missense polymorphisms, MTR c.2756A>G (D919G), MTHFR c.677C>T (A222V), and Tc2 c.776C>G (P259R), for a potential association with glioblastoma multiforme formation.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
We investigated 328 consecutive glioblastoma multiforme patients (59% male; average age ±1 SD, 58.8 ± 12.7 years) of Caucasian origin recruited for the tumor library of the Department of Neurosurgery of the University Hospital of Bonn between September 1994 and May 2006 (response rate, 75%). The Department of Neurosurgery is a tertiary referral center serving a population of 1,000,000 in the greater Bonn area. All histologic diagnoses were made at the Institute for Neuropathology/German Brain Tumor Reference Center at the University of Bonn. In 12 of the patients, the histologic subtype was gliosarcoma; in 6 patients, giant cell glioblastoma multiforme; in all others, glioblastoma multiforme. Four hundred apparently healthy white Caucasian Bonn area residents (52% female; average age ±1 SD, 52.9 ± 15.7 years) without a history of cancer served as controls (Table 1 ).


View this table:
[in this window]
[in a new window]
  		Table 1. Genetic variants of methionine metabolism in glioblastoma multiforme patients and controls

 
Genomic DNA prepared from peripheral leukocytes was used for allelotyping by PCR amplification and restriction analysis as previously published (12). The two-sided Pearson's {chi}2 test was employed to analyze the distribution of the respective allelotypes in the patient and the control group. The Hardy-Weinberg equation was tested with {alpha} = 0.05. Due to multiple testing (three polymorphisms), threshold was restrictively defined as {alpha} = 0.01. Because of the differences in age and gender between patients and controls, nominal regression analysis ({alpha} = 0.05) was additionally used to test the independent predictive character of allelotypes for glioblastoma multiforme formation with age and gender as covariables.

The study was approved by the local ethics committee.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The Hardy-Weinberg equilibrium was fulfilled for the three polymorphisms among patients and controls. The MTR c.2756G allele (i.e., the MTR c.2756AG and GG allelotypes) was significantly less frequently found among glioblastoma multiforme patients when compared with controls (28% versus 43%; odds ratio, 0.52; 95% confidence interval, 0.37-0.71; {chi}2 = 17.4; P = 0.00003; Table 1). The underrepresentation of the G-allele of MTR c.2756A>G in glioblastoma multiforme patients suggests that it protects against the incidence of glioblastoma multiforme. Multiple nominal regression analysis with age and gender as covariables proved that the MTR c.2756A>G (D919G) genotype was an independent predictive factor for glioblastoma multiforme formation ({chi}2 = 14.82; P = 0.001). If the 18 samples of patients with glioblastoma of giant cell or gliosarcoma subtype were left out of analysis, significance was {chi}2 = 12.73 (P = 0.002) in nominal regression analysis.

There was no significant association of the two other polymorphisms (MTHFR c.677C>T and Tc2 c.776C>G) with the incidence of glioblastoma multiforme in our study sample.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We have analyzed three polymorphisms of methionine metabolism in 328 glioblastoma multiforme patients and 400 controls. We observed a significant association between the G-allele of MTR c.2756A>G (D919G) and glioblastoma multiforme. A 28% prevalence of the G-allele among glioblastoma multiforme patients versus 43% in the control series suggests an epidemiologically relevant protective effect of the G-allele (odds ratio, 0.52).

As our data were created in a case-control design, the observed protective effect of the G-allele of MTR c.2756A>G should be in an independent sample. Nevertheless, the G-allele of MTR c.2756A>G (D919G) has been reported to reduce the susceptibility to a number of other cancers, colorectal cancer [protective in combination with low alcohol consumption (13); protective (14)], cervical intraepithelial neoplasia [protective in women when in combination with the MTHFR c.677C>T variant (15)], primary central nervous system non-Hodgkin lymphoma [protective (12)], and acute lymphoblastic leukemia and systemic non-Hodgkin's lymphoma [protective (16, 17)]. Our study suggests that this allele also protects against glioblastoma multiforme. The functional consequences of this missense polymorphism about MTR expression and activity have not been studied in detail. MTR catalyzes the remethylation of homocysteine to methionine and is therefore involved in methyl, folate, and nucleic acid metabolism (12). Impairment of these pathways can lead to uracil incorporation into DNA, hypomethylation or hypermethylation of DNA, inefficient DNA repair, and increased chromosome malsegregation and chromosomal breakage (20). In addition, the MTR c.2756A>G variant has been reported to influence the methylation of CpG islands in tumor suppressor genes (21). Chromosomal instability and modified DNA methylation are important mechanisms involved in the pathogenesis of most malignant tumors including glioblastoma multiforme (22-25). These findings suggest explanations for the association of the MTR c.2756A>G (D919G) polymorphism with glioblastoma multiforme and other cancers. Interestingly, the presence of the protective G-allele has been observed to promote disease-free longevity in the general German population (26).

The MTHFR c.677C>T polymorphism was suggested to influence the susceptibility to various extracranial tumors, but not to primary central nervous system lymphoma, which was found to be also influenced by the MTR c.2756A>G polymorphism (12). We did not observe any significant associations of MTHFR c.677C>T or Tc2 c.776C>G with glioblastoma multiforme in our study sample.

Finally, it is tempting to speculate about possible clinical implications of the data presented. MTR activity depends on folate and vitamin B12 (27), which might provide a link of nutritional factors and incidence of glioblastoma multiforme and other malignant tumors. Accordingly, an inverse relation between maternal folate intake, the use of various vitamins, and the risk to develop malignant brain tumors in young children has been reported (28). Additional studies on the functional consequences of the MTR c.2756A>G polymorphism and on the detailed influence of this polymorphism and of folate and vitamin B12 on the incidence of different types of cancer are warranted.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: A. Semmler and M. Simon contributed equally to this work.

Received 12/26/05; revised 7/15/06; accepted 9/13/06.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. DeAngelis LM. Brain tumors. N Engl J Med 2001;344:114–23.[Free Full Text]
  2. Radhakrishnan K, Mokri B, Parisi JE, et al. The trends in incidence of primary brain tumors in the population of Rochester, Minnesota. Ann Neurol 1995;37:67–73.[CrossRef][Medline]
  3. Buckner JC. Factors influencing survival in high-grade gliomas. Semin Oncol 2003;30:10–4.[Medline]
  4. Ichimura K, Ohgaki H, Kleihues P, Collins VP. Molecular pathogenesis of astrocytic tumours. J Neurooncol 2004;70:137–60.[Medline]
  5. Wiencke JK, Aldape K, McMillan A, et al. Molecular features of adult glioma associated with patient race/ethnicity, age, and a polymorphism in O6-methylguanine-DNA-methyltransferase. Cancer Epidemiol Biomarkers Prev 2005;14:1774–83.[Abstract/Free Full Text]
  6. Li YJ, Sanson M, Hoang-Xuan K, et al. Incidence of germ-line p53 mutations in patients with gliomas. Int J Cancer 1995;64:383–7.[Medline]
  7. Hamilton SR, Liu B, Parsons RE, et al. The molecular basis of Turcot's syndrome. N Engl J Med 1995;332:839–47.[Abstract/Free Full Text]
  8. Malmer B, Feychting M, Lonn S, Ahlbom A, Henriksson R. p53 Genotypes and risk of glioma and meningioma. Cancer Epidemiol Biomarkers Prev 2005;14:2220–3.[Abstract/Free Full Text]
  9. Wang LE, Bondy ML, Shen H, et al. Polymorphisms of DNA repair genes and risk of glioma. Cancer Res 2004;64:5560–3.[Abstract/Free Full Text]
  10. De Roos AJ, Rothman N, Inskip PD, et al. Genetic polymorphisms in GSTM1, -P1, -T1, and CYP2E1 and the risk of adult brain tumors. Cancer Epidemiol Biomarkers Prev 2003;12:14–22.[Abstract/Free Full Text]
  11. Schwartzbaum J, Ahlbom A, Malmer B, et al. Polymorphisms associated with asthma are inversely related to glioblastoma multiforme. Cancer Res 2005;65:6459–65.[Abstract/Free Full Text]
  12. Linnebank M, Schmidt S, Kolsch H, et al. The methionine synthase polymorphism D919G alters susceptibility to primary central nervous system lymphoma. Br J Cancer 2004;90:1969–71.[CrossRef][Medline]
  13. Ma J, Stampfer MJ, Christensen B, et al. A polymorphism of the methionine synthase gene: association with plasma folate, vitamin B12, homocyst(e)ine, and colorectal cancer risk. Cancer Epidemiol Biomarkers Prev 1999;8:825–9.[Abstract/Free Full Text]
  14. Ulvik A, Vollset SE, Hansen S, et al. Colorectal cancer and the methylenetetrahydrofolate reductase 677C->T and methionine synthase 2756A->G polymorphisms: a study of 2,168 case-control pairs from the JANUS cohort. Cancer Epidemiol Biomarkers Prev 2004;13:2175–80.[Abstract/Free Full Text]
  15. Henao OL, Piyathilake CJ, Waterbor JW, et al. Women with polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MS) are less likely to have cervical intraepithelial neoplasia (CIN) 2 or 3. Int J Cancer 2005;113:991–7.[Medline]
  16. Gemmati D, Ongaro A, Scapoli GL, et al. Common gene polymorphisms in the metabolic folate and methylation pathway and the risk of acute lymphoblastic leukemia and non-Hodgkin's lymphoma in adults. Cancer Epidemiol Biomarkers Prev 2004;13:787–94.[Abstract/Free Full Text]
  17. Lincz LF, Scorgie FE, Kerridge I, et al. Methionine synthase genetic polymorphism MS A2756G alters susceptibility to follicular but not diffuse large B-cell non-Hodgkin's lymphoma or multiple myeloma. Br J Haematol 2003;120:1051–4.[CrossRef][Medline]
  18. Fodinger M, Horl WH, Sunder-Plassmann G. Molecular biology of 5,10-methylenetetrahydrofolate reductase. J Nephrol 2000;13:20–33.[Medline]
  19. Linnebank M, Pels H, Kleczar N, et al. MTX-induced white matter changes are associated with polymorphisms of methionine metabolism. Neurology 2005;64:912–3.[Abstract/Free Full Text]
  20. Beetstra S, Thomas P, Salisbury C, Turner J, Fenech M. Folic acid deficiency increases chromosomal instability, chromosome 21 aneuploidy and sensitivity to radiation-induced micronuclei. Mutat Res 2005;578:317–26.[Medline]
  21. Paz MF, Avila S, Fraga MF, et al. Germ-line variants in methyl-group metabolism genes and susceptibility to DNA methylation in normal tissues and human primary tumors. Cancer Res 2002;62:4519–24.[Abstract/Free Full Text]
  22. Ohgaki H, Dessen P, Jourde B, et al. Genetic pathways to glioblastoma: a population-based study. Cancer Res 2004;64:6892–9.[Abstract/Free Full Text]
  23. Wooten EC, Fults D, Duggirala R, et al. A study of loss of heterozygosity at 70 loci in anaplastic astrocytoma and glioblastoma multiforme with implications for tumor evolution. Neurooncol 1999;1:169–76.[Abstract]
  24. Blount BC, Mack MM, Wehr CM, et al. Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage. Proc Natl Acad Sci U S A 1997;94:3290–5.[Abstract/Free Full Text]
  25. Harmon DL, Shields DC, Woodside JV, et al. Methionine synthase D919G polymorphism is a significant but modest determinant of circulating homocysteine concentrations. Genet Epidemiol 1999;17:298–309.[CrossRef][Medline]
  26. Linnebank M, Fliessbach K, Kolsch H, Rietschel M, Wullner U. The methionine synthase polymorphism c.2756Aright curved arrow G (D919G) is relevant for disease-free longevity. Int J Mol Med 2005;16:759–61.[Medline]
  27. Mudd SH, Levy HL, Kraus JP. Disorders of transsulfuration. The metabolic and molecular bases of inherited disease. 8th ed. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler K, Vogelstein B, editors. New York: Mc Graw-Hill; 2001. p. 2007–56.
  28. Bunin GR, Kuijten RR, Buckley JD, Rorke LB, Meadows AT. Relation between maternal diet and subsequent primitive neuroectodermal brain tumors in young children. N Engl J Med 1993;329:536–41.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Cancer Epidemiol. Biomarkers Prev.Home page
L. Bethke, E. Webb, A. Murray, M. Schoemaker, M. Feychting, S. Lonn, A. Ahlbom, B. Malmer, R. Henriksson, A. Auvinen, et al.
Functional Polymorphisms in Folate Metabolism Genes Influence the Risk of Meningioma and Glioma
Cancer Epidemiol. Biomarkers Prev., May 1, 2008; 17(5): 1195 - 1202.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Semmler, A.
Right arrow Articles by Linnebank, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Semmler, A.
Right arrow Articles by Linnebank, M.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Cell Growth & Differentiation