Methionine synthase (MTR) and methionine synthase reductase (MTRR) gene polymorphisms in progression to esophageal adenocarcinoma
Authors: Lori Hatcher, Joseph Knezetic, Poonam Sharma, Zoran Gatalica
Journal: Clinical Cancer Research (2007)

A43  Background: The ability of folate to function as a single-carbon carrier is affected by the activity of multiple enzymes in metabolic pathways, including methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR). The reaction catalyzed by MTR utilizes the enzyme product of MTHFR, 5-methyl-THF, generating methionine from homocysteine in a transmethylation reaction, which is essential for maintaining intracellular methionine. Vitamin B-12 is a cofactor in methionine generation by MTR and methionine synthase reductase (MTRR) is required to reactivate MTR. Common variants in MTR and MTRR influence enzyme activity, resulting in elevated serum folate levels. The A2756G in MTR generates a D919G (aspartic acid to glycine) substitution, while MTRR G66A variant yields an isoleucine to methionine substitution. Additionally, methionine serves as a methyl donor, via SAM (S-adenosylmethionine) in DNA methylation. Methylation of DNA in CpG islands directly regulates gene expression and aberrant methylation patterns can lead to dysfunctional proliferation and cancer progression. In Barrett’s metaplasia, protracted gastroesophagealreflux is involved in replacement of normal squamous with the columnar, intestinal type epithelium. The increased risk of adenocarcinoma development in patients diagnosed with Barrett’s metaplasiais 30- to 40-fold. The effects of these MTR and MTRR polymorphisms have not been evaluated in patients with esophageal adenocarcinoma arising in Barrett’s metaplasia.  Design: MTR and MTRR status has been evaluated using allele-specific TaqMan® probes with Cepheid’s SmartCycler II system in >200 patients undergoing upper GI endoscopy. Experimental groups consisted of 171 patients with Barrett’s: adenocarcinoma arising in Barrett’s (68) or with Barrett’s metaplasia without dysplasia (103), and age and sex-matched control group consisted of 61 patients with reflux esophagitis.  Results: For MTRR, an increased frequency of G66A was detected in the cancer (64.7%) and Barrett’s (62.1%) groups when compared to controls (57.4%). Contrasting published reports of 26-35% heterozygous MTR A2756G, our results indicated a low prevalence of the MTR 2756 G variant in all three groups (13.3 - 15.6 %, no statistical significance). Taken together, however the MTRR G variant was more strongly associated with the WT MTR A2756 allele in Cancer patients (65.1%) than Barrett’s patients (51.0%) or controls (41.0%), while the presence of both variants (MTR 2756G and MTRR GGA) were detected with lower frequency in Cancer (4.8%) or Barrett’s (10.6%) than in controls (16.4%).  Conclusion: These results correlate with previous results of MTHFR polymorphisms, where an inverse association between the development of Barrett’s adenocarcinoma was observed. Together, these results suggest a role of these polymorphisms in esophageal cancer development and progression. Further studies will investigate tumor suppressor and oncogene promoter methylation patterns with respect to these polymorphisms.  Support: LB595 Nebraska Department of Health and Human Services