Open Access Research article

Cancer-testis gene expression is associated with the methylenetetrahydrofolate reductase 677 C>T polymorphism in non-small cell lung carcinoma

Kerem M Senses1, Mithat Gonen2, Ahmet R Barutcu16, Zeynep Kalaylioglu3, Murat Isbilen1, Ozlen Konu1, Yao T Chen4, Nasser K Altorki5 and Ali O Gure1*

Author Affiliations

1 Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey

2 Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA

3 Department of Statistics, Middle East Technical University, Ankara, Turkey

4 Department of Pathology, Weill Medical College of Cornell University, New York, NY, USA

5 Department of Cardiothoracic Surgery, Weill Medical College of Cornell University, New York, NY, USA

6 Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA, USA

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BMC Medical Genetics 2013, 14:97  doi:10.1186/1471-2350-14-97

Published: 24 September 2013

Abstract

Background

Tumor-specific, coordinate expression of cancer-testis (CT) genes, mapping to the X chromosome, is observed in more than 60% of non-small cell lung cancer (NSCLC) patients. Although CT gene expression has been unequivocally related to DNA demethylation of promoter regions, the underlying mechanism leading to loss of promoter methylation remains elusive. Polymorphisms of enzymes within the 1-carbon pathway have been shown to affect S-adenosyl methionine (SAM) production, which is the sole methyl donor in the cell. Allelic variants of several enzymes within this pathway have been associated with altered SAM levels either directly, or indirectly as reflected by altered levels of SAH and Homocysteine levels, and altered levels of DNA methylation. We, therefore, asked whether the five most commonly occurring polymorphisms in four of the enzymes in the 1-carbon pathway associated with CT gene expression status in patients with NSCLC.

Methods

Fifty patients among a cohort of 763 with NSCLC were selected based on CT gene expression status and typed for five polymorphisms in four genes known to affect SAM generation by allele specific q-PCR and RFLP.

Results

We identified a significant association between CT gene expression and the MTHFR 677 CC genotype, as well as the C allele of the SNP, in this cohort of patients. Multivariate analysis revealed that the genotype and allele strongly associate with CT gene expression, independent of potential confounders.

Conclusions

Although CT gene expression is associated with DNA demethylation, in NSCLC, our data suggests this is unlikely to be the result of decreased MTHFR function.

Keywords:
Cancer-testis genes; 1-carbon pathway; Adomet; DNA methylation