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Analysis of the Cyclooxygenase-2 (COX-2) and Methylenetetrahydrofolate Reductase (MTHFR) Gene Polymorphisms in Esophageal Cancer
Evelise Pelegrinelli-Zaidan^*, Michele T. TomitãO, MáRcia Kubrusly, Adriana V. Safatle-Ribeiro, Evandro S. De Mello, Rubens a. Sallum, Ivan Cecconello, Ulysses Ribeiro
Gastroenterology, Uni versity of São Paulo, Sao Paulo, Brazil

Background: Cyclooxygenase-2 (COX-2) is induced in response to growth factors and cytokines, expressed in inflammatory diseases, premalignant and esophageal tumors. The product of folate metabolism by the enzyme methylenetetrahydrofolate reductase (MTHFR) acts in DNA synthesis, alteration or inhibition of this enzyme increases the susceptibility to mutations, damage and altered DNA methylation, gene expression of transforming the tumor suppressor and proto- ontogenesis, potential risk factors for esophageal cancer. Cox-2 and MTHFR polymorphisms might modify the levels of protein expression and may have a considerable influence on disease phenotype, which may have important clinical/genomic implications. Aims: To evaluate single nucleotide polymorphisms (SNPs) in the Cox-2 and MTHFR genes and their prognostic values for patients operated on for esophageal cancer; and to investigate possible interactions between these genetic variations and clinicopathologic characteristics in esophageal cancer. Methods: Cox-2 and MTHFR SNPs were analyzed in 114 prospective patients who underwent surgical resection, and had a minimum of 5 years follow-up. DNA was isolated from leukocyte using extraction and purification kit, followed by amplification by polymerase chain reaction (PCR). Real-time analysis was used for genotyping Cox-2 and MTHFR SNPs through the TaqMan ® SNP Genotyping Assay. Results: We determined frequencies of three COX-2 polymorphisms (1195A>G/ -1329A>G, 8437T>C, 1759G>A), with nine haplotypes; and two MTHFR biallelic polymorphisms (1298 A>C, 677 C>T), with six haplotypes. A high frequency of the wild genotype Cox-2-1195GG was detected in adenocarcinoma tumors. Homozygous Cox-2-8437CC was associated to Caucasians and younger patients at diagnosis. Polymorphic wild genotype MTHFR-1298AA was increased in squamous cell carcinoma, and younger patients. Wild homozigous MTHFR-677CC was associated to improved survivalship, and to heavy active tobacco smoking patients. Wild homozygous genotype of Cox-2 and MTFHR were significantly correlated to a worst progression-free survival and overall survival when compared to the combined heterozygous or recessive genotypes in a multivariate analysis. Conclusions: 1. Wild homozygous Cox-2 and MTHFR SNPs were associated to disease progression and survival in patients with advanced esophageal cancer; 2. Cox-2 and MTFHR SNPs may be useful markers of aggressiveness in these patients, and may orientate the appropriate target therapy in novel clinical trials.

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