Abstract
The purpose of this study was to determine the relationship between methylation status of the insulin-like growth factor 2 (IGF-2) gene and methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphisms in bladder transitional cell carcinoma tissues in a Chinese population. The polymorphisms of the folate metabolism enzyme gene MTHFR were studied by restrictive fragment length polymorphism (RFLP). PCR-based methods of DNA methylation analysis were used to detect the CpG island methylation status of the IGF-2 gene. The association between the methylation status of the IGF-2 gene and clinical characteristics, as well as MTHFR C677T polymorphisms, was analyzed. Aberrant hypomethylation of the IGF-2 gene was found in 68.3% bladder cancer tissues and 12.4% normal bladder tissues, respectively, while hypomethylation was not detected in almost all normal bladder tissues. The hypomethylation rate of the IGF-2 gene in cancer tissues was significantly higher in patients with lymph node metastasis than in those without lymph node metastasis (46.3% vs 17.2%, P = 0.018). No association was found between aberrant DNA methylation and selected factors including sex, age, tobacco smoking, alcohol consumption and green tea consumption. After adjusting for potential confounding variables the variant allele of MTHFR C677T was found to be associated with hypomethylation of the IGF-2 gene. Compared with wildtype CC, the odds ratio was 4.33 (95% CI=1.06-10.59) for CT and 4.95 (95% CI=1.18-12.74) for TT. MTHFR 677 CC and CT genotypes might be one of the reasons that cause abnormal hypomethylation of the IGF-2 gene, and the aberrant CpG island hypomethylation of the IGF-2 gene may contribute to the genesis and progression of bladder transitional cell carcinoma.
Highlights
500,000 individuals in the U.S have been diagnosed with bladder cancer[1], i.e., transitional cell carcinoma transitional cell carcinoma of the bladder
After adjusting other potential confounding variables such as age, gender, folate intake, we found that the insulin-like growth factor 2 (IGF-2) gene hypomethylation frequency in the transitional cell carcinoma tissues from carriers of methylenetetrahydrofolate reductase (MTHFR) variant CT and TT genotypes was significantly increased compared with the MTHFR wildtype genotype CC, with the OR values of 4.33 and 4.95, respectively (Figs. 2, 3 and Table 3)
Methylation is an epigenetic mechanism, which plays an important role in regulating gene expression at the transcription level[15]
Summary
500,000 individuals in the U.S have been diagnosed with bladder cancer[1], i.e., transitional cell carcinoma transitional cell carcinoma of the bladder. It is one of the most common malignancies affecting the genitourinary tract and is characterized by multifocality and a high incidence of recurrence[2]. DNA methylation alterations, which play a strong role in tumorigenesis[8], are probably the most widely studied epigenetic alterations in cancer[9] and are increasingly becoming a hot subject of research. Carcinogenesis is associated with changes in this epigenetic phenomenon, including two distinct and seemingly opposing trends: global decrease in cytosine methylation (hypomethylation or unmethylation) and methylation of cytosine in CpG islands (hypermethylation)[10]. It reported that failure to repress genes appropriately by abnormal demethylation of tissue-restricted genes or by hypomethylation of proto-oncogenes could result in the loss of tissue specificity and could promote cancer formation
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