Fast track — ArticlesGenomic DNA hypomethylation as a biomarker for bladder cancer susceptibility in the Spanish Bladder Cancer Study: a case–control study
Introduction
In tumour tissue, changes in patterns of DNA methylation, such as promoter CpG-island hypermethylation and global (genome-wide) hypomethylation, frequently occur. Global hypomethylation of DNA is thought to contribute to carcinogenesis by the induction of genome instability and gene-specific hypomethylation.1, 2 Genomic instability is a common occurrence in many cancers, and chromosomal instability and, to a lesser extent, microsatellite instability, has been noted in urothelial carcinomas of the bladder.3, 4, 5, 6, 7, 8 Studies have also shown that in bladder cancer, chromosomal instability is widespread, occurs early in the carcinogenic process, and is associated with alterations on chromosome 9, the first and most frequently altered chromosome in the development of bladder cancer.9, 10, 11, 12 One study suggested that loss of heterozygosity (LOH) of chromosome 9 was associated with genome-wide hypomethylation.12
Measures of global cytosine methylation in DNA of blood cells and of healthy tissue have been used as a phenotypic marker of genomic instability and potential cancer risk. One study13 of patients with head and neck cancer noted that amounts of global cytosine methylation were lower in the DNA in blood from patients with cancer compared with controls. Smoking and the methylene tetrahydrofolate reductase (MTHFR) variant genotype were associated with less methylation compared with controls, whereas exposure to human papilloma virus 16 was associated with more global methylation compared with controls.13 Another study14 of cancer-cell lines and tumour tissues showed that most long interspersed nuclear element-1 (LINE-1) sequences were hypomethylated compared with those in lymphocytes and healthy colon mucosa. Only one smaller study15 assessed global methylation as a susceptibility factor for bladder cancer, a tobacco-associated tumour for which genomic instability increases with disease progression.16, 17, 18 That study did not assess other covariates that might also affect the amount of methylation in genomic DNA, such as diet and genetic variation.
To ascertain whether the amount of DNA methylation was associated with risk of bladder cancer, we aimed to measure cytosine methylation (5-mC) content in leucocyte DNA in patients with bladder cancer (cases) and controls who were enrolled in a large hospital-based study (the Spanish Bladder Cancer Study). Information on variation in 34 single nucleotide polymorphisms (SNPs) in nine folate-metabolism-pathway genes, on vitamins B1, B2, B3, B6, B12, and folate, total protein, and alcohol intake was assessed to identify factors that contribute to the amount of genomic methylation in controls and to identify potential confounding factors and risk modifiers for bladder cancer.19, 20, 21
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Patients
The study population has been previously described.22, 23 This study was a hospital-based case–control study undertaken between Jan 1, 1998, and Dec 31, 2001, in five regions of Spain (Asturias, Barcelona, Vallés Occidental-Bages, Alicante, and Tenerife). Cases were men and women with newly diagnosed and histologically confirmed urothelial carcinoma of the bladder. Controls were selected from patients admitted to the same hospital for diseases or conditions unrelated to smoking and other known
Results
1219 of 1453 (84%) eligible cases and 1271 of 1442 (88%) eligible controls agreed to participate in the study. 1150 of 1219 (94%) cases and 1149 of 1271 (90%) controls provided suitable genomic DNA for molecular analyses of genotypes and amount of global methylation. Methylation analyses were done on DNA from 775 of 1150 (67%) cases and 397 of 1149 (35%) controls who had available leucocyte DNA for analysis. Nutritional data were available for 588 of 775 (76%) cases and 288 of 397 (73%)
Discussion
In this study, median amounts of global methylation, measured as %5-mC in leucocyte DNA, was significantly lower in cases than controls and lower amounts of DNA methylation (hypomethylation) were independently associated with increased cancer risk. This association was also dose-dependent and not modified by nutritional or polymorphic variants in genes known to be involved in DNA methylation or folate metabolism that were assessed in this study. Although smoking was not associated with amount
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