Aberrant DNA methylation of cancer-associated genes in gastric cancer in
the European Prospective Investigation into Cancer and Nutrition
(EPIC-EURGAST)
Epigenetic events have emerged as key mechanisms in the regulation of
critical biological processes and in the development of a wide variety
of human malignancies, including gastric cancer (GC), however precise
gene targets of aberrant DNA methylation in GC remain largely unknown.
Here, we have combined pyrosequencing-based quantitative analysis of DNA
methylation in 98 GC cases and 64 controls nested within the European
Prospective Investigation into Cancer and Nutrition (EPIC) cohort and in
cancer tissue and non-tumorigenic adjacent tissue of an independent
series of GC samples. A panel of 10 cancer-associated genes (CHRNA3,
DOK1, MGMT, RASSF1A, p14ARF, CDH1, MLH1, ALDH2, GNMT and MTHFR) and
LINE-1 repetitive elements were included in the analysis and their
association with clinicopathological characteristics (sex, age at
diagnosis, anatomical sub-site, histological sub-type) was examined.
Three out of the 10 genes analyzed exhibited a marked hypermethylation,
whereas two genes (ALDH2 and MTHFR) showed significant hypomethylation,
in gastric tumors. Among differentially methylated genes, we identified
new genes (CHRNA3 and DOK1) as targets of aberrant hypermethylation in
GC, suggesting that epigenetic deregulation of these genes and their
corresponding cellular pathways may promote the development and
progression of GC. We also found that global demethylation of tumor cell
genomes occurs in GC, consistent with the notion that abnormal
hypermethylation of specific genes occurs concomitantly with genome-wide
hypomethylation. Age and gender had no significant influence on
methylation states, but an association was observed between LINE-1 and
MLH1 methylation levels with histological subtype and anatomical
sub-site. This study identifies aberrant methylation patters in specific
genes in GC thus providing information that could be exploited as novel
biomarkers in clinics and molecular epidemiology of GC. (C) 2011
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