Open AccessMultiple tumor suppressor genes are increasingly methylated with age in non‐neoplastic gastric epithelia
Author(s) -
So Kanji,
Tamura Gen,
Honda Teiichiro,
Homma Naoyuki,
Waki Takayoshi,
Togawa Naoyuki,
Nishizuka Satoshi,
Motoyama Teiichi
Publication year - 2006
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2006.00302.x
Subject(s) - methylation , cpg site , dna methylation , cancer , microbiology and biotechnology , biology , neoplastic transformation , gastric mucosa , tumor suppressor gene , gene , cancer research , pathology , stomach , gene expression , medicine , carcinogenesis , genetics , biochemistry
A number of tumor suppressor and tumor‐related genes are silenced by promoter hypermethylation in gastric cancer. Hypermethylation is not restricted to cancer cells, but is also present in non‐neoplastic cells during aging. Such age‐related methylation in non‐neoplastic gastric epithelia is postulated to constitute a field defect that increases the risk for development of gastric cancer. To quantitatively evaluate age‐related methylation in non‐neoplastic gastric epithelia, we used a fiber‐type DNA microarray on which methylated and unmethylated sequence probes were mounted. After bisulfite modification, a part of the promoter CpG island of four tumor suppressor genes, lysyl oxidase ( LOX ), p16 , RUNX3 and tazarotene‐induced gene 1 ( TIG1 ), were amplified by PCR using Cy5 end labeled primers. Methylation rates (MRs) were calculated as the ratio of the fluorescence intensity of a methylated sequence probe to the total fluorescence intensity of methylated and unmethylated probes. Non‐neoplastic gastric mucosa was obtained from 24 non‐cancer‐bearing stomachs at autopsy. MRs ranged from 0.0% to 77.2% (mean, 15.8%) for LOX , 0.0% to 45.8% (mean, 10.0%) for p16 , 0.0% to 83.8% (mean, 9.0%) for RUNX3 , and 0.0% to 46.1% (mean, 6.6%) for TIG1 , and significantly correlated with aging ( P < 0.01). The regression curves were: y = 0.013x 2 − 0.6184x + 4.0512, R 2 = 0.5728 ( P < 0.001) for LOX ; y = 0.0107x 2 − 0.6055x + 5.2943, R 2 = 0.7891 ( P < 0.00001) for p16 ; y = 0.0182x 2 − 1.2234x + 11.566, R 2 = 0.5595 ( P < 0.001) for RUNX3 ; and y = 0.0068x 2 − 0.3586x + 2.4306, R 2 = 0.4670 ( P < 0.01) for TIG1 . Thus, our present results are consistent with the notion that age‐related methylation is associated with cancer susceptibility in the elderly. Quantitative analysis of DNA methylation using DNA microarrays is a promising method for risk assessment in the development of gastric cancer. ( Cancer Sci 2006; 97: 1155–1158)