TY - JOUR
T1 - Genes involved in development and differentiation are commonly methylated in cancers derived from multiple organs
T2 - A single-institutional methylome analysis using 1007 tissue specimens
AU - Ohara, Kentaro
AU - Arai, Eri
AU - Takahashi, Yoriko
AU - Ito, Nanako
AU - Shibuya, Ayako
AU - Tsuta, Koji
AU - Kushima, Ryoji
AU - Tsuda, Hitoshi
AU - Ojima, Hidenori
AU - Fujimoto, Hiroyuki
AU - Watanabe, Shun ichi
AU - Katai, Hitoshi
AU - Kinoshita, Takayuki
AU - Shibata, Tatsuhiro
AU - Kohno, Takashi
AU - Kanai, Yae
N1 - Publisher Copyright:
© The Author 2017.
PY - 2017/3/1
Y1 - 2017/3/1
N2 - The aim of this study was to clarify the significance of DNA methylation alterations shared by cancers derived from multiple organs. We analyzed single-institutional methylome data by single-CpG-resolution Infinium assay for 1007 samples of non-cancerous tissue (N) and corresponding cancerous tissue (T) obtained from lung, stomach, kidney, breast and liver. Principal component analysis revealed that N samples of each organ showed distinct DNA methylation profiles, DNA methylation profiles of N samples of each organ being inherited by the corresponding T samples and DNA methylation profiles of T samples being more similar to those of N samples in the same organ than those of T samples in other organs. In contrast to such organ and/or carcinogenetic factor-specificity of DNA methylation profiles, when compared with the corresponding N samples, 231 genes commonly showed DNA hypermethylation in T samples in four or more organs. Gene ontology enrichment analysis showed that such commonly methylated genes were enriched among "transcriptional factors" participating in development and/or differentiation, which reportedly show bivalent histone modification in embryonic stem cells. Pyrosequencing and quantitative reverse transcription-PCR revealed an inverse correlation between DNA methylation levels and mRNA expression levels of representative commonly methylated genes, such as ALX1, ATP8A2, CR1 and EFCAB1, in tissue samples. These data suggest that disruption of the differentiated state of precancerous cells via alterations of expression, independent of differences in organs and/or carcinogenetic factors, may be a common feature of DNA methylation alterations during carcinogenesis in multiple organs.
AB - The aim of this study was to clarify the significance of DNA methylation alterations shared by cancers derived from multiple organs. We analyzed single-institutional methylome data by single-CpG-resolution Infinium assay for 1007 samples of non-cancerous tissue (N) and corresponding cancerous tissue (T) obtained from lung, stomach, kidney, breast and liver. Principal component analysis revealed that N samples of each organ showed distinct DNA methylation profiles, DNA methylation profiles of N samples of each organ being inherited by the corresponding T samples and DNA methylation profiles of T samples being more similar to those of N samples in the same organ than those of T samples in other organs. In contrast to such organ and/or carcinogenetic factor-specificity of DNA methylation profiles, when compared with the corresponding N samples, 231 genes commonly showed DNA hypermethylation in T samples in four or more organs. Gene ontology enrichment analysis showed that such commonly methylated genes were enriched among "transcriptional factors" participating in development and/or differentiation, which reportedly show bivalent histone modification in embryonic stem cells. Pyrosequencing and quantitative reverse transcription-PCR revealed an inverse correlation between DNA methylation levels and mRNA expression levels of representative commonly methylated genes, such as ALX1, ATP8A2, CR1 and EFCAB1, in tissue samples. These data suggest that disruption of the differentiated state of precancerous cells via alterations of expression, independent of differences in organs and/or carcinogenetic factors, may be a common feature of DNA methylation alterations during carcinogenesis in multiple organs.
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U2 - 10.1093/carcin/bgw209
DO - 10.1093/carcin/bgw209
M3 - Article
C2 - 28069692
AN - SCOPUS:85028539811
SN - 0143-3334
VL - 38
SP - 241
EP - 251
JO - Carcinogenesis
JF - Carcinogenesis
IS - 3
ER -
