Genes involved in development and differentiation are commonly methylated in cancers derived from multiple organs: A single-institutional methylome analysis using 1007 tissue specimens

Kentaro Ohara, Eri Arai, Yoriko Takahashi, Nanako Ito, Ayako Shibuya, Koji Tsuta, Ryoji Kushima, Hitoshi Tsuda, Hidenori Ojima, Hiroyuki Fujimoto, Shun ichi Watanabe, Hitoshi Katai, Takayuki Kinoshita, Tatsuhiro Shibata, Takashi Kohno, Yae Kanai

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Abstract

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.

Original languageEnglish
Pages (from-to)241-251
Number of pages11
JournalCarcinogenesis
Volume38
Issue number3
DOIs
Publication statusPublished - 2017 Mar 1

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ASJC Scopus subject areas

  • Cancer Research

Cite this

Ohara, K., Arai, E., Takahashi, Y., Ito, N., Shibuya, A., Tsuta, K., Kushima, R., Tsuda, H., Ojima, H., Fujimoto, H., Watanabe, S. I., Katai, H., Kinoshita, T., Shibata, T., Kohno, T., & Kanai, Y. (2017). Genes involved in development and differentiation are commonly methylated in cancers derived from multiple organs: A single-institutional methylome analysis using 1007 tissue specimens. Carcinogenesis, 38(3), 241-251. https://doi.org/10.1093/carcin/bgw209