Abstract 5378: Genes involved in development and differentiation are commonly methylated in cancers derived from multiple organs: A single-institutional methylome analysis using 1007 tissue specimens
Authors: Ohara Kentaro , Arai Eri , Takahashi Yoriko , Ito Nanako , Shibuya Ayako , Tsuta Koji , Kushima Ryoji , Tsuda Hitoshi , Ojima Hidenori , Fujimoto Hiroyuki , Watanabe Shun-ichi , Katai Hitoshi , Kinoshita Takayuki , Shibata Tatsuhiro , Kohno Takashi , Kanai Yae 
Published: July 2017

Aim: The aim of this study was to clarify the significance of DNA methylation alterations shared by cancers derived from multiple organs.

Background: Little is known about DNA methylation alterations during carcinogenesis shared by various organs. In this single-institutional study, consistency of sample quality, diagnostic criteria and technical platforms may be advantageous for providing an overall view of DNA methylation profiles of cancers arising in multiple organs.

Methods: We analyzed single-institutional methylome data by Infinium HumanMethylation27 or HumanMethylation450 BeadChip (Illumina) for 1,007 samples of non-cancerous tissue (N) and corresponding cancerous tissue (T) obtained from the lung, stomach, kidney, breast and liver.

Results: 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. We identified 2,636, 2,209, 1,915, 2,914 and 5,665 probes that were aberrantly methylated in lung adenocarcinomas, gastric adenocarcinomas, clear cell renal cell carcinomas, breast cancers (e.g. invasive ductal carcinomas, ductal carcinomas in situ and invasive lobular carcinomas) and hepatocellular carcinomas, respectively, in comparison with the corresponding N samples. When we examined pairs of organs, only 6.9% (between stomach cancers and kidney cancers) to 35.4% (between lung cancers and breast cancers) of aberrantly methylated probes were shared between cancers of any two organs, indicating that the majority of DNA methylation alterations were diverse among multiple organs. In contrast to such organ and/or carcinogenetic factor-specificity of DNA methylation profiles, when compared to 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.

Conclusion: 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.

Citation Format: 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. Genes involved in development and differentiation are commonly methylated in cancers derived from multiple organs: A single-institutional methylome analysis using 1007 tissue specimens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5378. doi:10.1158/1538-7445.AM2017-5378