Abstract 4315: Colorectal cancer epigenomic landscape
| Autor: | Kunal Rai, Elias Orouji, Ayush Raman, Mayura Dhamdhere, Ming Tang |
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| Rok vydání: | 2018 |
| Předmět: | |
| Zdroj: | Cancer Research. 78:4315-4315 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/1538-7445.am2018-4315 |
| Popis: | Cancer cells utilize genetic and epigenetic aberrations for their excessive growth. Although we have sufficient understanding of the genomic alterations in colorectal cancer, we have incomplete knowledge of epigenomic aberrations and their impact on tumor growth. In order to comprehensively define the epigenetic patterns specific to colorectal cancer, we generated profiles for 6 histone modification marks, including H3K4me1 (enhancer), H3K27Ac (active enhancer), H3K9me3 (heterochromatin), H3K27me3 (polycomb repression), H3K79me2 (transcription) and H3K4me3 (promoter), using a high-throughput ChIP-Seq methodology developed in house applicable to frozen tumors. Chromatin state transitions specifically pointed to drastic changes in enhancer patterns, consistent with some prior studies. Furthermore, using similarity network fusion (SNF) we identified the best singular mark and are currently developing a tool to identify combinatorial chromatin states that could most efficiently distinguish and eventually predict CRC from normal colon. In a more detailed investigation into patterns of active enhancers using normal colon, adenomas and colorectal cancers, we identified specific changes in enhancers from normal tissue to these neoplastic lesions. Importantly, we noted gains of enhancers in a large number of genomic loci in colon cancer compared to adjacent normal tissues. These enhancers are enriched in important signaling components including Notch, Wnt, and stem cell regulators. We specifically noted changes in enhancer regions in the proximity of ASCL2 (intestinal cancer stem cell gene), SALL4 (early pluripotency marker) as well as FZD10 and CTNNB1 (Wnt signaling). A preliminary Cas9-based deletion study suggested these enhancers to be functional in regulating gene expression, and currently its effect on cell proliferation and other cancer properties is being investigated. Further, we reasoned that blocking aberrantly gained enhancers using BRD inhibitor in combination with pathway inhibitors could be a useful strategy in this cancer. Our data supported this hypothesis, and we are currently performing a systematic study to identify most effective combinations. In summary, we have identified aberrant enhancer gains as a major feature of colorectal cancer and propose this to be utilized as a therapeutic approach. Citation Format: Elias Orouji, Ayush Raman, Ming Tang, Mayura Dhamdhere, Kunal Rai. Colorectal cancer epigenomic landscape [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4315. |
| Databáze: | OpenAIRE |
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