101. Abstract 4583: Computational analysis predicts unbalanced IDH1/IDH2 expression associate with 2-HG-inactivating beta-oxygenation pathway in colorectal cancer
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Takahito Fukusumi, Kenta Tsunekuni, Masaki Mori, Naohiro Nishida, Yuichiro Doki, Hideshi Ishii, Koichi Kawamoto, Hugh Colvin, Jun Koseki, and Masamitsu Konno
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Cancer Research ,IDH1 ,Colorectal cancer ,Cancer ,Biology ,Bioinformatics ,medicine.disease ,IDH2 ,Breast cancer ,Isocitrate dehydrogenase ,Oncology ,Gene expression ,Cancer research ,medicine ,Gene - Abstract
Bioinformatics and computational modeling offer innovative approaches to investigate cancer metabolism and predict the secondary and tertiary cellular responses. Dysregulation of metabolism has also been implicated in the pathophysiology of cancer. A significant proportion of patients with glioblastoma and hematological malignancies harbor the mutated forms of the oxidative phosphorylation (OxPhos) enzymes, isocitrate dehydrogenase (IDH) 1 or 2. The mutated forms of IDH1 and IDH2 produce an oncogenic metabolite, D-2-hydroxyglutarate (D2HG). A recent study of breast cancer patients showed that D2HG can also be produced in the absence of mutated IDH, through an alternative route involving over-activated MYC signaling. We developed a novel methodology to computationally analyze gene expression in colorectal cancer, and identified novel sets of genes that are associated with patient survival. The study of OxPhos-related genes revealed that an imbalance between the expression of IDH1 and IDH2, defined as overexpression of one isoform in relation to the other, was associated with worse prognosis in colorectal cancer patients. This effect was further accentuated by reduced expression of the beta-oxygenation enzyme, 3-D-hydroxyacyl-CoA dehydratase (HCDH) 4, which has been reported to contribute to metabolism of intracellular D2HG. The present computational analysis revealed a novel and potential mechanism of colorectal cancer development, through over-production of D2HG when there is an imbalance between IDH1 and IDH2 expression, resulting in decreased clearance of D2HG when the beta-oxidization pathway is diminished. Additional validation analysis with other gene expression dataset has resulted in that IDH1/2 imbalanced expression had a shorter DFS compared with balanced expression. Altogether, these findings provide a strong rationale for studying this mechanism further in order to discover novel therapeutic targets for the treatment of colorectal cancer. Citation Format: Jun Koseki, Hugh Colvin, Takahito Fukusumi, Naohiro Nishida, Masamitsu Konno, Koichi Kawamoto, Kenta Tsunekuni, Yuichiro Doki, Masaki Mori, Hideshi Ishii. Computational analysis predicts unbalanced IDH1/IDH2 expression associate with 2-HG-inactivating beta-oxygenation pathway in colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4583. doi:10.1158/1538-7445.AM2015-4583 more...
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- 2015
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