title: Mathematical analysis predicts imbalanced IDH1/2 expression associates with 2-HG-inactivating β-oxygenation pathway in colorectal cancer.
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 (CRC), 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 CRC patients. This effect was further accentuated by reduced expression of the β-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 CRC development, through over-production of D2HG when there is an imbalance between IDH1 and IDH2 expression, resulting in decreased clearance of D2HG when the β-oxidization pathway is diminished. Additional validation analysis with another gene expression dataset resulted in IDH1/2 imbalanced expression with 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 CRC.
authors.affiliation: Department of Cancer Profiling Discovery, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Koseki
authors.affiliation: Department of Cancer Profiling Discovery, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
authors.forename: Hugh
authors.initials: H
authors.lastname: Colvin
authors.affiliation: Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
authors.forename: Takahito
authors.initials: T
authors.lastname: Fukusumi
authors.affiliation: Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Nishida
authors.affiliation: Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Konno
authors.affiliation: Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Kawamoto
authors.affiliation: Department of Cancer Profiling Discovery, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Tsunekuni
authors.affiliation: Faculty of Mathematics, Kyushu University, Fukuoka 812-8581, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Matsui
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Doki
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.affiliation: Department of Cancer Profiling Discovery, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
authors.forename: Hideshi
authors.initials: H
authors.lastname: Ishii
mesh_terms: D019069:Cell Respiration / Q000235:genetics; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D019295:Computational Biology / Q000379:methods*; D020869:Gene Expression Profiling / Q000706:statistics & numerical data; D015972:Gene Expression Regulation, Neoplastic; D056726:Genetic Association Studies / Q000706:statistics & numerical data; D005977:Glutarates / Q000378:metabolism*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D053858:Metabolic Networks and Pathways / Q000235:genetics; D008962:Models, Theoretical; D010085:Oxidative Phosphorylation; D011379:Prognosis; D016019:Survival Analysis
chemical_list: D005977:Glutarates; C019417:alpha-hydroxyglutarate; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human