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.

Metabolic Adaptation to Nutritional Stress in Human Colorectal Cancer

“…Therefore, the published GSE17536 database was used for screening of genes related to the prognosis of colorectal cancer patients, as described previously2324 (Supplementary Table S1). SLC25A13 was identified by analyses of the GLUD1 gene and other genes involved in amino acid metabolism in all possible combinations as pairs.…”

Elevated d -2-hydroxyglutarate during colitis drives progression to colorectal cancer

“…D2HG elevation due to mutations in IDH1 or IDH2 is frequent in glioma and acute myeloid leukemia and is emerging in some solid tumors ( 6 – 13 ). A recent mathematical analysis of CRC gene expression predicted that IDH1 and IDH2 expression is imbalanced in CRC and is associated with worse patient prognosis ( 25 ). Here, we show that IDH1 and IDH2 did not harbor common gene mutations that can drive elevated D2HG levels ( 6 , 7 ) during colitis or after advanced neoplasia formation in the AOM-DSS mouse model of CAC.…”

The importance of mitochondrial folate enzymes in human colorectal cancer

“…Prognosis of patients with colorectal cancer. The published GSE17536 database (http://www.ncbi.nlm.nih.gov/geo/query/ acc.cgi?acc=GSE17536), which included microarray data for 177 patients, was used to screen for genes related to the prognosis of patients with colorectal cancer, as described previously (15). The patient data were divided into two groups (low-and high-expression groups) based on the mean levels of SHMT2, MTHFD2 and ALDH1L2 expression.…”