Isocitrate dehydrogenase gene mutations and 2-hydroxyglutarate accumulation in esophageal squamous cell carcinoma

Journal Article · Tue Jan 15 04:00:00 EST 2019 · Medical Oncology (Online)

DOI:https://doi.org/10.1007/S12032-018-1229-X· OSTI ID:22938457

Miyake, Keisuke; Baba, Yoshifumi; Ishimoto, Takatsugu; Hiyoshi, Yukiharu; Iwatsuki, Masaaki; Miyamoto, Yuji; Yoshida, Naoya ^[1]; Watanabe, Masayuki ^[2]; Ogata, Yoko ^[1]; Nagayama, Megumi; Silsirivanit, Atit; Kobayashi, Daiki; Araki, Norie ^[3]; Baba, Hideo ^[1]

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1. Kumamoto University, Department of Gastroenterological Surgery, Graduate School of Medical Science (Japan)
2. Japanese Foundation for Cancer Research, Department of Gastroenterological Surgery, Cancer Institute Hospital (Japan)
3. Kumamoto University, Department of Tumor Genetics and Biology, Graduate School of Medical Sciences (Japan)

Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are key metabolic enzymes that convert isocitrate to α-ketoglutarate. Somatic point mutations in IDH1/2 confer a gain-of-function in cancer cells, resulting in overproduction of an oncometabolite, 2-hydroxyglutarate (2HG). 2HG interferes with cellular metabolism and epigenetic regulation, contributing to oncogenesis. Given that IDH1 and IDH2 are attracting attention as promising therapeutic targets, better evaluation of the incidence of IDH1 and IDH2 mutations and 2HG level in human cancers is clinically important. This is the first study to assess their incidence in esophageal squamous cell carcinomas (ESCCs). First, we established pyrosequencing assays for IDH1 and IDH2 mutations and revealed that these mutations were absent in 10 ESCC cell lines and 96 ESCC tissues. Second, utilizing IDH1 and IDH2 overexpression vectors, we demonstrated that LC-MS/MS assays can accurately evaluate 2HG level and found that some ESCC cases presented a high level of 2HG. In conclusion, IDH1 or IDH2 mutations play a limited role in the development of ESCC. 2HG is potentially synthesized to high levels in the absence of IDH1 and IDH2 mutations, and this may correlate with progression of ESCCs.

• OSTI ID: 22938457
• Journal Information: Medical Oncology (Online), Journal Name: Medical Oncology (Online) Journal Issue: 1 Vol. 36; ISSN 1559-131X
• Country of Publication: United States
• Language: English

Related Subjects

62 RADIOLOGY AND NUCLEAR MEDICINE
CARCINOMAS
ESOPHAGUS
GENE MUTATIONS
METABOLISM
OXIDOREDUCTASES