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

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Abstract

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.

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Abbreviations

IDH:

Isocitrate dehydrogenase (IDH)

2HG:

2-Hydroxyglutarate

α-KG:

α-ketoglutarate

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Acknowledgements

We thank Yuko Taniguchi and Naomi Yokoyama for technical assistance. This work was supported in part by a Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Scientific Research, Grant Number 17H04273.

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Authors and Affiliations

  1. Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan

    Keisuke Miyake, Yoshifumi Baba, Takatsugu Ishimoto, Yukiharu Hiyoshi, Masaaki Iwatsuki, Yuji Miyamoto, Naoya Yoshida, Yoko Ogata & Hideo Baba

  2. Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan

    Masayuki Watanabe

  3. Department of Tumor Genetics and Biology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan

    Megumi Nagayama, Atit Silsirivanit, Daiki Kobayashi & Norie Araki

  4. Department of Biochemistry, Faculty of Medicine, Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen, 40002, Thailand

    Atit Silsirivanit

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  1. Keisuke Miyake
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  2. Yoshifumi Baba
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Correspondence to Hideo Baba.

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Miyake, K., Baba, Y., Ishimoto, T. et al. Isocitrate dehydrogenase gene mutations and 2-hydroxyglutarate accumulation in esophageal squamous cell carcinoma. Med Oncol 36, 11 (2019). https://doi.org/10.1007/s12032-018-1229-x

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