Skip to main content

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

Medical Oncology volume 36, Article number: 11 (2019) Cite this article

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.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Abbreviations

IDH:

Isocitrate dehydrogenase (IDH)

2HG:

2-Hydroxyglutarate

α-KG:

α-ketoglutarate

References

  1. Lehnert T. Multimodal therapy for squamous carcinoma of the oesophagus. Br J Surg. 1999;86(6):727–39.

    CAS  Article  Google Scholar 

  2. Katlic MR, Wilkins EW Jr, Grillo HC. Three decades of treatment of esophageal squamous carcinoma at the Massachusetts General Hospital. J Thorac Cardiovasc Surg. 1990;99(5):929–38.

    CAS  PubMed  Google Scholar 

  3. Flamen P, Van Cutsem E, Lerut A, et al. Positron emission tomography for assessment of the response to induction radiochemotherapy in locally advanced oesophageal cancer. Ann Oncol. 2002;13(3):361–8.

    CAS  Article  Google Scholar 

  4. Brucher BL, Weber W, Bauer M, et al. Neoadjuvant therapy of esophageal squamous cell carcinoma: response evaluation by positron emission tomography. Ann Surg. 2001;233(3):300–9.

    CAS  Article  Google Scholar 

  5. Downey RJ, Akhurst T, Ilson D, et al. Whole body 18FDG-PET and the response of esophageal cancer to induction therapy: results of a prospective trial. J Clin Oncol. 2003;21(3):428–32.

    Article  Google Scholar 

  6. Dang L, White DW, Gross S, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009;462(7274):739–44.

    CAS  Article  Google Scholar 

  7. Ward PS, Patel J, Wise DR, et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell. 2010;17(3):225–34.

    CAS  Article  Google Scholar 

  8. Gross S, Cairns RA, Minden MD, et al. Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. J Exp Med. 2010;207(2):339–44.

    CAS  Article  Google Scholar 

  9. Yan H, Parsons DW, Jin G, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009;360(8):765–73.

    CAS  Article  Google Scholar 

  10. Parsons DW, Jones S, Zhang X, et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008;321(5897):1807–12.

    CAS  Article  Google Scholar 

  11. Amary MF, Bacsi K, Maggiani F, et al. IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J Pathol. 2011;224(3):334–43.

    CAS  Article  Google Scholar 

  12. Borger DR, Tanabe KK, Fan KC, et al. Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping. Oncologist. 2012;17(1):72–9.

    CAS  Article  Google Scholar 

  13. Mardis ER, Ding L, Dooling DJ, et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med. 2009;361(11):1058–66.

    CAS  Article  Google Scholar 

  14. Marcucci G, Maharry K, Wu YZ, et al. IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol. 2010;28(14):2348–55.

    CAS  Article  Google Scholar 

  15. Cerami E, Gao J, Dogrusoz U, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2(5):401–4.

    Article  Google Scholar 

  16. Lu J, Xu L, Zou Y, et al. IDH1 p.R132 mutations may not be actively involved in the carcinogenesis of hepatocellular carcinoma. Med Sci Monit. 2014;20:247–54.

    CAS  Article  Google Scholar 

  17. Li WL, Xiao MS, Zhang DF, et al. Mutation and expression analysis of the IDH1, IDH2, DNMT3A, and MYD88 genes in colorectal cancer. Gene. 2014;546(2):263–70.

    CAS  Article  Google Scholar 

  18. Koivunen P, Lee S, Duncan CG, et al. Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature. 2012;483(7390):484–8.

    CAS  Article  Google Scholar 

  19. Chowdhury R, Yeoh KK, Tian YM, et al. The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep. 2011;12(5):463–9.

    CAS  Article  Google Scholar 

  20. Xu W, Yang H, Liu Y, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011;19(1):17–30.

    CAS  Article  Google Scholar 

  21. Iwagami S, Baba Y, Watanabe M, et al. Pyrosequencing assay to measure LINE-1 methylation level in esophageal squamous cell carcinoma. Ann Surg Oncol. 2012;19(8):2726–32.

    Article  Google Scholar 

  22. Iwagami S, Baba Y, Watanabe M, et al. LINE-1 hypomethylation is associated with a poor prognosis among patients with curatively resected esophageal squamous cell carcinoma. Ann Surg. 2013;257(3):449–55.

    Article  Google Scholar 

  23. Niibori-Nambu A, Midorikawa U, Mizuguchi S, et al. Glioma initiating cells form a differentiation niche via the induction of extracellular matrices and integrin alphaV. PLoS ONE. 2013;8(5):e59558.

    CAS  Article  Google Scholar 

  24. Matsunaga H, Futakuchi-Tsuchida A, Takahashi M, Ishikawa T, Tsuji M, Ando O. IDH1 and IDH2 have critical roles in 2-hydroxyglutarate production in D-2-hydroxyglutarate dehydrogenase depleted cells. Biochem Biophys Res Commun. 2012;423(3):553–6.

    CAS  Article  Google Scholar 

  25. Struys EA. 2-Hydroxyglutarate is not a metabolite; D-2-hydroxyglutarate and L-2-hydroxyglutarate are! Proc. Natl. Acad. Sci. USA. 2013;110(51):E4939.

    CAS  Article  Google Scholar 

  26. Kranendijk M, Struys EA, Salomons GS, Van der Knaap MS, Jakobs C. Progress in understanding 2-hydroxyglutaric acidurias. J Inherit Metab Dis. 2012;35(4):571–87.

    CAS  Article  Google Scholar 

  27. Cairns RA, Mak TW. Oncogenic isocitrate dehydrogenase mutations: mechanisms, models, and clinical opportunities. Cancer Discov. 2013;3(7):730–41.

    CAS  Article  Google Scholar 

  28. Fujii T, Khawaja MR, DiNardo CD, Atkins JT, Janku F. Targeting isocitrate dehydrogenase (IDH) in cancer. Discov Med. 2016;21(117):373–80.

    PubMed  Google Scholar 

  29. Zhao G, Winkler ME. A novel alpha-ketoglutarate reductase activity of the serA-encoded 3-phosphoglycerate dehydrogenase of Escherichia coli K-12 and its possible implications for human 2-hydroxyglutaric aciduria. J Bacteriol. 1996;178(1):232–9.

    CAS  Article  Google Scholar 

  30. Achouri Y, Noel G, Vertommen D, Rider MH, Veiga-Da-Cunha M, Van Schaftingen E. Identification of a dehydrogenase acting on D-2-hydroxyglutarate. Biochem J. 2004;381(Pt 1):35–42.

    CAS  Article  Google Scholar 

  31. Linster CL, Van Schaftingen E, Hanson AD. Metabolite damage and its repair or pre-emption. Nat Chem Biol. 2013;9(2):72–80.

    CAS  Article  Google Scholar 

  32. Intlekofer AM, Dematteo RG, Venneti S, et al. Hypoxia Induces Production of L-2-Hydroxyglutarate. Cell Metab. 2015;22(2):304–11.

    CAS  Article  Google Scholar 

  33. Rzem R, Van Schaftingen E, Veiga-da-Cunha M. The gene mutated in l-2-hydroxyglutaric aciduria encodes l-2-hydroxyglutarate dehydrogenase. Biochimie. 2006;88(1):113–6.

    CAS  Article  Google Scholar 

  34. Shim EH, Livi CB, Rakheja D, et al. L-2-Hydroxyglutarate: an epigenetic modifier and putative oncometabolite in renal cancer. Cancer Discov. 2014;4(11):1290–8.

    CAS  Article  Google Scholar 

Download references

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.

Author information

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

Authors
  1. Keisuke Miyake
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yoshifumi Baba
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takatsugu Ishimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yukiharu Hiyoshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Masaaki Iwatsuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yuji Miyamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Naoya Yoshida
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Masayuki Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yoko Ogata
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Megumi Nagayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Atit Silsirivanit
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Daiki Kobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Norie Araki
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Hideo Baba
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hideo Baba.

Ethics declarations

Conflict of interest

The authors have no conflict of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 19 KB)

Supplementary material 2 (DOCX 21 KB)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-018-1229-x

Keywords

  • Esophageal squamous cell carcinoma
  • Isocitrate dehydrogenase
  • 2-Hydroxyglutarate
  • α-Ketoglutaric acid
  • Oncometabolite