Isocitrate dehydrogenase 1 and 2 mutations in cholangiocarcinoma

Benjamin R. Kipp, Jesse S. Voss, Sarah E. Kerr, Emily G. Barr Fritcher, Rondell Graham, Lizhi Zhang, W Edward Jr. Highsmith, Jun Zhang, Lewis Rowland Roberts, Gregory James Gores, Kevin C. Halling

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Abstract

Somatic mutations in isocitrate dehydrogenase 1 and 2 genes are common in gliomas and help stratify patients with brain cancer into histologic and molecular subtypes. However, these mutations are considered rare in other solid tumors. The aims of this study were to determine the frequency of isocitrate dehydrogenase 1 and 2 mutations in cholangiocarcinoma and to assess histopathologic differences between specimens with and without an isocitrate dehydrogenase mutation. We sequenced 94 formalin-fixed, paraffin-embedded cholangiocarcinoma (67 intrahepatic and 27 extrahepatic) assessing for isocitrate dehydrogenase 1 (codon 132) and isocitrate dehydrogenase 2 (codons 140 and 172) mutations. Multiple histopathologic characteristics were also evaluated and compared with isocitrate dehydrogenase 1/2 mutation status. Of the 94 evaluated specimens, 21 (22%) had a mutation including 14 isocitrate dehydrogenase 1 and 7 isocitrate dehydrogenase 2 mutations. Isocitrate dehydrogenase mutations were more frequently observed in intrahepatic cholangiocarcinoma than in extrahepatic cholangiocarcinoma (28% versus 7%, respectively; P =.030). The 14 isocitrate dehydrogenase 1 mutations were R132C (n = 9), R132S (n = 2), R132G (n = 2), and R132L (n = 1). The 7 isocitrate dehydrogenase 2 mutations were R172K (n = 5), R172M (n = 1), and R172G (n = 1). Isocitrate dehydrogenase mutations were more frequently observed in tumors with clear cell change (P <.001) and poorly differentiated histology (P =.012). The results of this study show for the first time that isocitrate dehydrogenase 1 and 2 genes are mutated in cholangiocarcinoma. The results of this study are encouraging because it identifies a new potential target for genotype-directed therapeutic trials and may represent a potential biomarker for earlier detection of cholangiocarcinoma in a subset of cases.

Original languageEnglish (US)
Pages (from-to)1552-1558
Number of pages7
JournalHuman Pathology
Volume43
Issue number10
DOIs
StatePublished - Oct 2012

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Keywords

  • 2-hydroxyglutarate
  • Bile duct
  • Biliary tract
  • Cholangiocarcinoma
  • Isocitrate dehydrogenase

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Kipp, B. R., Voss, J. S., Kerr, S. E., Barr Fritcher, E. G., Graham, R., Zhang, L., Highsmith, W. E. J., Zhang, J., Roberts, L. R., Gores, G. J., & Halling, K. C. (2012). Isocitrate dehydrogenase 1 and 2 mutations in cholangiocarcinoma. Human Pathology, 43(10), 1552-1558. https://doi.org/10.1016/j.humpath.2011.12.007