Elsevier

Human Pathology

Volume 43, Issue 10, October 2012, Pages 1552-1558
Human Pathology

Original contribution
Isocitrate dehydrogenase 1 and 2 mutations in cholangiocarcinoma

https://doi.org/10.1016/j.humpath.2011.12.007Get rights and content

Summary

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.

Introduction

Cholangiocarcinoma is a tumor arising by malignant transformation of biliary tract epithelium. Cholangiocarcinoma can present as an intrahepatic mass or as an obstructing tumor involving the intrahepatic and/or extrahepatic bile ducts [1], [2]. Curative treatments for early-stage cholangiocarcinoma include surgical resection or liver transplantation [2], [3], [4]. Unfortunately, the median survival of patients with cholangiocarcinoma is less than 24 months because most patients present with advanced-stage disease that is not amenable to surgical therapy [2], [3], [5]. Recent advances in imaging technologies and the clinical implementation of new molecular markers have modestly improved the ability to detect cholangiocarcinoma earlier [6], [7]. However, new biomarkers are still needed to detect most of the cholangiocarcinoma at earlier stages when treatments are beneficial. More effective traditional chemotherapeutic or targeted therapy strategies are also needed to treat patients with advanced stage disease [6].

Advancements in the understanding of cancer pathways have intensified the search for improved diagnostic, therapeutic, and prognostic molecular markers. Personalized cancer therapies are now being designed to target single proteins or complex pathways that regulate cellular proliferation, apoptosis, and/or migration [8]. Dysregulated metabolic enzymes also contribute to carcinogenesis and may provide novel therapeutic targets [9], [10], [11], [12], [13], [14], [15], [16]. Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are examples of metabolic enzymes that, when altered, promote carcinogenesis. IDH1 and IDH2 are NADP+-dependent enzymes encoded by IDH1 and IDH2 (IDH1/2) genes, which catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG) [9], [10], [11], [12], [13], [14], [15], [16]. Somatic mutations in IDH1/2 result in proteins with neomorphic enzyme activity that allows α-KG to be more effectively converted to 2-hydroxyglutarate (2-HG) [17], [18]. Increased levels of 2-HG are thought to promote carcinogenesis by competitively inhibiting enzymes that use α-KG as a cofactor [17], [18], [19], [20].

IDH1/2 gene mutations have been identified in 70% to 75% of low-grade gliomas and secondary glioblastomas [9], [21]. The identification of IDH1/2 mutations is clinically relevant because it can help stratify patients with brain cancer into molecular subtypes that predict improved overall survival, improved progression-free survival, and chemosensitivity [9], [22], [23], [24]. As a result, much research is now focused on the mechanism and therapeutic targets associated with IDH1/2 mutations and the role these genes have in the development of other types of cancer. IDH1/2 mutations have recently been identified in acute myeloid leukemia [25] and chondrosarcomas [26]. IDH1/2 mutations are rarely identified in other solid tumors including cancers from the lung, stomach, ovary, breast, colon, rectum, pancreas, prostate, liver, esophagus, bladder, cervix, skin, and kidney [9], [24]. To our knowledge, no one has reported whether or not IDH1/2 mutations exist in cholangiocarcinoma. We recently tested 94 cholangiocarcinomas for IDH1/2 mutations and identified 21 mutations in either the IDH1 or IDH2 gene. This finding is encouraging and opens the door for additional research assessing the role of IDH as a potential diagnostic, prognostic, and/or therapeutic marker for patients with cholangiocarcinoma.

Section snippets

Materials and methods

Formalin-fixed, paraffin-embedded (FFPE) tissue blocks and corresponding hematoxylin and eosin (H&E)–stained slides from 94 surgically resected primary cholangiocarcinomas (67 intrahepatic and 27 extrahepatic) were retrieved from Mayo Clinic tissue archives for IDH1 and IDH2 mutation analysis. The H&E slides were reviewed by a pathologist (S. E. K., J. Z., K. C. H.) to select tissue blocks with adequate tumor for subsequent DNA testing. Eight serial 10-μm sections were then cut from selected

Results

Sequence analysis of the 94 cholangiocarcinomas (67 intrahepatic and 27 extrahepatic) revealed 21 IDH mutations including 14 IDH1 mutations and 7 IDH2 mutations. Of the 21 mutations, 19 (90%) were in intrahepatic cholangiocarcinoma. The 14 IDH1 mutations included R132C (n = 9), R132S (n = 2), R132G (n = 2), and R132L (n = 1; Fig. 1). Of the 14 IDH1 mutations, 13 (93%) were in intrahepatic cholangiocarcinoma, whereas a single R132C mutation was identified in 1 extrahepatic (hilar)

Discussion

The results of this study show that IDH1 and IDH2 genes are mutated in cholangiocarcinoma. Overall, 22% of specimens evaluated in this study harbored an IDH1 or IDH2 mutation. We also determined that the histology of IDH1/2-mutated tumors differ from non–IDH1/2-mutated tumors in that the IDH1/2-mutated tumors are often poorly differentiated, organoid tumors with clear cell changes. Interestingly, IDH1/2 mutations were more frequently observed in intrahepatic cholangiocarcinoma compared with

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