Circulating oncometabolite 2-hydroxyglutarate is a potential surrogate biomarker in patients with isocitrate dehydrogenase-mutant intrahepatic cholangiocarcinoma

Mutations in the IDH1 and IDH2 (IDH1/2) genes occur in approximately 20% of intrahepatic cholangiocarcinoma and lead to accumulation of 2-hydroxyglutarate (2HG) in the tumor tissue. However, it remains unknown whether IDH1/2 mutations can lead to high levels of 2HG circulating in the blood and wheth...

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Vydáno v:Clinical cancer research Ročník 20; číslo 7; s. 1884
Hlavní autoři: Borger, Darrell R, Goyal, Lipika, Yau, Thomas, Poon, Ronnie T, Ancukiewicz, Marek, Deshpande, Vikram, Christiani, David C, Liebman, Hannah M, Yang, Hua, Kim, Hyeryun, Yen, Katharine, Faris, Jason E, Iafrate, A John, Kwak, Eunice L, Clark, Jeffrey W, Allen, Jill N, Blaszkowsky, Lawrence S, Murphy, Janet E, Saha, Supriya K, Hong, Theodore S, Wo, Jennifer Y, Ferrone, Cristina R, Tanabe, Kenneth K, Bardeesy, Nabeel, Straley, Kimberly S, Agresta, Sam, Schenkein, David P, Ellisen, Leif W, Ryan, David P, Zhu, Andrew X
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 01.04.2014
Témata:
Adult
Aged
Bile Duct Neoplasms - blood
Bile Duct Neoplasms - genetics
Bile Duct Neoplasms - pathology
Bile Ducts, Intrahepatic - pathology
Biomarkers, Tumor - blood
Cholangiocarcinoma - blood
Cholangiocarcinoma - genetics
Cholangiocarcinoma - pathology
Female
Glutarates - blood
Humans
Isocitrate Dehydrogenase - blood
Isocitrate Dehydrogenase - genetics
Male
Middle Aged
Mutation
ISSN:1078-0432, 1557-3265, 1557-3265
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Popis
Shrnutí:Mutations in the IDH1 and IDH2 (IDH1/2) genes occur in approximately 20% of intrahepatic cholangiocarcinoma and lead to accumulation of 2-hydroxyglutarate (2HG) in the tumor tissue. However, it remains unknown whether IDH1/2 mutations can lead to high levels of 2HG circulating in the blood and whether serum 2HG can be used as a biomarker for IDH1/2 mutational status and tumor burden in intrahepatic cholangiocarcinoma. We initially measured serum 2HG concentration in blood samples collected from 31 patients with intrahepatic cholangiocarcinoma in a screening cohort. Findings were validated across 38 resected patients with intrahepatic cholangiocarcinoma from a second cohort with tumor volume measures. Circulating levels of 2HG were evaluated relative to IDH1/2 mutational status, tumor burden, and a number of clinical variables. Circulating levels of 2HG in the screening cohort were significantly elevated in patients with IDH1/2-mutant (median, 478 ng/mL) versus IDH1/2-wild-type (median, 118 ng/mL) tumors (P < 0.001). This significance was maintained in the validation cohort (343 ng/mL vs. 55 ng/mL, P < 0.0001) and levels of 2HG directly correlated with tumor burden in IDH1/2-mutant cases (P < 0.05). Serum 2HG levels ≥170 ng/mL could predict the presence of an IDH1/2 mutation with a sensitivity of 83% and a specificity of 90%. No differences were noted between the allelic variants IDH1 or IDH2 in regard to the levels of circulating 2HG. This study indicates that circulating 2HG may be a surrogate biomarker of IDH1 or IDH2 mutation status in intrahepatic cholangiocarcinoma and that circulating 2HG levels may correlate directly with tumor burden. Clin Cancer Res; 20(7); 1884-90. ©2014 AACR.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1078-0432
1557-3265
1557-3265
DOI:10.1158/1078-0432.CCR-13-2649