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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Authors' Affiliations: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston; Agios Pharmaceuticals, Cambridge, Massachusetts; and Queen Mary Hospital, The University of Hong Kong, Hong Kong, China.
Darrell R
DR
Borger
Lipika
L
Goyal
Thomas
T
Yau
Ronnie T
RT
Poon
Marek
M
Ancukiewicz
Vikram
V
Deshpande
David C
DC
Christiani
Hannah M
HM
Liebman
Hua
H
Yang
Hyeryun
H
Kim
Katharine
K
Yen
Jason E
JE
Faris
A John
AJ
Iafrate
Eunice L
EL
Kwak
Jeffrey W
JW
Clark
Jill N
JN
Allen
Lawrence S
LS
Blaszkowsky
Janet E
JE
Murphy
Supriya K
SK
Saha
Theodore S
TS
Hong
Jennifer Y
JY
Wo
Cristina R
CR
Ferrone
Kenneth K
KK
Tanabe
Nabeel
N
Bardeesy
Kimberly S
KS
Straley
Sam
S
Agresta
David P
DP
Schenkein
Leif W
LW
Ellisen
David P
DP
Ryan
Andrew X
AX
Zhu
D000328:Adult; D000368:Aged; D001650:Bile Duct Neoplasms / Q000097:blood / Q000235:genetics* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000473:pathology; D014408:Biomarkers, Tumor / Q000097:blood*; D018281:Cholangiocarcinoma / Q000097:blood / Q000235:genetics* / Q000473:pathology; D005260:Female; D005977:Glutarates / Q000097:blood*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000097:blood / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation
D014408:Biomarkers, Tumor; D005977:Glutarates; C019417:alpha-hydroxyglutarate; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human