title: Clinical aggressiveness of malignant gliomas is linked to augmented metabolism of amino acids.
abstract: Glutamine, glutamate, asparagine, and aspartate are involved in an enzyme-network that controls nitrogen metabolism. Branched-chain-amino-acid aminotransferase-1 (BCAT1) promotes proliferation of gliomas with wild-type IDH1 and is closely connected to the network. We hypothesized that metabolism of asparagine, glutamine, and branched-chain-amino-acids is associated with progression of malignant gliomas. Gene expression for asparagine synthetase (ASNS), glutaminase (GLS), and BCAT1 were analyzed in 164 gliomas from 156 patients [33-anaplastic gliomas (AG) and 131-glioblastomas (GBM), 64 of which were recurrent GBMs]. ASNS and GLS were twofold higher in GBMs versus AGs. BCAT1 was also higher in GBMs. ASNS expression was twofold higher in recurrent versus new GBMs. Five patients had serial samples: 4-showed higher ASNS and 3-higher GLS at recurrence. We analyzed grade and treatment in 4 groups: (1) low ASNS, GLS, and BCAT1 (n = 96); (2) low ASNS and GLS, but high BCAT1 (n = 26); (3) high ASNS or GLS, but low BCAT1 (n = 25); and (4) high ASNS or GLS and high BCAT1 (n = 17). Ninety-one  % of patients (29/32) with grade-III lesions were in group 1. In contrast, 95 % of patients (62/65) in groups 2-4 had GBMs. Treatment was similar in 4 groups (radiotherapy-80 %; temozolomide-30 %; other chemotherapy-50 %). High expression of ASNS, GLS, and BCAT1 were each associated with poor survival in the entire group. The combination of lower ASNS, GLS, and BCAT1 levels correlated with better survival for newly diagnosed GBMs (66 patients; P = 0.0039). Only tumors with lower enzymes showed improved outcome with temozolomide. IDH1(WT) gliomas had higher expression of these genes. Manipulation of amino acid metabolism in malignant gliomas may be further studied for therapeutics development.
authors.affiliation: Harbor-UCLA Medical Center/Los Angeles Biomedical Research Institute (LA BioMed), 1000 W. Carson Street, N25, Box 468, Torrance, CA, 90509, USA. epanosyan@labiomed.org.
authors.forename: Eduard H
authors.initials: EH
authors.lastname: Panosyan
authors.affiliation: Harbor-UCLA Medical Center/Los Angeles Biomedical Research Institute (LA BioMed), 1000 W. Carson Street, N25, Box 468, Torrance, CA, 90509, USA.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Lasky
authors.affiliation: Harbor-UCLA Medical Center/Los Angeles Biomedical Research Institute (LA BioMed), 1000 W. Carson Street, N25, Box 468, Torrance, CA, 90509, USA.
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Lin
authors.affiliation: UCLA Neuro-Oncology, 710 Westwood Plaza, Reed Bldg RM 1-230, Los Angeles, CA, 90095, USA.
authors.forename: Albert
authors.initials: A
authors.lastname: Lai
authors.affiliation: Harbor-UCLA Medical Center/Los Angeles Biomedical Research Institute (LA BioMed), 1000 W. Carson Street, N25, Box 468, Torrance, CA, 90509, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Hai
authors.affiliation: Harbor-UCLA Medical Center/Los Angeles Biomedical Research Institute (LA BioMed), 1000 W. Carson Street, N25, Box 468, Torrance, CA, 90509, USA.
authors.forename: Xiuqing
authors.initials: X
authors.lastname: Guo
authors.affiliation: SiliconMED North America Inc., 445 Park Avenue, 9th Floor, New York, NY, 10022, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Quinn
authors.affiliation: Clinical Genomics Center, David Geffen School of Medicine, University of California, Los Angeles, 90095, USA.
authors.forename: Stanley F
authors.initials: SF
authors.lastname: Nelson
authors.affiliation: UCLA Neuro-Oncology, 710 Westwood Plaza, Reed Bldg RM 1-230, Los Angeles, CA, 90095, USA.
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Cloughesy
authors.affiliation: UCLA Neuro-Oncology, 710 Westwood Plaza, Reed Bldg RM 1-230, Los Angeles, CA, 90095, USA.
authors.forename: P Leia
authors.initials: PL
authors.lastname: Nghiemphu
mesh_terms: D000596:Amino Acids / Q000235:genetics / Q000378:metabolism*; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000596:Amino Acids
keywords: Asparagine; Branched chain amino acids; Glioma; Glutamine; Metabolism