Genotype-Specific Differences in the Tumor Metabolite Profile of Pheochromocytoma and Paraganglioma Using Untargeted and Targeted Metabolomics

被引：30

作者：

Rao, J. U. ^{[1
,2
]}

Engelke, U. F. H. ^{[1
]}

Sweep, F. C. G. J. ^{[1
]}

Pacak, K. ^{[3
]}

Kusters, B. ^{[4
,9
]}

Goudswaard, A. G. ^{[1
]}

Hermus, A. R. M. M. ^{[2
]}

Mensenkamp, A. R. ^{[5
]}

Eisenhofer, G. ^{[6
,7
]}

Qin, N. ^{[6
,7
]}

Richter, S. ^{[6
,7
]}

Kunst, H. P. M. ^{[8
]}

Timmers, H. J. L. M. ^{[2
]}

Wevers, R. A. ^{[1
]}

机构：

[1] Radboud Univ Nijmegen, Lab Genet Endocrine & Metab Dis, Dept Lab Med, Med Ctr, NL-6525 ED Nijmegen, Netherlands

[2] Radboud Univ Nijmegen, Endocrinol Sect, Dept Internal Med, Med Ctr, NL-6525 ED Nijmegen, Netherlands

[3] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA

[4] Radboud Univ Nijmegen, Med Ctr, Dept Pathol, NL-6525 ED Nijmegen, Netherlands

[5] Radboud Univ Nijmegen, Med Ctr, Dept Genet, NL-6525 ED Nijmegen, Netherlands

[6] Univ Hosp Carl Gustav Carus, Dept Med, Dresden, Germany

[7] Univ Hosp Carl Gustav Carus, Inst Clin Chem & Lab Med, Dresden, Germany

[8] Radboud Univ Nijmegen, Dept Otolaryngol, NL-6525 ED Nijmegen, Netherlands

[9] Maastricht Univ, Med Ctr, Dept Pathol, NL-6200 MD Maastricht, Netherlands

来源：

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM | 2015年 / 100卷 / 02期

关键词：

PURINE METABOLISM; IN-VIVO; H-1-NMR;

D O I：

10.1210/jc.2014-2138

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Context and Objective: Pheochromocytomas and paragangliomas (PGLs) are neuroendocrine tumors of sympathetic or parasympathetic paraganglia. Nearly 40% of PGLs are caused by germline mutations. The present study investigated the effect of genetic alterations on metabolic networks in PGLs. Design: Homogenates of 32 sporadic PGLs and 48 PGLs from patients with mutations in SDHB, SDHD, SDHAF-2, VHL, RET, and NF-1 were subjected to proton (H-1) nuclear magnetic resonance (NMR) spectroscopy at 500 MHz for untargeted and HPLC tandem mass spectrometry for targeted metabolite profiling. Results: 1H NMR spectroscopy identified 28 metabolites in PGLs of which 12 showed genotype-specific differences. Part of these results published earlier reported low complex II activity (P < .0001) and low ATP/ADP/AMP content (P < .001) in SDH-related PGLs compared with sporadics and PGLs of other genotypes. Extending these results, low levels of N-acetylaspartic acid (NAA; P < .05) in SDH tumors and creatine (P < .05) in VHL tumors were observed compared with sporadics and other genotypes. Positive correlation was observed between NAA and ATP/ADP/AMP content (P < .001) and NAA and complex II activity (P < .0001) of PGLs. Targeted purine analysis in PGLs showed low adenine in cluster 1 compared with cluster 2 tumors (SDH P < .0001; VHL P < .05) whereas lower levels (P < .05) of guanosine and hypoxanthine were observed in RET tumors compared with SDH tumors. Principal component analysis (PCA) of metabolites could distinguish PGLs of different genotypes. Conclusions: The present study gives a comprehensive picture of alterations in energy metabolism in SDH- and VHL-related PGLs and establishes the interrelationship of energy metabolism and amino acid and purine metabolism in PGLs.

引用

页码：E214 / E222

页数：9

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