Plasma Metabolome Profiling for the Diagnosis of Catecholamine Producing Tumors

März, Juliane; Kurlbaum, Max; Roche-Lancaster, Oisin; Deutschbein, Timo; Peitzsch, Mirko; Prehn, Cornelia; Weismann, Dirk; Robledo, Mercedes; Adamski, Jerzy; Fassnacht, Martin; Kunz, Meik; Kroiß, Matthias

doi:10.3389/fendo.2021.722656

Cited by 9 publications

(6 citation statements)

References 44 publications

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“…Two recent studies of plasma from patients with PPGL used targeted LC-MS/MS with an extended panel of over 100 metabolites. Unfortunately, low patient numbers and high inter-individual differences may have prevented the identification of suitable signatures for PPGL diagnosis, but it was demonstrated that the metabolic aberrations that occurred with PPGL were reversed after surgery (Marz et al, 2021, Erlic et al, 2019.…”

Section: Metabolome-guided Diagnostics and Future Directionsmentioning

confidence: 99%

Metabolomics in paraganglioma: applications and perspectives from genetics to therapy

Richter

Garrett

Bechmann

et al. 2023

Endocrine-Related Cancer

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Metabolites represent the highest layer of biological information. Their diverse chemical nature enables networks of chemical reactions that are critical for maintaining life by providing energy and building blocks. Quantification by targeted and untargeted analytical methods using either mass spectrometry or nuclear magnetic resonance spectroscopy has been applied to pheochromocytoma/paraganglioma (PPGL) with the long-term goal to improve diagnosis and therapy. PPGLs have unique features that provide useful biomarkers and clues for targeted treatments. Firstly, high production rates of catecholamines and metanephrines allow for specific and sensitive detection of the disease in plasma or urine. Secondly, PPGLs are associated with heritable pathogenic variants (PV) in around 40% of cases, many of which occur in genes encoding enzymes, such as succinate dehydrogenase (SDH) and fumarate hydratase (FH). These genetic aberrations lead to overproduction of oncometabolites succinate or fumarate, respectively, and are detectable in tumors and blood. Such metabolic dysregulation can be exploited diagnostically, with the aim to ensure appropriate interpretation of gene variants, especially those with unknown significance, and facilitate early tumor detection through regular patient follow-up. Furthermore, SDHx and FH PV alter cellular pathways, including DNA hypermethylation, hypoxia signaling, redox homeostasis, DNA repair, calcium signaling, kinase cascades, and central carbon metabolism. Pharmacological interventions targeted towards such features have the potential to uncover treatments against metastatic PPGL, around 50% of which are associated with germline PV in SDHx. With the availability of omics technologies for all layers of biological information personalized diagnostics and treatment is in close reach.

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Section: Metabolome-guided Diagnostics and Future Directionsmentioning

confidence: 99%

Metabolomics in paraganglioma: applications and perspectives from genetics to therapy

Richter

Garrett

Bechmann

et al. 2023

Endocrine-Related Cancer

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“…No biochemical pathway could be identified with these thirteen metabolites via principal component analysis (see Supplementary Figure S1). At 1-year follow-up patients of the RYGB-surgery group achieved a significant weight loss of −34.3% (BMI 49.1 [46][47][48][49][50][51] kg/m 2 vs. 32 [30][31][32][33] kg/m 2 , p < 0.01) as well as a significant improvement in IR measured by the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) (5.1 [4.6-6.1] vs. 1.4 [1-1.9], p < 0.01). In contrast, a non-significant weight loss of −1.2% (BMI 48.2 [45][46][47][48][49][50] vs. 47.5 [45][46][47][48][49] kg/m 2 , p = 0.07) was detected in the LS group one year after randomization.…”

Section: Participants From the Was Trialmentioning

confidence: 99%

“…The Biocrates AbsoluteIDQ p180 kit simultaneously identifies and quantifies 188 metabolites including 21 amino acids, 21 biogenic amines, 40 acylcarnitines, 15 sphingolipids, 14 lysophosphatidylcholines, 76 phosphatidylcholines and 1 hexose (>90% glucose). The assay-specific procedures have been described in detail elsewhere [49,50].…”

Section: Targeted Metabolomicsmentioning

confidence: 99%

Changes in Plasma Metabolomic Profile Following Bariatric Surgery, Lifestyle Intervention or Diet Restriction—Insights from Human and Rat Studies

Balonov

Kurlbaum

Koschker³

et al. 2023

IJMS

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Although bariatric surgery is known to change the metabolome, it is unclear if this is specific for the intervention or a consequence of the induced bodyweight loss. As the weight loss after Roux-en-Y Gastric Bypass (RYGB) can hardly be mimicked with an evenly effective diet in humans, translational research efforts might be helpful. A group of 188 plasma metabolites of 46 patients from the randomized controlled Würzburg Adipositas Study (WAS) and from RYGB-treated rats (n = 6) as well as body-weight-matched controls (n = 7) were measured using liquid chromatography tandem mass spectrometry. WAS participants were randomized into intensive lifestyle modification (LS, n = 24) or RYGB (OP, n = 22). In patients in the WAS cohort, only bariatric surgery achieved a sustained weight loss (BMI −34.3% (OP) vs. −1.2% (LS), p ≤ 0.01). An explicit shift in the metabolomic profile was found in 57 metabolites in the human cohort and in 62 metabolites in the rodent model. Significantly higher levels of sphingolipids and lecithins were detected in both surgical groups but not in the conservatively treated human and animal groups. RYGB leads to a characteristic metabolomic profile, which differs distinctly from that following non-surgical intervention. Analysis of the human and rat data revealed that RYGB induces specific changes in the metabolome independent of weight loss.

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“…Recently, plasma metabolomics by mass spectrometry (MS) proved useful for the quantification of predetermined tumor markers and for the identification of cancer-associated metabolomic profiles [ 22 – 24 ]. In patients affected with chromaffin PGLs a targeted metabolomic approach demonstrated changes in the concentration of specific amino acids (ornithine, sarcosine, tyrosine, creatinine, histidine, threonine) and lysophosphatidylcholine, that correlated with the results of the urine catecholamines and plasma free metanephrines tests [ 25 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

Targeted metabolomics detects a putatively diagnostic signature in plasma and dried blood spots from head and neck paraganglioma patients

Fabritiis

Valentinuzzi

Piras³

et al. 2023

Oncogenesis

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Head and neck paragangliomas (HNPGLs), rare chemoresistant tumors curable only with surgery, are strongly influenced by genetic predisposition, hence patients and relatives require lifetime follow-up with MRI and/or PET-CT because of de novo disease risk. This entails exposure to electromagnetic/ionizing radiation, costs, and organizational challenges, because patients and relatives are scattered far from reference centers. Simplified first-line screening strategies are needed. We employed flow injection analysis tandem mass spectrometry, as used in newborn metabolic screening, to compare the plasma metabolic profile of HNPGL patients (59 samples, 56 cases) and healthy controls (24 samples, 24 cases). Principal Component Analysis (PCA) and Partial Least Discriminant Analysis (PLS-DA) highlighted a distinctive HNPGL signature, likely reflecting the anaplerotic conversion of the TCA cycle to glutaminolysis and catabolism of branched amino acids, DNA damage and deoxyadenosine (dAdo) accumulation, impairment of fatty acid oxidation, switch towards the Warburg effect and proinflammatory lysophosphatidylcholines (LPCs) signaling. Statistical analysis of the metabolites that most impacted on PLS-DA was extended to 10 acoustic neuroma and 2 cholesteatoma patients, confirming significant differences relative to the HNPGL plasma metabolomic profile. The best confusion matrix from the ROC curve built on 2 metabolites, dAdo and C26:0-LPC, provided specificity of 94.29% and sensitivity of 89.29%, with positive and negative predictive values of 96.2% and 84.6%, respectively. Analysis of dAdo and C26:0-LPC levels in dried venous and capillary blood confirmed that dAdo, likely deriving from 2′-deoxy-ATP accumulated in HNPGL cells following endogenous genotoxic damage, efficiently discriminated HNPGL patients from healthy controls and acoustic neuroma/cholesteatoma patients on easily manageable dried blood spots.

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Plasma Metabolome Profiling for the Diagnosis of Catecholamine Producing Tumors

Cited by 9 publications

References 44 publications

Metabolomics in paraganglioma: applications and perspectives from genetics to therapy

Metabolomics in paraganglioma: applications and perspectives from genetics to therapy

Changes in Plasma Metabolomic Profile Following Bariatric Surgery, Lifestyle Intervention or Diet Restriction—Insights from Human and Rat Studies

Targeted metabolomics detects a putatively diagnostic signature in plasma and dried blood spots from head and neck paraganglioma patients

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