Pyruvate dehydrogenase inactivation causes glycolytic phenotype in BAP1 mutant uveal melanoma

Han, Anna; Chua, Vivian; Baqai, Usman; Purwin, Timothy J.; Bechtel, Nelisa; Hunter, Emily; Tiago, Manoela; Seifert, Erin L.; Speicher, David W.; Schug, Zachary T.; Harbour, J. William; Aplin, Andrew E.

doi:10.1038/s41388-021-02154-0

Cited by 7 publications

(9 citation statements)

References 62 publications

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“…Furthermore, consistent with oncogenic processes, decreased adenine and guanine suggest either decreased purine degradation or increased salvage of purine bases. Several metabolite studies in UM focused on metastatic cell lines [ 44 , 45 , 46 ]. BAP1-mutated cell lines show the upregulation of oxidative phosphorylation, pyruvate dehydrogenase, and succinate dehydrogenase subunit A (SDHA) [ 44 , 45 ].…”

Section: Discussionmentioning

confidence: 99%

“…Several metabolite studies in UM focused on metastatic cell lines [ 44 , 45 , 46 ]. BAP1-mutated cell lines show the upregulation of oxidative phosphorylation, pyruvate dehydrogenase, and succinate dehydrogenase subunit A (SDHA) [ 44 , 45 ]. In lung cancer, the TCA cycle is restored by the upregulation of SDHA and valine metabolism [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

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Uveal Melanoma Patients Have a Distinct Metabolic Phenotype in Peripheral Blood

Bruyn

Bongaerts

Bonte

et al. 2023

IJMS

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Uveal melanomas (UM) are detected earlier. Consequently, tumors are smaller, allowing for novel eye-preserving treatments. This reduces tumor tissue available for genomic profiling. Additionally, these small tumors can be hard to differentiate from nevi, creating the need for minimally invasive detection and prognostication. Metabolites show promise as minimally invasive detection by resembling the biological phenotype. In this pilot study, we determined metabolite patterns in the peripheral blood of UM patients (n = 113) and controls (n = 46) using untargeted metabolomics. Using a random forest classifier (RFC) and leave-one-out cross-validation, we confirmed discriminatory metabolite patterns in UM patients compared to controls with an area under the curve of the receiver operating characteristic of 0.99 in both positive and negative ion modes. The RFC and leave-one-out cross-validation did not reveal discriminatory metabolite patterns in high-risk versus low-risk of metastasizing in UM patients. Ten-time repeated analyses of the RFC and LOOCV using 50% randomly distributed samples showed similar results for UM patients versus controls and prognostic groups. Pathway analysis using annotated metabolites indicated dysregulation of several processes associated with malignancies. Consequently, minimally invasive metabolomics could potentially allow for screening as it distinguishes metabolite patterns that are putatively associated with oncogenic processes in the peripheral blood plasma of UM patients from controls at the time of diagnosis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Uveal Melanoma Patients Have a Distinct Metabolic Phenotype in Peripheral Blood

Bruyn

Bongaerts

Bonte

et al. 2023

IJMS

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show abstract

“…Furthermore, consistent with oncogenic processes, decreased adenine and guanine suggest either decreased purine degradation or increased salvage of purine bases. Several metabolite studies in UM focused on metastatic cell lines [12][13][14] . BAP1-mutated cell lines show upregulation of oxidative phosphorylation, pyruvate dehydrogenase and succinate dehydrogenase subunit A (SDHA) 12,13 .…”

Section: Discussionmentioning

confidence: 99%

“…Several metabolite studies in UM focused on metastatic cell lines [12][13][14] . BAP1-mutated cell lines show upregulation of oxidative phosphorylation, pyruvate dehydrogenase and succinate dehydrogenase subunit A (SDHA) 12,13 . In lung cancer, the TCA-cycle is restored by upregulation of SDHA and valine metabolism 15 .…”

Section: Discussionmentioning

confidence: 99%

Blood Plasma Metabolomics to Support Uveal Melanoma Diagnosis

Bruyn

Bongaerts²,

Bonte³

et al. 2022

Preprint

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ImportanceUveal Melanomas (UM) micro-metastasis can be present prior to diagnosis and relapse after treatment. Earlier detection resulted in an increased incidence of small (T1 and T2) tumors allowing for novel eye-preserving treatment strategies but reducing available tumor tissue needed for prognostic genomic profiling, creating the need for minimal-invasive detection and novel prognostication methods.ObjectiveTo determine whether tumor presence can be confirmed using metabolite patterns in blood plasma and to evaluate if these patterns differ between high risk (BRCA1-associated protein-1, BAP1), intermediate risk (Splicing Factor 3b Subunit 1, SF3B1) and low risk (Eukaryotic Translation Initiation Factor 1A X-Linked, EIF1AX) mutated tumors.DesignRetrospective observational study including discovery (n=53) and replication (n=42) convenience sample sets compared to unaffected control-participants (n=46) as well as across mutation-based subgroups.SettingPatients from two tertiary referral centers specialized in ocular oncology: The Rotterdam Eye Hospital and the Erasmus MC Cancer Institute were included.ParticipantsSex-matched controls and patients were included based on their prognostic relevant secondary driver mutations. Peripheral blood plasma was collected at diagnosis, prior to treatment. Exclusion criteria were the presence of other malignancies or co-occurrence of systemic diseases at time of diagnosis.Main outcome and measureMetabolite profiles of patients and control-participants were generated as mass/charge (m/z) features using ultra-high performance liquid chromatography mass-spectrometry. After normalization, discriminatory feature patterns were determined using a random forest classifier and leave-one-out cross-validation.ResultsWe detected differential metabolic patterns with a sensitivity of 0.95 and 0.90 and a specificity of 0.98 and 0.98 in the positive and negative ion modes, respectively. The accuracy of the model for classifying the subgroups was insufficient for the discovery (0.600 and 0.614 in the positive and negative ion modes, respectively) and replication cohort (0.544 and 0.672 in the positive and negative ion modes, respectively).Conclusion and relevanceMinimally invasive metabolomics does not discriminate between the prognostic relevant BAP1, SF3B1 and EIF1AX mutated UM-subgroups. However, this technique has the potential to allow for minimal invasive screening as it distinguishes metabolite patterns in peripheral blood derived plasma of UM-patients from control-participants.Key pointsQuestionCan we discriminate uveal melanoma patients and mutation subgroups from unaffected control-participants using the metabolome of peripheral blood plasma taken at time of diagnosis?FindingsIn this retrospective observational study, we find a low sensitivity and specificity to detect subgroups but a high sensitivity and specificity to discriminate patients from control-participants by measuring metabolite abundancy in plasma using ultra-high performance liquid chromatography mass-spectrometry and reach a receiver operating characteristic area under the curve of 0.993.MeaningThese results suggest that surveying the metabolome of uveal melanoma patients could aid in the minimal invasive detection of uveal melanoma.

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“…Metabolic adaptations also commonly occur in UM as a result of BAP1 mutations and loss of chromosome 3 ( Chattopadhyay et al, 2019 ; Han, Purwin, & Aplin, 2021 ). For example, increased dependency on the glycolytic pathway and altered energy-sensing abilities are potential vulnerabilities that can be targeted to reduce UM cell growth ( Chua et al, 2022 ; Han et al, 2022 ). Furthermore, BAP1 mutant UM cases have distinct metabolic subtypes, classified according to their oxidative phosphorylation activity, and respond differentially to metabolic inhibitors ( Han et al, 2021 ).…”

Section: Targeted Kinase Inhibitors and Combinations In Rare Melanoma...mentioning

confidence: 99%