Metabolomic identification of diagnostic serum-based biomarkers for advanced stage melanoma
Melanoma is a highly aggressive malignancy and is currently one of the fastest growing cancers worldwide. While early stage (I and II) disease is highly curable with excellent prognosis, mortality rates rise dramatically after distant spread. We sought to identify differences in the metabolome of melanoma patients to further elucidate the pathophysiology of melanoma and identify potential biomarkers to aid in earlier detection of recurrence.
Using 1H NMR and DI–LC–MS/MS, we profiled serum samples from 26 patients with stage III (nodal metastasis) or stage IV (distant metastasis) melanoma and compared their biochemical profiles with 46 age- and gender-matched controls.
We accurately quantified 181 metabolites in serum using a combination of 1H NMR and DI–LC–MS/MS. We observed significant separation between cases and controls in the PLS-DA scores plot (permutation test p-value = 0.002). Using the concentrations of PC-aa-C40:3, dl-carnitine, octanoyl-l-carnitine, ethanol, and methylmalonyl-l-carnitine we developed a diagnostic algorithm with an AUC (95% CI) = 0.822 (0.665–0.979) with sensitivity and specificity of 100 and 56%, respectively. Furthermore, we identified arginine, proline, tryptophan, glutamine, glutamate, glutathione and ornithine metabolism to be significantly perturbed due to disease (p < 0.05).
Targeted metabolomic analysis demonstrated significant differences in metabolic profiles of advanced stage (III and IV) melanoma patients as compared to controls. These differences may represent a potential avenue for the development of multi-marker serum-based assays for earlier detection of recurrences, allow for newer, more effective targeted therapy when tumor burden is less, and further elucidate the pathophysiologic changes that occur in melanoma.
KeywordsMelanoma Metabolomics Amino acids Serum biomarkers
AB, RK, SG and RBS were responsible for conceiving and designing the study. DB and RC wrote the manuscript. AB, AS, DB, ZH and OT performed the research. DW, TB, BH and RM analyzed the data and developed the predictive models. All authors read and approved of the final manuscript.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest to disclose.
This study was approved by the institutional review board (IRB) at William Beaumont Hospital in Royal Oak, Michigan. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
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