Abstract
The aim of this study was to identify novel plasma metabolic signatures with possible relevance during multiple myeloma (MM) development and progression. A biochemical quantitative phenotyping platform based on targeted electrospray ionization tandem mass spectrometry technology was used to aid in the identification of any eventual perturbed biochemical pathway in peripheral blood plasma from 36 MM patients and 73 healthy controls. Our results showed that MM cases present an increase in short and medium/long-chain species of acylcarnitines resembling Multiple AcylCoA Dehydrogenase Deficiency (MADD), particularly, associated with MM advanced International Staging System (ISS). Lipids profile showed lower concentrations of phosphatidylcholine (PC), lysophosphatidylcholine (LPC) and sphingomyelins (SM) in the MM patients and its respective ISS groups. MM cases were accompanied by a drop in the concentration of essential amino acids, especially tryptophan, with a significant inverse correlation between the progressive drop in tryptophan with the elevation of β2-microglobulin, with the increase in systemic methylation levels (Symmetric Arginine Dimethylation, SDMA) and with the accumulation of esterified carnitines in relation to free carnitine (AcylC/C0). Serotonin was significantly elevated in cases of MM, without a clear association with ISS. Kynurenine/tryptophan ratio demonstrates that the activity of dioxigenases is even higher in the cases classified as ISS 3. In conclusion, our study showed that MM patients at diagnosis showed metabolic disorders resembling both mitochondrial complexes I and II and Hartnup-like disturbances as underlying conditions, also influencing different stages of the disease.
Highlights
Multiple myeloma (MM) is characterized by proliferation and infiltration of clonal plasma cells into the bone marrow microenvironment, which produce and secrete monoclonal immunoglobulin that can be detected in patients’ urine or serum[1] (Palumbo and Anderson, 2011)
There are a few risk factors that could increase the chance of MM development such as: (1) increasing age; (2) MM is more frequently diagnosed in men than women; (3) it is more common in African than in white Americans; (4) MM can be diagnosed in more than one member in some families. (5) apparently, obesity increases the risk of developing MM3,4
These results reveal that MM samples show elevation of acylcarnitines with short carbon chains such as C2, C3-OH, C4, C4: 1, C5, C5-DC, C5-M-DC
Summary
Multiple myeloma (MM) is characterized by proliferation and infiltration of clonal plasma cells into the bone marrow microenvironment, which produce and secrete monoclonal immunoglobulin that can be detected in patients’ urine or serum[1] (Palumbo and Anderson, 2011). There are a few risk factors that could increase the chance of MM development such as: (1) increasing age (less than 1% of MM cases are diagnosed in patients under 35 years old and most of them occur after 65 years); (2) MM is more frequently diagnosed in men than women; (3) it is more common in African than in white Americans; (4) MM can be diagnosed in more than one member in some families. Case-controlled studies have suggested a significant risk of developing MM in individuals with important occupational exposures in the agriculture, food, and petrochemical industries, especially in patients exposed to herbicides or insecticides and to benzene and other organic solvents[4,5]. Proteomics and metabolomics analysis have contributed significantly with new insights in cancer biology, since both approaches contribute to a better understanding of the disease, diagnosis, classification, treatment decision, treatment efficacy evaluation and identification of new therapeutic t argets[10,11,12,13,14]
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