Abstract
BackgroundLittle is known about the relationship between the metabolite profile of plasma from pre-operative prostate cancer (PCa) patients and the risk of PCa progression. In this study we investigated the association between pre-operative plasma metabolites and risk of biochemical-, local- and metastatic-recurrence, with the aim of improving patient stratification.MethodsWe conducted a case-control study within a cohort of PCa patients recruited between 1996 and 2015. The age-matched primary cases (n = 33) were stratified in low risk, high risk without progression and high risk with progression as defined by the National Comprehensive Cancer Network. These samples were compared to metastatic (n = 9) and healthy controls (n = 10). The pre-operative plasma from primary cases and the plasma from metastatic patients and controls were assessed with untargeted metabolomics by LC-MS. The association between risk of progression and metabolite abundance was calculated using multivariate Cox proportional-hazard regression and the relationship between metabolites and outcome was calculated using median cut-off normalized values of metabolite abundance by Log-Rank test using the Kaplan Meier method.ResultsMedium-chain acylcarnitines (C6-C12) were positively associated with the risk of PSA progression (p = 0.036, median cut-off) while long-chain acylcarnitines (C14-C16) were inversely associated with local (p = 0.034) and bone progression (p = 0.0033). In primary cases, medium-chain acylcarnitines were positively associated with suberic acid, which also correlated with the risk of PSA progression (p = 0.032, Log-Rank test). In the metastatic samples, this effect was consistent for hexanoylcarnitine, L.octanoylcarnitine and decanoylcarnitine. Medium-chain acylcarnitines and suberic acid displayed the same inverse association with tryptophan, while indoleacetic acid, a breakdown product of tryptophan metabolism was strongly associated with PSA (p = 0.0081, Log-Rank test) and lymph node progression (p = 0.025, Log-Rank test). These data were consistent with the increased expression of indoleamine 2,3 dioxygenase (IDO1) in metastatic versus primary samples (p = 0.014). Finally, functional experiments revealed a synergistic effect of long chain fatty acids in combination with dihydrotestosterone administration on the transcription of androgen responsive genes.ConclusionsThis study strengthens the emerging link between fatty acid metabolism and PCa progression and suggests that measuring levels of medium- and long-chain acylcarnitines in pre-operative patient plasma may provide a basis for improving patient stratification.
Highlights
Little is known about the relationship between the metabolite profile of plasma from pre-operative prostate cancer (PCa) patients and the risk of PCa progression
Suberic acid and indoleacetic acid are associated with prostate specific antigen (PSA) progression When the analysis was extended to all the annotated metabolites, we found a positive and significant correlation in primary patients between medium- and longchain acylcarnitines and suberic acid, an unsaturated dicarboxylic acid that is frequently elevated in patients with fatty acid oxidation disorders [51] (Fig. 5c)
When we looked at the distribution of Indoleamine 2 (IDO1) and Medium-chain Acyl-CoA Dehydrogenase (ACADM) genomic alteration in a panel of PCa studies, we found a substantial distribution of deletions and amplifications of IDO1 while ACADM appeared to be mutated in a considerable fraction of the samples (Additional file 7: Figure S5A and S5B)
Summary
Little is known about the relationship between the metabolite profile of plasma from pre-operative prostate cancer (PCa) patients and the risk of PCa progression. In this study we investigated the association between pre-operative plasma metabolites and risk of biochemical-, local- and metastatic-recurrence, with the aim of improving patient stratification. Giskeødegård et al measured higher levels of plasma FAs ( acylcarnitines) in PCa patients compared to BPH controls [18]. In a multi-center study [19], comparison of pre-diagnostic plasma from 1077 PCa cases and 1077 controls showed that long-chain acylcarnitines (C14:1, C18:1 and C18:2) were inversely associated with advanced PCa stages, while short-chain acylcarnitine C3 was positively associated with aggressive and lethal disease. These findings suggest that shorterchain acylcarnitines are positively correlated with aggressive disease
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