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Metabolomic profile of prostate cancer-specific survival among 1812 Finnish men

BACKGROUND: Abnormal metabolism and perturbations in metabolic pathways play significant roles in the development and progression of prostate cancer; however, comprehensive metabolomic analyses of human data are lacking and needed to elucidate the interrelationships. METHODS: We examined the serum m...

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Autores principales: Huang, Jiaqi, Zhao, Bin, Weinstein, Stephanie J., Albanes, Demetrius, Mondul, Alison M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9594924/
https://www.ncbi.nlm.nih.gov/pubmed/36280842
http://dx.doi.org/10.1186/s12916-022-02561-4
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author Huang, Jiaqi
Zhao, Bin
Weinstein, Stephanie J.
Albanes, Demetrius
Mondul, Alison M.
author_facet Huang, Jiaqi
Zhao, Bin
Weinstein, Stephanie J.
Albanes, Demetrius
Mondul, Alison M.
author_sort Huang, Jiaqi
collection PubMed
description BACKGROUND: Abnormal metabolism and perturbations in metabolic pathways play significant roles in the development and progression of prostate cancer; however, comprehensive metabolomic analyses of human data are lacking and needed to elucidate the interrelationships. METHODS: We examined the serum metabolome in relation to prostate cancer survival in a cohort of 1812 cases in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Using an ultrahigh-performance LC-MS/MS platform, we identified 961 known metabolites in prospectively collected serum. Median survival time from diagnosis to prostate cancer-specific death (N=472) was 6.6 years (interquartile range=2.9–11.1 years). Cox proportional hazards regression models estimated hazard ratios and 95% confidence intervals of the associations between the serum metabolites (in quartiles) and prostate cancer death, adjusted for age at baseline and diagnosis, disease stage, and Gleason sum. In order to calculate risk scores, we first randomly divided the metabolomic data into a discovery set (70%) and validated in a replication set (30%). RESULTS: Overall, 49 metabolites were associated with prostate cancer survival after Bonferroni correction. Notably, higher levels of the phospholipid choline, amino acid glutamate, long-chain polyunsaturated fatty acid (n6) arachidonate (20:4n6), and glutamyl amino acids gamma-glutamylglutamate, gamma-glutamylglycine, and gamma-glutamylleucine were associated with increased risk of prostate cancer-specific mortality (fourth versus first quartile HRs=2.07–2.14; P-values <5.2×10(−5)). By contrast, the ascorbate/aldarate metabolite oxalate, xenobiotics S-carboxymethyl-L-cysteine, fibrinogen cleavage peptides ADpSGEGDFXAEGGGVR and fibrinopeptide B (1-12) were related to reduced disease-specific mortality (fourth versus first quartile HRs=0.82–0.84; P-value <5.2×10(−5)). Further adjustment for years from blood collection to cancer diagnosis, body mass index, smoking intensity and duration, and serum total and high-density lipoprotein cholesterol did not alter the results. Participants with a higher metabolic score based on the discovery set had an elevated risk of prostate cancer-specific mortality in the replication set (fourth versus first quartile, HR=3.9, P-value for trend<0.0001). CONCLUSIONS: The metabolic traits identified in this study, including for choline, glutamate, arachidonate, gamma-glutamyl amino acids, fibrinopeptides, and endocannabinoid and redox pathways and their composite risk score, corroborate our previous analysis of fatal prostate cancer and provide novel insights and potential leads regarding the molecular basis of prostate cancer progression and mortality. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12916-022-02561-4.
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spelling pubmed-95949242022-10-26 Metabolomic profile of prostate cancer-specific survival among 1812 Finnish men Huang, Jiaqi Zhao, Bin Weinstein, Stephanie J. Albanes, Demetrius Mondul, Alison M. BMC Med Research Article BACKGROUND: Abnormal metabolism and perturbations in metabolic pathways play significant roles in the development and progression of prostate cancer; however, comprehensive metabolomic analyses of human data are lacking and needed to elucidate the interrelationships. METHODS: We examined the serum metabolome in relation to prostate cancer survival in a cohort of 1812 cases in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Using an ultrahigh-performance LC-MS/MS platform, we identified 961 known metabolites in prospectively collected serum. Median survival time from diagnosis to prostate cancer-specific death (N=472) was 6.6 years (interquartile range=2.9–11.1 years). Cox proportional hazards regression models estimated hazard ratios and 95% confidence intervals of the associations between the serum metabolites (in quartiles) and prostate cancer death, adjusted for age at baseline and diagnosis, disease stage, and Gleason sum. In order to calculate risk scores, we first randomly divided the metabolomic data into a discovery set (70%) and validated in a replication set (30%). RESULTS: Overall, 49 metabolites were associated with prostate cancer survival after Bonferroni correction. Notably, higher levels of the phospholipid choline, amino acid glutamate, long-chain polyunsaturated fatty acid (n6) arachidonate (20:4n6), and glutamyl amino acids gamma-glutamylglutamate, gamma-glutamylglycine, and gamma-glutamylleucine were associated with increased risk of prostate cancer-specific mortality (fourth versus first quartile HRs=2.07–2.14; P-values <5.2×10(−5)). By contrast, the ascorbate/aldarate metabolite oxalate, xenobiotics S-carboxymethyl-L-cysteine, fibrinogen cleavage peptides ADpSGEGDFXAEGGGVR and fibrinopeptide B (1-12) were related to reduced disease-specific mortality (fourth versus first quartile HRs=0.82–0.84; P-value <5.2×10(−5)). Further adjustment for years from blood collection to cancer diagnosis, body mass index, smoking intensity and duration, and serum total and high-density lipoprotein cholesterol did not alter the results. Participants with a higher metabolic score based on the discovery set had an elevated risk of prostate cancer-specific mortality in the replication set (fourth versus first quartile, HR=3.9, P-value for trend<0.0001). CONCLUSIONS: The metabolic traits identified in this study, including for choline, glutamate, arachidonate, gamma-glutamyl amino acids, fibrinopeptides, and endocannabinoid and redox pathways and their composite risk score, corroborate our previous analysis of fatal prostate cancer and provide novel insights and potential leads regarding the molecular basis of prostate cancer progression and mortality. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12916-022-02561-4. BioMed Central 2022-10-25 /pmc/articles/PMC9594924/ /pubmed/36280842 http://dx.doi.org/10.1186/s12916-022-02561-4 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research Article
Huang, Jiaqi
Zhao, Bin
Weinstein, Stephanie J.
Albanes, Demetrius
Mondul, Alison M.
Metabolomic profile of prostate cancer-specific survival among 1812 Finnish men
title Metabolomic profile of prostate cancer-specific survival among 1812 Finnish men
title_full Metabolomic profile of prostate cancer-specific survival among 1812 Finnish men
title_fullStr Metabolomic profile of prostate cancer-specific survival among 1812 Finnish men
title_full_unstemmed Metabolomic profile of prostate cancer-specific survival among 1812 Finnish men
title_short Metabolomic profile of prostate cancer-specific survival among 1812 Finnish men
title_sort metabolomic profile of prostate cancer-specific survival among 1812 finnish men
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9594924/
https://www.ncbi.nlm.nih.gov/pubmed/36280842
http://dx.doi.org/10.1186/s12916-022-02561-4
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