Stefano Cacciatore1,2, Martha Wium1, Cristina Licari3, Aderonke Ajayi-Smith1, Lorenzo Masieri4,5, Chanelle Anderson1, Azola Samkele Salukazana6, Lisa Kaestner6, Marco Carini4, Giuseppina M Carbone7, Carlo V Catapano7,8,9, Massimo Loda10,11,12, Towia A Libermann12,13, Luiz F Zerbini14. 1. Cancer Genomics Group, International Centre for Genetic Engineering and Biotechnology, Cape Town, South Africa. 2. Institute for Reproductive and Developmental Biology, Imperial College, London, UK. 3. Magnetic Resonance Center (CERM), University of Florence, Sesto Fiorentino, Italy. 4. Department of Urology, Clinica Urologica I, Azienda Ospedaliera Careggi, University of Florence, Florence, Italy. 5. Pediatric Urology Unit, Meyer Children Hospital, University of Florence, Florence, Italy. 6. Division of Urology, University of Cape Town, Groote Schuur Hospital, Cape Town, South Africa. 7. Institute of Oncology Research (IOR), Università della Svizzera italiana, Bellinzona, Switzerland. 8. Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland. 9. Department of Oncology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland. 10. Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA. 11. Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA. 12. Harvard Medical School, MA, Boston, USA. 13. BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center, MA, Boston, USA. 14. Cancer Genomics Group, International Centre for Genetic Engineering and Biotechnology, Cape Town, South Africa. luiz.zerbini@icgeb.org.
Abstract
BACKGROUND: Men with African ancestry are more likely to develop aggressive prostate cancer (PCa) and to die from this disease. The study of PCa in the South African population represents an opportunity for biomedical research due to the high prevalence of aggressive PCa. While inflammation is known to play a significant role in PCa progression, its association with tumor stage in populations of African descent has not been explored in detail. Identification of new metabolic biomarkers of inflammation may improve diagnosis of patients with aggressive PCa. METHODS: Plasma samples were profiled from 41 South African men with PCa using nuclear magnetic resonance (NMR) spectroscopy. A total of 41 features, including metabolites, lipid classes, total protein, and the inflammatory NMR markers, GlycA, and GlycB, were quantified from each NMR spectrum. The Bruker's B.I.-LISA protocols were used to characterize 114 parameters related to the lipoproteins. The unsupervised KODAMA method was used to stratify the patients of our cohort based on their metabolic profile. RESULTS: We found that the plasma of patients with very high risk, aggressive PCa and high level of C-reactive protein have a peculiar metabolic phenotype (metabotype) characterized by extremely high levels of GlycA and GlycB. The inflammatory processes linked to the higher level of GlycA and GlycB are characterized by a deep change of the plasma metabolome that may be used to improve the stratification of patients with PCa. We also identified a not previously known relationship between high values of VLDL and low level of GlycB in a different metabotype of patients characterized by lower-risk PCa. CONCLUSIONS: For the first time, a portrait of the metabolic changes in African men with PCa has been delineated indicating a strong association between inflammation and metabolic profiles. Our findings indicate how the metabolic profile could be used to identify those patients with high level of inflammation, characterized by aggressive PCa and short life expectancy. Integrating a metabolomic analysis as a tool for patient stratification could be important for opening the door to the development of new therapies. Further investigations are needed to understand the prevalence of an inflammatory metabotype in patients with aggressive PCa.
BACKGROUND:Men with African ancestry are more likely to develop aggressive prostate cancer (PCa) and to die from this disease. The study of PCa in the South African population represents an opportunity for biomedical research due to the high prevalence of aggressive PCa. While inflammation is known to play a significant role in PCa progression, its association with tumor stage in populations of African descent has not been explored in detail. Identification of new metabolic biomarkers of inflammation may improve diagnosis of patients with aggressive PCa. METHODS: Plasma samples were profiled from 41 South African men with PCa using nuclear magnetic resonance (NMR) spectroscopy. A total of 41 features, including metabolites, lipid classes, total protein, and the inflammatory NMR markers, GlycA, and GlycB, were quantified from each NMR spectrum. The Bruker's B.I.-LISA protocols were used to characterize 114 parameters related to the lipoproteins. The unsupervised KODAMA method was used to stratify the patients of our cohort based on their metabolic profile. RESULTS: We found that the plasma of patients with very high risk, aggressive PCa and high level of C-reactive protein have a peculiar metabolic phenotype (metabotype) characterized by extremely high levels of GlycA and GlycB. The inflammatory processes linked to the higher level of GlycA and GlycB are characterized by a deep change of the plasma metabolome that may be used to improve the stratification of patients with PCa. We also identified a not previously known relationship between high values of VLDL and low level of GlycB in a different metabotype of patients characterized by lower-risk PCa. CONCLUSIONS: For the first time, a portrait of the metabolic changes in African men with PCa has been delineated indicating a strong association between inflammation and metabolic profiles. Our findings indicate how the metabolic profile could be used to identify those patients with high level of inflammation, characterized by aggressive PCa and short life expectancy. Integrating a metabolomic analysis as a tool for patient stratification could be important for opening the door to the development of new therapies. Further investigations are needed to understand the prevalence of an inflammatory metabotype in patients with aggressive PCa.
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