title: Integrated transcriptomic and metabolomic analysis shows that disturbances in metabolism of tumor cells contribute to poor survival of RCC patients.
abstract: Cellular metabolism of renal cell carcinoma (RCC) tumors is disturbed. The clinical significance of these alterations is weakly understood. We aimed to find if changes in metabolic pathways contribute to survival of RCC patients.
  
  
  
  35 RCC tumors and matched controls were used for metabolite profiling using gas chromatography-mass spectrometry and transcriptomic analysis with qPCR-arrays targeting the expression of 93 metabolic genes. The clinical significance of obtained data was validated on independent cohort of 468 RCC patients with median follow-up of 43.22months.
  
  
  
  The levels of 31 metabolites were statistically significantly changed in RCC tumors compared with controls. The top altered metabolites included beta-alanine (+4.2-fold), glucose (+3.4-fold), succinate (-11.0-fold), myo-inositol (-4.6-fold), adenine (-4.2-fold), uracil (-3.7-fold), and hypoxanthine (-3.0-fold). These disturbances were associated with altered expression of 53 metabolic genes. ROC curve analysis revealed that the top metabolites discriminating between tumor and control samples included succinate (AUC=0.91), adenine (AUC=0.89), myo-inositol (AUC=0.87), hypoxanthine (AUC=0.85), urea (AUC=0.85), and beta-alanine (AUC=0.85). Poor survival of RCC patients correlated (p<0.0001) with altered expression of genes involved in metabolism of succinate (HR=2.7), purines (HR=2.4), glucose (HR=2.4), beta-alanine (HR=2.5), and myo-inositol (HR=1.9).
  
  
  
  We found that changes in metabolism of succinate, beta-alanine, purines, glucose and myo-inositol correlate with poor survival of RCC patients.
authors.affiliation: Centre of Postgraduate Medical Education, Department of Biochemistry and Molecular Biology, Warsaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Popławski
authors.affiliation: Max-Planck Institute of Molecular Plant Physiology, Potsdam-Golm, Germany.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Tohge
authors.affiliation: Centre of Postgraduate Medical Education, Department of Biochemistry and Molecular Biology, Warsaw, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Bogusławska
authors.affiliation: Centre of Postgraduate Medical Education, Department of Biochemistry and Molecular Biology, Warsaw, Poland.
authors.forename: Beata
authors.initials: B
authors.lastname: Rybicka
authors.affiliation: Masovian Specialist Hospital in Ostroleka, Ostroleka, Poland.
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Tański
authors.affiliation: Cátedra de Bioinformática, Tecnológico de Monterrey, Monterrey, Nuevo León, Mexico.
authors.forename: Victor
authors.initials: V
authors.lastname: Treviño
authors.affiliation: Max-Planck Institute of Molecular Plant Physiology, Potsdam-Golm, Germany.
authors.forename: Alisdair R
authors.initials: AR
authors.lastname: Fernie
authors.affiliation: Centre of Postgraduate Medical Education, Department of Biochemistry and Molecular Biology, Warsaw, Poland. Electronic address: apiekielko@cmkp.edu.pl.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Piekiełko-Witkowska
mesh_terms: D002292:Carcinoma, Renal Cell / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D006801:Humans; D007294:Inositol / Q000235:genetics / Q000378:metabolism; D007680:Kidney Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D008297:Male; D053858:Metabolic Networks and Pathways; D055442:Metabolome; D055432:Metabolomics; D016019:Survival Analysis; D059467:Transcriptome; D015091:beta-Alanine / Q000235:genetics / Q000378:metabolism
chemical_list: D015091:beta-Alanine; D007294:Inositol
keywords: Beta-alanine; Metabolism; Myo-inositol; RCC; Renal cell carcinoma; Survival