title: Chromosome 3p loss of heterozygosity is associated with a unique metabolic network in clear cell renal carcinoma.
abstract: Several common oncogenic pathways have been implicated in the emergence of renowned metabolic features in cancer, which in turn are deemed essential for cancer proliferation and survival. However, the extent to which different cancers coordinate their metabolism to meet these requirements is largely unexplored. Here we show that even in the heterogeneity of metabolic regulation a distinct signature encompassed most cancers. On the other hand, clear cell renal cell carcinoma (ccRCC) strongly deviated in terms of metabolic gene expression changes, showing widespread down-regulation. We observed a metabolic shift that associates differential regulation of enzymes in one-carbon metabolism with high tumor stage and poor clinical outcome. A significant yet limited set of metabolic genes that explained the partial divergence of ccRCC metabolism correlated with loss of von Hippel-Lindau tumor suppressor (VHL) and a potential activation of signal transducer and activator of transcription 1. Further network-dependent analyses revealed unique defects in nucleotide, one-carbon, and glycerophospholipid metabolism at the transcript and protein level, which contrasts findings in other tumors. Notably, this behavior is recapitulated by recurrent loss of heterozygosity in multiple metabolic genes adjacent to VHL. This study therefore shows how loss of heterozygosity, hallmarked by VHL deletion in ccRCC, may uniquely shape tumor metabolism.
authors.affiliation: Department of Chemical and Biological Engineering, Chalmers University of Technology, 41296 Göteborg, Sweden.
authors.forename: Francesco
authors.initials: F
authors.lastname: Gatto
authors.forename: Intawat
authors.initials: I
authors.lastname: Nookaew
authors.forename: Jens
authors.initials: J
authors.lastname: Nielsen
mesh_terms: D001499:Bayes Theorem; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D016000:Cluster Analysis; D019295:Computational Biology; D056915:DNA Copy Number Variations; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D019656:Loss of Heterozygosity / Q000235:genetics*; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D025341:Principal Component Analysis; D050794:STAT1 Transcription Factor / Q000235:genetics; D018709:Statistics, Nonparametric; D016019:Survival Analysis; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics
chemical_list: D050794:STAT1 Transcription Factor; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human
keywords: cancer metabolism; genome-scale metabolic modeling; renal cancer; systems biology