title: Genetic alterations in fatty acid transport and metabolism genes are associated with metastatic progression and poor prognosis of human cancers.
abstract: Reprogramming of cellular metabolism is a hallmark feature of cancer cells. While a distinct set of processes drive metastasis when compared to tumorigenesis, it is yet unclear if genetic alterations in metabolic pathways are associated with metastatic progression of human cancers. Here, we analyzed the mutation, copy number variation and gene expression patterns of a literature-derived model of metabolic genes associated with glycolysis (Warburg effect), fatty acid metabolism (lipogenesis, oxidation, lipolysis, esterification) and fatty acid uptake in >9000 primary or metastatic tumor samples from the multi-cancer TCGA datasets. Our association analysis revealed a uniform pattern of Warburg effect mutations influencing prognosis across all tumor types, while copy number alterations in the electron transport chain gene SCO2, fatty acid uptake (CAV1, CD36) and lipogenesis (PPARA, PPARD, MLXIPL) genes were enriched in metastatic tumors. Using gene expression profiles, we established a gene-signature (CAV1, CD36, MLXIPL, CPT1C, CYP2E1) that strongly associated with epithelial-mesenchymal program across multiple cancers. Moreover, stratification of samples based on the copy number or expression profiles of the genes identified in our analysis revealed a significant effect on patient survival rates, thus confirming prominent roles of fatty acid uptake and metabolism in metastatic progression and poor prognosis of human cancers.
authors.affiliation: Genetics Program, Michigan State University, East Lansing, Michigan 48824, USA.
authors.forename: Aritro
authors.initials: A
authors.lastname: Nath
authors.affiliation: Genetics Program, Michigan State University, East Lansing, Michigan 48824, USA.|Department of Chemical Engineering and Materials Science, Michigan State University, East Lansing, Michigan 48824, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Chan
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality / Q000556:secondary*; D001692:Biological Transport / Q000235:genetics; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D005227:Fatty Acids / Q000378:metabolism; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D053208:Kaplan-Meier Estimate; D050356:Lipid Metabolism / Q000235:genetics; D053858:Metabolic Networks and Pathways; D009154:Mutation; D011379:Prognosis; D059467:Transcriptome
chemical_list: D005227:Fatty Acids