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Metabolic gene alterations impact the clinical aggressiveness and drug responses of 32 human cancers.

ABSTRACT: Malignant cells reconfigure their metabolism to support oncogenic processes such as accelerated growth and proliferation. The mechanisms by which this occurs likely involve alterations to genes that encode metabolic enzymes. Here, using genomics data for 10,528 tumours of 32 different cancer types, we characterise the alterations of genes involved in various metabolic pathways. We find that mutations and copy number variations of metabolic genes are pervasive across all human cancers. Based on the frequencies of metabolic gene alterations, we further find that there are two distinct cancer supertypes that tend to be associated with different clinical outcomes. By utilising the known dose-response profiles of 825 cancer cell lines, we infer that cancers belonging to these supertypes are likely to respond differently to various anticancer drugs. Collectively our analyses define the foundational metabolic features of different cancer supertypes and subtypes upon which discriminatory strategies for treating particular tumours could be constructed.

SUBMITTER: Sinkala M

PROVIDER: S-EPMC6856368 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Metabolic gene alterations impact the clinical aggressiveness and drug responses of 32 human cancers.

Sinkala Musalula M Mulder Nicola N Patrick Martin Darren D

Communications biology 20191114

Malignant cells reconfigure their metabolism to support oncogenic processes such as accelerated growth and proliferation. The mechanisms by which this occurs likely involve alterations to genes that encode metabolic enzymes. Here, using genomics data for 10,528 tumours of 32 different cancer types, we characterise the alterations of genes involved in various metabolic pathways. We find that mutations and copy number variations of metabolic genes are pervasive across all human cancers. Based on t ...[more]

PMID: 31754644

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Project description:Glioblastoma (GBM) is uniformly fatal with a 1-year median survival, despite best available treatment, including radiotherapy (RT). Impacts of prior RT on tumor recurrence are poorly understood but may increase tumor aggressiveness. Metabolic changes have been investigated in radiation-induced brain injury; however, the tumor-promoting effect following prior radiation is lacking. Since RT is vital to GBM management, we quantified tumor-promoting effects of prior RT on patient-derived intracranial GBM xenografts and characterized metabolic alterations associated with the protumorigenic microenvironment. Human xenografts (GBM143) were implanted into nude mice 24 hrs following 20 Gy cranial radiation vs. sham animals. Tumors in pre-radiated mice were more proliferative and more infiltrative, yielding faster mortality (p < 0.0001). Histologic evaluation of tumor associated macrophage/microglia (TAMs) revealed cells with a more fully activated ameboid morphology in pre-radiated animals. Microdialyzates from radiated brain at the margin of tumor infiltration contralateral to the site of implantation were analyzed by unsupervised liquid chromatography-mass spectrometry (LC-MS). In pre-radiated animals, metabolites known to be associated with tumor progression (i.e., modified nucleotides and polyols) were identified. Whole-tissue metabolomic analysis of pre-radiated brain microenvironment for metabolic alterations in a separate cohort of nude mice using 1H-NMR revealed a significant decrease in levels of antioxidants (glutathione (GSH) and ascorbate (ASC)), NAD+, Tricarboxylic acid cycle (TCA) intermediates, and rise in energy carriers (ATP, GTP). GSH and ASC showed highest Variable Importance on Projection prediction (VIPpred) (1.65) in Orthogonal Partial least square Discriminant Analysis (OPLS-DA); Ascorbate catabolism was identified by GC-MS. To assess longevity of radiation effects, we compared survival with implantation occurring 2 months vs. 24 hrs following radiation, finding worse survival in animals implanted at 2 months. These radiation-induced alterations are consistent with a chronic disease-like microenvironment characterized by reduced levels of antioxidants and NAD+, and elevated extracellular ATP and GTP serving as chemoattractants, promoting cell motility and vesicular secretion with decreased levels of GSH and ASC exacerbating oxidative stress. Taken together, these data suggest IR induces tumor-permissive changes in the microenvironment with metabolomic alterations that may facilitate tumor aggressiveness with important implications for recurrent glioblastoma. Harnessing these metabolomic insights may provide opportunities to attenuate RT-associated aggressiveness of recurrent GBM.

Dataset Information

Metabolic gene alterations impact the clinical aggressiveness and drug responses of 32 human cancers.

Publications

Metabolic gene alterations impact the clinical aggressiveness and drug responses of 32 human cancers.

Similar Datasets

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