Chromosome 3p loss of heterozygosity is associated with a unique metabolic network in clear cell renal carcinoma
Journal article, 2014

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.

genome-scale metabolic modeling

HETEROGENEITY

MODEL

cancer metabolism

GROWTH

DRUG TARGETS

VHL

CANCER

HYPOXIA

GENE-EXPRESSION

NOVO PYRIMIDINE SYNTHESIS

systems biology

SET

renal cancer

Author

Francesco Gatto

Chalmers, Chemical and Biological Engineering, Life Sciences, System Biology

Intawat Nookaew

Chalmers, Chemical and Biological Engineering, Life Sciences, System Biology

Jens B Nielsen

Chalmers, Chemical and Biological Engineering, Life Sciences, System Biology

Proceedings of the National Academy of Sciences of the United States of America

0027-8424 (ISSN) 1091-6490 (eISSN)

Vol. 111 9 E866-E875

Infrastructure

C3SE (Chalmers Centre for Computational Science and Engineering)

Areas of Advance

Life Science Engineering (2010-2018)

Subject Categories

Chemical Sciences

Cancer and Oncology

DOI

10.1073/pnas.1319196111

More information

Created

10/7/2017