Abstract
Somatic copy number alterations frequently occur in the cancer genome affecting not only oncogenic or tumor suppressive genes, but also passenger and potential codriver genes. An intrinsic feature resulting from such genomic perturbations is the deregulation in the metabolism of tumor cells. In this study, we have shown that metabolic and cancer-causing genes are unexpectedly often proximally positioned in the chromosome and share loci with coaltered copy numbers across multiple cancers (19 cancer types from The Cancer Genome Atlas). We have developed an analysis pipeline, Identification of Metabolic Cancer Genes (iMetCG), to infer the functional impact on metabolic remodeling from such coamplifications and codeletions and delineate genes driving cancer metabolism from those that are neutral. Using our identified metabolic genes, we were able to classify tumors based on their tissue and developmental origins. These metabolic genes were similar to known cancer genes in terms of their network connectivity, isoform frequency, and evolutionary features. We further validated these identified metabolic genes by (i) using gene essentiality data from several tumor cell lines, (ii) showing that these identified metabolic genes are strong indicators for patient survival, and (iii) observing a significant overlap between our identified metabolic genes and known cancer-metabolic genes. Our analyses revealed a hitherto unknown generic mechanism for large-scale metabolic reprogramming in cancer cells based on linear gene proximities between cancer-causing and -metabolic genes. We have identified 119 new metabolic cancer genes likely to be involved in rewiring cancer cell metabolism. Cancer Res; 76(14); 4058-67. ©2016 AACR.
Highlights
Tumorigenesis can occur through numerous mechanisms giving the malignant cells ceaseless proliferative advantages [1]
On the basis of these cancer relevant features, we find that our predicted metabolic cancer genes were similar to known cancer genes while being distinctively different from the remaining metabolic genes, in line with our hypothesis that these genes are central to cancer cell metabolism
If during the course of genome evolution, genes vital for cellular proliferation were preferentially positioned near cancer "drivers" in the chromosomes or vice versa, in tumors, these proximally placed genes would be more susceptible to copy number coalteration
Summary
Tumorigenesis can occur through numerous mechanisms giving the malignant cells ceaseless proliferative advantages [1]. Evolutionary processes result in a perpetual conflict between the fitness of the host cell community and the cancer-initiating cells. Evolutionary forces may have shaped inherent vulnerabilities in the host genome, providing cancer-initiating potential, a consequence of various genetic trade-offs during the selection process. These trade-offs are reflected by changes to the fitness balance that determine tumor progression or expulsion via protumorigenic or tumor-suppressive mechanisms. The existence of tumor suppressors and oncogenes in the genome makes this evolutionary dilemma apparent [2]. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/)
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