Copy Number Alterations in Enzyme-Coding and Cancer-Causing Genes Reprogram Tumor Metabolism

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.

DNA damage and growth hormone hypersecretion in pituitary somatotroph adenomas

“…Furthermore, we did not detect many somatic mutations in secreting or nonsecreting pituitary tumors, supporting the findings of prior reports (22,38,39). SCNAs reflect DNA damage and genomic instability and occur in normal tissue and cancerous tumors (23,40). Our observation of genome instability with sparse SNV/InDel mutations was previously described in nonproliferating, terminally differentiated cells, which are highly metabolically active (41,42).…”

Tissue-specific and convergent metabolic transformation of cancer correlates with metastatic potential and patient survival

“…It is therefore tempting to speculate that evolution of cancer might be driven by phenotypic traits, and that oncogenes and tumour suppressors might be selected for their efficiency in regulating these metabolic changes. In line with this hypothesis, a recent study found that metabolic and cancer-causing genes undergo co-altered somatic copy number variation 28 , indicating that alteration of cancer-associated genes is often linked with metabolic rewiring. These findings may catalyse a better understanding of the role of dysregulated metabolism in cancer and provide novel means to stratify patients based on their metabolic features.…”

A Conceptual Framework for Studying and Investing in Precision Nutrition

“…In addition, many phenotypes are polygenic, apparent only when pathways involving multiple genes are perturbed. SNPs are not the only genetic variants that need to be considered; for example, gene copy number variation can cause functionally important perturbations in metabolism (Reiter et al, 2016; Sharma et al, 2016). For these reasons, studies advancing precision nutrition need to focus on developing computational and mathematical modeling of the underlying complex genetics and then develop algorithms for calculating the integrated effects of multiple genetic contributions that together predict metabolic inefficiencies.…”