Mitochondrial DNA copy number variation across human cancers

Mutations, deletions, and changes in copy number of mitochondrial DNA (mtDNA), are observed throughout cancers. Here, we survey mtDNA copy number variation across 22 tumor types profiled by The Cancer Genome Atlas project. We observe a tendency for some cancers, especially of the bladder, breast, and kidney, to be depleted of mtDNA, relative to matched normal tissue. Analysis of genetic context reveals an association between incidence of several somatic alterations, including IDH1 mutations in gliomas, and mtDNA content. In some but not all cancer types, mtDNA content is correlated with the expression of respiratory genes, and anti-correlated to the expression of immune response and cell-cycle genes. In tandem with immunohistochemical evidence, we find that some tumors may compensate for mtDNA depletion to sustain levels of respiratory proteins. Our results highlight the extent of mtDNA copy number variation in tumors and point to related therapeutic opportunities. DOI: http://dx.doi.org/10.7554/eLife.10769.001
eLife digest Within each cell of your body lie hundreds or thousands of mitochondria. These structures are perhaps best known for making energy, but mitochondria also play roles in processes like the immune response and cell signaling. However, in the mutant cells that form cancerous tumors, these roles can be subverted and altered. Mitochondria contain their own DNA, which is distinct from the DNA stored in the nucleus of the cell, and codes for the proteins that the mitochondria need to produce energy. Reznik et al. used next-generation DNA sequencing data produced by The Cancer Genome Atlas consortium to estimate the number of copies of mitochondrial DNA in tumor cells and the adjacent normal tissue. This revealed that in many types of cancer, tumor cells have fewer copies of mitochondrial DNA than the cells that make up normal tissue. In many cases, the depletion of mitochondrial DNA was accompanied by a reduction of the expression of mitochondrial genes, suggesting that mitochondrial activity may be suppressed in these tumor types. Reznik et al. also found that the number of copies of mitochondrial DNA in certain tumor types is related to the incidence of key 'driver' mutations that cause cells to become cancerous. This knowledge may help to develop new treatments for these tumors. DOI: http://dx.doi.org/10.7554/eLife.10769.002