Mitochondrial DNA copy number variation across human cancers.

Ed Reznik,A Ari Hakimi,Martin L Miller,William Lee,Venkatraman E Seshan,Satish K Tickoo,Hikmat A Al-Ahmadie,Chris Sander,Nadeem Riaz,Yasin Şenbabaoğlu,Judy Sarungbam

doi:10.7554/elife.10769

Abstract

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.

Highlights

Human cells contain many copies of the 16-kilobase mitochondrial genome, which encodes 13 essential components of the mitochondrial electron transport chain and ATP synthase
To investigate whether mitochondrial DNA (mtDNA) depletion was associated with a concurrent decrease of mitochondrial protein expression, we examined the abundance of a mitochondrial protein using immunohistochemistry (IHC) (Thermo Fisher Scientific Mitochondria Ab-2, Clone MTC02, see Materials and methods) in 3 tumor/normal pairs of clear-cell renal cell carcinoma, papillary renal cell carcinoma, and high-grade muscle-invasive urothelial bladder carcinoma
In BLCA, we found that 2/3 BLCA tumors showed increased levels of mitochondrial protein, which contrasted with Figure 3, where most samples showed evidence of mtDNA depletion

Summary

Introduction

Human cells contain many copies of the 16-kilobase mitochondrial genome, which encodes 13 essential components of the mitochondrial electron transport chain and ATP synthase. A number of studies have examined the role of mtDNA mutations in carcinogenesis (Wallace, 2012; Ju et al, 2014; Larman et al, 2012; He et al, 2010). The contribution of changes in the gross number of mtDNA genomes in a tumor (i.e. the ‘mtDNA copy number’) to tumor development and progression has not been adequately investigated. In contrast to the fixed (diploid) copy number of the nuclear genome, many copies of mtDNA exist within each cell, and these levels can fluctuate. Studies have focused on measuring mtDNA copy number per cell, with estimates for humans that vary between a few hundred and over one hundred thousand copies, depending on the tissue under examination (Wai et al, 2010).

Methods

Results

Conclusion