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BMC Cancer. 2012; 12: 53.
Published online Feb 2, 2012. doi:  10.1186/1471-2407-12-53
PMCID: PMC3342922
Somatic mitochondrial DNA mutations in cancer escape purifying selection and high pathogenicity mutations lead to the oncocytic phenotype: pathogenicity analysis of reported somatic mtDNA mutations in tumors
Luísa Pereira,1,2 Pedro Soares,1 Valdemar Máximo,1,2 and David C Samuelscorresponding author3
1Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, Portugal
2Faculdade de Medicina da Universidade do Porto, Porto, Portugal
3Center for Human Genetics Research, Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN, USA
corresponding authorCorresponding author.
Luísa Pereira: lpereira/at/ipatimup.pt; Pedro Soares: pedroa/at/ipatimup.pt; Valdemar Máximo: vmaximo/at/ipatimup.pt; David C Samuels: david.samuels/at/chgr.mc.vanderbilt.edu
Received September 28, 2011; Accepted February 2, 2012.
Abstract
Background
The presence of somatic mitochondrial DNA (mtDNA) mutations in cancer cells has been interpreted in controversial ways, ranging from random neutral accumulation of mutations, to positive selection for high pathogenicity, or conversely to purifying selection against high pathogenicity variants as occurs at the population level.
Methods
Here we evaluated the predicted pathogenicity of somatic mtDNA mutations described in cancer and compare these to the distribution of variations observed in the global human population and all possible protein variations that could occur in human mtDNA. We focus on oncocytic tumors, which are clearly associated with mitochondrial dysfunction. The protein variant pathogenicity was predicted using two computational methods, MutPred and SNPs&GO.
Results
The pathogenicity score of the somatic mtDNA variants were significantly higher in oncocytic tumors compared to non-oncocytic tumors. Variations in subunits of Complex I of the electron transfer chain were significantly more common in tumors with the oncocytic phenotype, while variations in Complex V subunits were significantly more common in non-oncocytic tumors.
Conclusions
Our results show that the somatic mtDNA mutations reported over all tumors are indistinguishable from a random selection from the set of all possible amino acid variations, and have therefore escaped the effects of purifying selection that act strongly at the population level. We show that the pathogenicity of somatic mtDNA mutations is a determining factor for the oncocytic phenotype. The opposite associations of the Complex I and Complex V variants with the oncocytic and non-oncocytic tumors implies that low mitochondrial membrane potential may play an important role in determining the oncocytic phenotype.
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