MtDNA mutations increase tumorigenicity in prostate cancer

John A. Petros, Amanda K. Baumann, Eduardo Ruiz-Pesini, Mahul Amin, Carrie Qi Sun, John Hall, So Dug Lim, Muta M. Issa, W. Dana Flanders, Seyed H. Hosseini, Fray F. Marshall, Douglas C. Wallace

Research output: Contribution to journalArticle

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Abstract

Mutations in the mtDNA have been found to fulfill all of the criteria expected for pathogenic mutations causing prostate cancer. Focusing on the cytochrome oxidase subunit I (COI) gene, we found that 11-12% of all prostate cancer patients harbored COI mutations that altered conserved amino acids (mean conservation index = 83%), whereas <2% of no-cancer controls and 7.8% of the general population had COI mutations, the latter altering less conserved amino acids (conservation index = 71%). Four conserved prostate cancer COI mutations were found in multiple independent patients on different mtDNA backgrounds. Three other tumors contained heteroplasmic COI mutations, one of which created a stop codon. This latter tumor also contained a germ-line ATP6 mutation. Thus, both germ-line and somatic mtDNA mutations contribute to prostate cancer. Many tumors have been found to produce increased reactive oxygen species (ROS), and mtDNA mutations that inhibit oxidative phosphorylation can increase ROS production and thus contribute to tumorigenicity. To determine whether mutant tumors had increased ROS and tumor growth rates, we introduced the pathogenic mtDNA ATP6 T8993G mutation into the PC3 prostate cancer cell line through cybrid transfer and tested for tumor growth in nude mice. The resulting mutant (T8993G) cybrids were found to generate tumors that were 7 times larger than the wild-type (T8993T) cybrids, whereas the wild-type cybrids barely grew in the mice. The mutant tumors also generated significantly more ROS. Therefore, mtDNA mutations do play an important role in the etiology of prostate cancer.

Original languageEnglish (US)
Pages (from-to)719-724
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number3
DOIs
StatePublished - Jan 18 2005

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Prostatic Neoplasms
Mutation
Mitochondrial DNA
Electron Transport Complex IV
Neoplasms
Reactive Oxygen Species
Amino Acids
Germ-Line Mutation
Terminator Codon
Oxidative Phosphorylation
Growth
Nude Mice
Germ Cells
Cell Line
Population
Genes

All Science Journal Classification (ASJC) codes

  • General

Cite this

MtDNA mutations increase tumorigenicity in prostate cancer. / Petros, John A.; Baumann, Amanda K.; Ruiz-Pesini, Eduardo; Amin, Mahul; Sun, Carrie Qi; Hall, John; Lim, So Dug; Issa, Muta M.; Flanders, W. Dana; Hosseini, Seyed H.; Marshall, Fray F.; Wallace, Douglas C.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 3, 18.01.2005, p. 719-724.

Research output: Contribution to journalArticle

Petros, JA, Baumann, AK, Ruiz-Pesini, E, Amin, M, Sun, CQ, Hall, J, Lim, SD, Issa, MM, Flanders, WD, Hosseini, SH, Marshall, FF & Wallace, DC 2005, 'MtDNA mutations increase tumorigenicity in prostate cancer', Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 3, pp. 719-724. https://doi.org/10.1073/pnas.0408894102
Petros, John A. ; Baumann, Amanda K. ; Ruiz-Pesini, Eduardo ; Amin, Mahul ; Sun, Carrie Qi ; Hall, John ; Lim, So Dug ; Issa, Muta M. ; Flanders, W. Dana ; Hosseini, Seyed H. ; Marshall, Fray F. ; Wallace, Douglas C. / MtDNA mutations increase tumorigenicity in prostate cancer. In: Proceedings of the National Academy of Sciences of the United States of America. 2005 ; Vol. 102, No. 3. pp. 719-724.
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