Journal Article

Simultaneous generation of multiple mitochondrial DNA mutations in human prostate tumors suggests mitochondrial hyper-mutagenesis

Junjian Z. Chen, Neriman Gokden, Graham F. Greene, Bridgett Green and Fred F. Kadlubar

in Carcinogenesis

Volume 24, issue 9, pages 1481-1487
Published in print September 2003 | ISSN: 0143-3334
Published online September 2003 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgg102
Simultaneous generation of multiple mitochondrial DNA mutations in human prostate tumors suggests mitochondrial hyper-mutagenesis

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Multiple somatic mitochondrial DNA mutations are frequently reported in human tumors, but the process leading to homoplasmic transformation and accumulation of multiple mutations in the same tumor cell lineage remains a mystery. We address possible mechanisms responsible for the generation of multiple mitochondrial (mt)DNA mutations observed in a high frequency of prostate tumors using sensitive mutant-specific PCR coupled with laser capture microdissection. Analysis of prostate tumors with multiple mtDNA mutations in the control region indicates that the mutations are locally confined, that the multiple mutations exist on the same molecules and that more than one mtDNA mutant species co-exists in the same neoplastic lesion. These results suggest an unusually rapid process in mtDNA mutagenesis during tumor progression. On the basis of prostate tumor cell kinetics, we propose a unique process of mitochondrial hyper-mutagenesis, probably mediated by cellular oxidative stress, to account for a burst of multiple mtDNA mutations in human prostate tumors.

Keywords: D-loop, displacement loop; HV1, hyper-variable region 1; HV2, hyper-variable region 2; LCM, laser capture microdissection; mtDNA, mitochondrial DNA; PIN, prostatic intra-epithelial neoplasia; ROS, reactive oxygen species

Journal Article.  4848 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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