Nature Genetics
20, 291 - 293 (1998)
doi:10.1038/3108
Somatic mutations of the mitochondrial genome in human colorectal tumoursKornelia Polyak1, 2, 5, Yunbo Li3, Hong Zhu3, Christoph Lengauer2, James K.V. Willson4, Sanford D. Markowitz1, 4, Michael A. Trush3, Kenneth W. Kinzler2
& Bert Vogelstein1, 21
The Howard Hughes Medical Institute,Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland 21231, USA. 2
The Johns Hopkins Oncology Center,Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland 21231, USA. 3
Division of Toxicological Sciences, Department of Environmental Health Sciences, Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland 21231, USA
. 4
Department of Medicine and Ireland Cancer Center, Case
Western Reserve University, Cleveland, Ohio
44106, USA. 5
Present address: Dana-Farber Cancer Institute, Department of Adult Oncology, Boston, Massachusetts 02115, USA.
Correspondence should be addressed to Bert Vogelstein vogelbe@welchlink.welch.jhu.eduAlterations of oxidative phosphorylation in tumour cells were originally
believed to have a causative role in cancerous growth1. More
recently, mitochondria have again received attention with regards to neoplasia,
largely because of their role in apoptosis and other aspects of tumour biology2,
3,
4,
5,
6,
7,
8. The mitochondrial genome is particularly susceptible
to mutations because of the high level of reactive oxygen species (ROS) generation
in this organelle, coupled with a low level of DNA repair9,
10,
11,
12.
However, no detailed analysis of mitochondrial DNA in human tumours has yet
been reported. In this study, we analysed the complete mtDNA genome of ten
human colorectal cancer cell lines by sequencing and found mutations in seven
(70%). The majority of mutations were transitions at purines, consistent with
an ROS-related derivation. The mutations were somatic, and those evaluated
occurred in the primary tumour from which the cell line was derived. Most
of the mutations were homoplasmic, indicating that the mutant genome was dominant
at the intracellular and intercellular levels. We showed that mitochondria
can rapidly become homogeneous in colorectal cancer cells using cell fusions.
These findings provide the first examples of homoplasmic mutations in the
mtDNA of tumour cells and have potential implications for the abnormal metabolic
and apoptotic processes in cancer.
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