Abstract
Alterations 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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Warburg, O. On the origin of cancer cells. Science 123, 309–314 (1956).
Kroemer, G., Zamzami, N. & Susin, S.A. Mitochondrial control of apoptosis. Immunol. Today 18, 45–51 (1997).
Korsmeyer, S.J., Yin, X.M., Oltvai, Z.N., Veis-Novack, D.J. & Linette, G.P. Reactive oxygen species and the regulation of cell death by the Bcl-2 gene family. Biochim. Biophys. Acta 1271, 63–66 (1995).
Rudin, C.M. & Thompson, C.B. Apoptosis and disease: regulation and clinical relevance of programmed cell death. Annu. Rev. Med. 48, 267–281 (1997).
Wang, H.G. & Reed, J.C. Mechanisms of Bcl-2 protein function. Histol. Histopathol. 13, 521– 530 (1998).
Cavalli, L.R. & Liang, B.C. Mutagenesis, tumorigenicity, and apoptosis: are the mitochondria involved? Mutat. Res. 398, 19–26 (1998).
Chen, L.B. Mitochondrial membrane potential in living cells. Annu. Rev. Cell Biol. 4, 155–181 (1988).
Augenlicht, L.H. & Heerdt, B.G. Modulation of gene expression as a biomarker in colon. J. Cell. Biochem. Suppl. 16G, 151–157 (1992).
Lightowlers, R.N., Chinnery, P.F., Turnbull, D.M. & Howell, N. Mammalian mitochondrial genetics: heredity, heteroplasmy and disease. Trends Genet. 13, 450–455 (1997).
Beal, M. Mitochondria, free radicals, and neurodegeneration. Curr. Opin. Neurobiol. 6, 661–666 (1996).
Li, Y., Zhou, H., Stansbury, K. & Trush, M. Role of reactive oxygen species in multistage carcinogenesis. in Oxygen radicals and the disease process (eds Thomas, C. & Kalyanaraman, B.) 237–277 (Harwood Academic Publishers, Amsterdam, The Netherlands, 1997).
Croteau, D.L. & Bohr, V.A. Repair of oxidative damage to nuclear and mitochondrial DNA in mammalian cells. J. Biol. Chem. 272, 25409–25412 (1997).
Parfait, B., Rustin, P., Munnich, A. & Rotig, A. Co-amplification of nuclear pseudogenes and assessment of heteroplasmy of mitochondrial DNA mutations. Biochem. Biophys. Res. Commun. 247, 57–59 (1998).
Beckman, K.B. & Ames, B.N. Oxidative decay of DNA. J. Biol. Chem. 272, 19633–19636 (1997).
Cadet, J., Berger, M., Douki, T. & Ravanat, J.L. Oxidative damage to DNA: formation, measurement, and biological significance. Rev. Physiol. Biochem. Pharmacol. 131, 1– 87 (1997).
Wallace, D.C., Brown, M.D., Melov, S., Graham, B. & Lott, M. Mitochondrial biology, degenerative diseases and aging. Biofactors 7, 187–190 (1998).
Shay, J. & Ishii, S. Unexpected nonrandom mitochondrial DNA segregation in human cell hybrids. Anticancer Res. 10, 279–284 (1990).
Lengauer, C., Kinzler, K.W. & Vogelstein, B. Genetic instability in colorectal cancers. Nature 386, 623–627 (1997).
Khrapko, K. et al. Mitochondrial mutational spectra in human cells and tissues. Proc. Natl Acad. Sci. USA 94, 13798– 13803 (1997).
Beckman, K. & Ames, B. Detection and quantification of oxidative adducts of mitochondrial DNA. Methods Enzymol. 264, 442–453 (1996).
Welter, C., Kovacs, G., Seitz, G. & Blin, N. Alteration of mitochondrial DNA in human oncocytomas. Genes Chromosomes Cancer 1, 79–82 (1989).
Yamamoto, H. et al. Significant existence of deleted mitochondrial DNA in cirrhotic liver surrounding hepatic tumor. Biochem. Biophys. Res. Commun. 182, 913–920 (1992).
Burgart, L.J., Zheng, J., Shu, Q., Strickler, J.G. & Shibata, D. Somatic mitochondrial mutation in gastric cancer. Am. J. Pathol. 147, 1105–1111 (1995).
Tallini, G., Ladanyi, M., Rosai, J. & Jhanwar, S. Analysis of nuclear and mitochondrial DNA alterations in thyroid and renal oncocytic tumour. Cytogenet. Cell. Genet. 66, 253–259 (1994).
Heerdt, B.G., Chen, J., Stewart, L.R. & Augenlicht, L.H. Polymorphisms, but lack of mutations or instability, in the promotor region of the mitochondrial genome in human colonic tumors. Cancer Res. 54, 3912–3915 (1994).
Wallace, D.C. Mitochondrial DNA sequence variation in human evolution and disease. Proc. Natl Acad. Sci. USA 91, 8739– 8746 (1994).
Attardi, G., Yoneda, M. & Chomyn, A. Complementation and segregation behavior of disease-causing mitochondrial DNA mutations in cellular model systems. Biochim. Biophys. Acta 1271, 241–248 (1995).
Chee, M. et al. Accessing genetic information with high-density DNA arrays. Science 274, 610–614 (1996).
Parsons, R. et al. Microsatellite instability and mutations of the transforming growth factor b type II receptor gene in colorectal cancer. Cancer Res. 55, 5548–5550 (1995).
Jen, J. et al. Allelic loss of chromosome 18q and prognosis in colorectal cancer. N. Engl. J. Med. 331, 213– 221 (1994).
Armour, J.A., Neumann, R., Gobert, S. & Jeffreys, A.J. Isolation of human simple repeat loci by hybridization selection. Hum. Mol. Genet. 3, 599–665 (1994).
Hofhaus, G. & Attardi, G. Efficient selection and characterization of mutants of a human cell line which are defective in mitochondrial DNA-encoded subunits of respiratory NADH dehydrogenase. Mol. Cell. Biol. 15, 964–974 (1995).
Acknowledgements
This work was supported by the Clayton Fund, the American Cancer Society and NIH grants CA 43460, CA 57345, C A67409, C72160, CA 43703, CA 59366, ES03760 and ES03819.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Polyak, K., Li, Y., Zhu, H. et al. Somatic mutations of the mitochondrial genome in human colorectal tumours. Nat Genet 20, 291–293 (1998). https://doi.org/10.1038/3108
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/3108
This article is cited by
-
Population genetics of clonally transmissible cancers
Nature Ecology & Evolution (2022)
-
Mitochondrial impairments in aetiopathology of multifactorial diseases: common origin but individual outcomes in context of 3P medicine
EPMA Journal (2021)
-
Cracking the enigma of mitochondrial-DNA variants and cancer
Nature Metabolism (2020)
-
Age-associated mitochondrial DNA mutations cause metabolic remodeling that contributes to accelerated intestinal tumorigenesis
Nature Cancer (2020)
-
Evaluation of mitochondria in oocytes following γ-irradiation
Scientific Reports (2019)