Mitochondrial genome instability in human cancers

Malfunction of mismatch repair (MMR) genes produces nuclear genome instabil ity (NGI) and plays an important role in the origin of some hereditary and sporadic human cancers. The appearance of non-inherited microsatellite alle les in tumor cells (microsatellite instability, MSI) is one of the expressi ons of NGI. We present here data showing mitochondrial genome instability ( mtGI) in most of the human cancers analyzed so far. The mtDNA markers used were point mutations, length-tract instability of mono- or dinucleotide rep eats, mono- or dinucleotide insertions or deletions, and long deletions. Co mparison of normal and tumoral tissues from the same individual reveals tha t mt-mutations may show as homoplasmic (all tumor cells have the same varia nt haplotype) or as heteroplasmic (tumor cells are a mosaic of inherited an d acquired variant haplotypes). Breast, colorectal, gastric and kidney canc ers exhibit mtGI with a pattern of mt-mutations specific for each tumor. No correlation between NGI and mtGI was found in breast, colorectal or kidney cancers, while a positive correlation was found in gastric cancer. Convers ely, germ cell testicular cancers lack mtGI. Damage by reactive oxygen spec ies (ROS), slipped-strand mispairing (SSM) and deficient repair are the cau ses explaining the appearance of mtGI. The replication and repair of mtDNA are controlled by nuclear genes. So far, there is no clear evidence linking MMR gene malfunction with mtGI. Polymerase gamma (POL gamma) carries out t he mtDNA synthesis. Since this process is error-prone due to a deficiency i n the proofreading activity of POL gamma, this enzyme has been assumed to b e involved in the origin of mt-mutations. Somatic cells have hundreds to th ousands of mtDNA molecules with a very high rate of spontaneous mutations. Accordingly, most somatic cells probably have a low frequency of randomly m utated mtDNA molecules. Most cancers are of monoclonal origin. Hence, to ex plain the appearance of mtGI in tumors we have to explain why a given varia nt mt-haplotype expands and replaces part of (heteroplasmy) or all (homopla smy) wild mt-haplotypes in cancer cells. Selective and/or replicative advan tage of some mutations combined with a severe bottleneck during the mitocho ndrial segregation accompanying mitosis are the mechanisms probably involve d in the origin of mtGI. (C) 2001 Elsevier Science B.V. All rights reserved .