Mitochondrial genome instability in human cancers

doi:10.1016/S1383-5742(00)00063-6

Mutation Research/Reviews in Mutation Research

Volume 488, Issue 1, March 2001, Pages 9-23

https://doi.org/10.1016/S1383-5742(00)00063-6 Get rights and content

Abstract

Malfunction of mismatch repair (MMR) genes produces nuclear genome instability (NGI) and plays an important role in the origin of some hereditary and sporadic human cancers. The appearance of non-inherited microsatellite alleles in tumor cells (microsatellite instability, MSI) is one of the expressions 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 repeats, mono- or dinucleotide insertions or deletions, and long deletions. Comparison of normal and tumoral tissues from the same individual reveals that mt-mutations may show as homoplasmic (all tumor cells have the same variant haplotype) or as heteroplasmic (tumor cells are a mosaic of inherited and acquired variant haplotypes). Breast, colorectal, gastric and kidney cancers 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. Conversely, germ cell testicular cancers lack mtGI. Damage by reactive oxygen species (ROS), slipped-strand mispairing (SSM) and deficient repair are the causes 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 γ (POLγ) carries out the mtDNA synthesis. Since this process is error-prone due to a deficiency in the proofreading activity of POLγ, this enzyme has been assumed to be involved in the origin of mt-mutations. Somatic cells have hundreds to thousands of mtDNA molecules with a very high rate of spontaneous mutations. Accordingly, most somatic cells probably have a low frequency of randomly mutated mtDNA molecules. Most cancers are of monoclonal origin. Hence, to explain the appearance of mtGI in tumors we have to explain why a given variant mt-haplotype expands and replaces part of (heteroplasmy) or all (homoplasmy) wild mt-haplotypes in cancer cells. Selective and/or replicative advantage of some mutations combined with a severe bottleneck during the mitochondrial segregation accompanying mitosis are the mechanisms probably involved in the origin of mtGI.

Introduction

Background: Several types of hereditary and sporadic human tumors show high rates of spontaneous mutations due to malfunction of one or more of the genes forming the cohort of mismatch repair genes (MMR) [1], [2]. Nuclear genome instability (NGI) is the term coined to identify this phenomenon, and the presence of microsatellite instability (MSI, appearance of novel, non-inherited alleles in tumor cells) is the most frequent event used for detection of NGI.

For colorectal cancers, data on MSI was reviewed and standardized by a panel of experts [3] who recommended to define as high-frequency microsatellite instability (MSI-H) those cases showing allelic changes in two or more of at least five MS loci and to identify as low-frequency microsatellite instability (MSI-L) mutations in only one MS locus of the set of loci tested [3]. Definitions of colorectal cancers MSI-H and L are usually extrapolated to other forms of cancer such as breast, gastric, endometrial, head and neck, bladder and lung tumors [4], [5], [6], [7], [8]. Moreover, for colorectal as well as for other forms of cancer, it is generally accepted that MSI-H is an indication of MMR gene mutations, while MSI-L might or might not be due to MMR gene malfunction [3].

Eukaryote cells not only have a nuclear genome but also cytoplasmic genomes that are compartimentalized in the mitochondria. Thus, the finding of NGI in human cancers raises the question of whether malignant cells may also show mitochondrial genome instability (mtGI) and, if so, what is the correlation between NGI and mtGI and what is the functional importance of this last event for the evolution of cancer cells. The aim of this report is to review the data on the presence, origin and role of mitochondrial mutations in human cancers. Since the definition mtGI and the characteristics of this phenomenon will be strongly influenced by the pecularities of mitochondrial genomes, a summary of the most relevant properties of mtDNA will be an appropriate starting point for this review.

Section snippets

Mitochondrial DNA structure and properties

Mitochondrial genomes (mt-genomes) are short circular molecules that, with the exception of viruses, represent the most economically packed forms of DNA in the whole biosphere. The human mt-genome is only 16,569 bp long [9]; within this extension, we find the coding sequences for seven subunits of the NADH-ubiquitone reductase (respiratory complex I), the apocytochrome b of the ubiquitone cytochrome c reductase (respiratory complex III), three subunits of the cytochrome c oxidase complex

Mitochondrial GI, mtDNA markers, homo- and heteroplasmy

Cancer mtGI can be defined as the occurrance of mutations in tumor cells which are not found in the normal cell counterpart of the same individual.

Previous to the use of PCR techniques, the analysis of mtGI required the isolation of pure mtDNA by cellular homogeneization with separation of nuclei and cytoplasmic organelles, subsequent mtDNA purification by preparative centrifugation in sucrose gradients and the search of RFLPs. Alternatively, mtRFLPs could be also detected by endonuclease

Caveat

Severely damaged mtDNA molecules become fragmented. These fragments undergo degradation in the mt-microenvironment or in the cytoplasm or, in some cases, enter the nucleus and may become inserted into the nuclear DNA [40], [41]. In this regard, the transposition of mtDNA fragments within the nuclear genome has been proposed to play a role in certain cases of cell transformation [41].

In human HeLa cells, several authors [39], [42] have demonstrated the nuclear insertion of mt fragments belonging

Mitochondrial GI in colon cancer

Initial studies on colon cancer mitochondria showed structural and functional abnormalities of these organelles in tumor cells [48], [49]. For instance, the expression of cytochrome c oxidase II, III and ND3 mt-genes was lower in colorectal tumors than in normal colorectal tissues of the same individual [50], [51]. Accordingly, it is not surprising that colon cancers were the first variety of tumors tested for mtGI with the use of PCR techniques [52]. Several groups of investigators have

Mitochondrial GI in breast cancer

Different types of extensive deletions and point mutations are known to accumulate in brain and muscle tissues of aging human individuals [31], [57], [58], [59]. Due to the hormonal stimulus, mammary gland cells of sexually mature women undergo periodic changes in structure and function [60]. On the other hand, the marked changes in hormonal secretion taking place in post-menopausal females decrease the activity of breast cells starting a process of premature aging that might be accompanied by

Mitochondrial GI in gastric cancer

A total of 192 normal/gastric cancer tissue pairs were tested for mtGI by four independent groups. Burgart et al. [63] used DNA from paraffin-embedded tissues to study the D-loop region delimited by bp positions 75–520 in 77 tumors. In four gastric adenocarcinomas of the gastroaesophageal junction, the authors detected a deletion of 50 bp extending from 289 to 348 bp that was not present in normal gastric tissues. Deletion breakpoints had 5′-CCAAACCCC-3′ direct repeats. Cases showing the 50 bp

Renal tumors

Kidney oncocytomas were the first tumors in which the existence of cancer-specific mt-mutations was demonstrated during the pre-PCR period. In 1989, Welter et al. [25] isolated mtDNA from cancer and normal tissues in six patients undergoing surgical treatment, and digested these mtDNA samples with a panel of five restriction enzymes. In one oncocytoma, they found an extra 40 bp HinfI fragment not observed in the normal mtDNA counterpart. By using Southern analysis, the authors concluded that

Testicular tumors

Multicenter sperm analysis in more than 17,000 normal males indicate a decrease of about 50% in sperm concentration and quality during the last 30–50 years [67], [68], [69]. During the same period, in addition to sperm decrease of ejaculates, there was a clear time-trend increase in the incidence of germ cell testicular cancers [70], [71]. Mechanisms playing a role in the origin of the above phenomena are not clear, but increased germ cell damage by free radicals due to dietary changes and

Mechanisms of mtGI in tumors

DNA damage, slipped-strand mispairing (SSM), defective DNA repair and unequal crossing-over are the causes producing allelic changes in the nuclear genome. With the exception of unequal crossing-over, the other three mechanisms also generate the genomic changes detected for the cytoplasmic DNA of tumors. Yet, the specific mutation patterns observed in each of the tumor forms analyzed so far (Table 1) suggest a differential relevance for each of the mechanisms involved in the appearance of mtDNA

Heteroplasmy versus homoplasmy

A somatic cell has hundreds to thousands of mtDNA molecules which, due to the high rate of spontaneous mutations, have an assorted set of random polymorphisms. Since most cancers have a monoclonal origin, it remains to be explained how a given mt-haplotype, among the many haplotypes that probably exist in the primary transformed cell, may reach during the process of clonal expansion a frequency high enough to be detected as a heteroplasmic or homoplasmic haplotype.

Two hypotheses have been so

Final remarks

Malignant cell transformation is a multistep process that usually involves a cascade of events in which malfunction of one gene triggers the sequential malfunction of other genes generating changes in the cell cycle that initiates transformation. In many hereditary and sporadic cancers, mutation, epigenetic factors such as abnormal methylation [105], [106] and LOH in one or more genes of the cohort of DNA repair genes produce NGI. Data in this review show that, with the exception of testicular

Acknowledgements

This work was supported by grants from the “Consejo Nacional de Investigaciones Cientı́ficas y Técnicas” (CONICET), “Agencia Nacional de Promoción Cientı́fica y Tecnológica” (ANPCYT), “Liga Argentina de Lucha contra el Cáncer” (LALCEC), and “Comisión de Investigaciones Cientı́ficas de la Provincia de Buenos Aires” (CICPBA).

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Mitochondrial genome instability in human cancers

Abstract

Introduction

Section snippets

Mitochondrial DNA structure and properties

Mitochondrial GI, mtDNA markers, homo- and heteroplasmy

Caveat

Mitochondrial GI in colon cancer

Mitochondrial GI in breast cancer

Mitochondrial GI in gastric cancer

Renal tumors

Testicular tumors

Mechanisms of mtGI in tumors

Heteroplasmy versus homoplasmy

Final remarks

Acknowledgements

Curr. Opin. Genet. Dev.

Rev. Mutat. Res.

Gastroenterology

Exp. Cell Res.

Am. J. Hum. Genet.

Am. J. Hum. Genet.

Am. J. Hum. Genet.

Leukemic Res.

Biochim. Biophys. Acta

Biochem. Biophys. Res. Commun.

J. Mol. Biol.

Mutat. Res.

Trends Biochem.

Mutat. Res.

Mutat. Res.

Mutat. Res.

Eur. J. Cancer

Fertil. Steril.

Am. J. Hum. Genet.

Mutat. Res.

J. Mol. Biol.

Cell

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Gene

Cell

J. Biol. Chem.

J. Biol. Chem.

Genomics

Trends Genet.

A National Cancer Institute workshop on microsatellite instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer

Cancer Res.

Microsatellite instability and loss of heterozygosity in primary breast tumours

Tumor Biol.

Microsatellite instability in sporadic human breast cancers

Int. J. Cancer

Mutations in DNA mismatch repair genes are not responsible for microsatellite instability in most sporadic endometrial carcinomas

Cancer Res.

Molecular detection of primary bladder cancer by microsatellite analysis

Science

Biogenesis of mitochondria

Ann. Rev. Cell Biol.

Efficient repair of abasic sites in DNA by mitochondrial enzymes

Mol. Cell. Biol.

Mitochondrial targeting of human DNA glycosylases for repair of oxidative DNA damage

Nucleic Acids Res.

Rapid evolution of animal mitochondrial DNA

Proc. Natl. Acad. Sci. U.S.A.

How rapidly does the human mitochondrial genome evolve?

Am. J. Hum. Genet.

Mutational hot spots in the mitochondrial microcosm

Am. J. Hum. Genet.

A high observed substitution rate in the human mitochondrial DNA control region

Nat. Genet.

Human brain contains high levels of heteroplasmy in the noncoding regions of mitochondrial DNA

Proc. Natl. Acad. Sci. U.S.A.

Heteroplasmic point mutations in the human mtDNA control region

Am. J. Hum. Genet.

Alteration of mitochondrial DNA in human oncocytomas

Genes Chrom. Cancer

Circular dimers and catenate of mitochondrial DNA in human leukemic leukocytes

Nature