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High Incidence of Somatic Mitochondrial DNA Mutations in Human Ovarian Carcinomas

Departments of Obstetrics and Gynecology [V. W. S. L., H. H. S., T. W. L., L. C. W., H. Y. S. N.] and Pathology [A. N. Y. C., P. M. C.], University of Hong Kong, Queen Mary Hospital, Hong Kong, and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia [P. N.]

	ABSTRACT

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To investigate the potential role of somatic mitochondrial DNA (mtDNA) mutations in tumorigenesis, the occurrence of mutations in mtDNA of ovarian carcinomas was studied. We sequenced the D-loop region of mtDNA of 15 primary ovarian carcinomas and their matched normal controls. Somatic mtDNA mutations were detected in 20% (3 of 15) tumor samples carrying single or multiple changes. Complete sequence analysis of the mtDNA genomes of another 10 pairs of primary ovarian carcinomas and control tissues revealed somatic mtDNA mutations in 60% (6 of 10) of tumor samples. Most of these mutations were homoplasmic, and most were TC or GA transitions, but one represented a differential length within a run of identical C residues. A region of mtDNA sequence including the 16S and 12S rRNA genes, the D-loop and the cytochrome b gene, may represent the zone of preferred mtDNA mutation in ovarian cancer. The high incidence of mtDNA mutations found in ovarian carcinomas and other human cancers suggests that genetic instability of mtDNA might play a significant role in tumorigenesis.

	Introduction

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Tumor cells generally carry a large number of DNA changes. Investigations until recently have concentrated mainly on the alterations of nuclear DNA in various cancers. However, the alterations of mtDNA² in tumors have received much less attention, despite the fact that the mutational rate of mtDNA is at least 10 times higher than nuclear DNA (1) . The recently recognized involvement of mitochondria in apoptosis (2) , and probably also tumorigenesis (3) , have stimulated interest in examining the potential role of mtDNA mutation in the development and maintenance of cancers.

The human mtDNA has been sequenced in its entirety (4) . It is circular, small (16,569 bp), and present at high copy numbers (10³ to 10⁴) per cell. It contains 37 genes, including the structural genes for 13 of the protein subunits of the oxidative phosphorylation system, the 12S and 16S rRNA genes, and 22 tRNAs. In addition, there is a noncoding region, the so called D-loop, which contains regulatory sequences controlling both replication and transcription of mtDNA. The mtDNA is highly susceptible to mutations because of its continuous exposure to high levels of reactive oxygen species generated during oxidative phosphorylation. Given the paucity of spacer regions between human mitochondrial genes, a mutation of the mtDNA will most likely involve a functionally important region of the genome.

Recently, the occurrence of somatic mtDNA mutations in several human cancers has been reported. By sequencing the complete mitochondrial genome of 10 colorectal tumors, 70% of such cases were demonstrated to carry one to three mutations (5) . In another study, mtDNA mutations were found in 64% of cases of bladder cancers, 46% of head and neck cancers, and 43% of lung cancers (6) . Somatic mtDNA mutations were also found in 80% of pancreatic cancers (7) and 23% of papillary thyroid carcinomas (8) .

In this communication, we report the finding of a high incidence (60%) of somatic mtDNA mutations in human ovarian carcinomas. On the basis of the relatively tight distribution of these mtDNA mutations observed in this study, a 3-kb segment of mtDNA encompassing the D-loop may represent a hotspot region of mtDNA mutation in ovarian cancer.

	Materials and Methods

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Tissue Samples.
Frozen samples of primary ovarian carcinomas and those of their matched normal tissues (including cervix, endometrium, or lymphocytes) obtained after surgery were retrieved without specific selection from our tissue bank and used for DNA analysis in this study. In addition, pathological paraffin-embedded tumor tissues and sera from the same set of individuals were also used to cross check the DNA changes found. This study was approved (EC 1517-00) by the Ethics Committee of the University of Hong Kong.

DNA Isolation.
DNA was purified from frozen tissues by the standard Proteinase K treatment followed by phenol/chloroform extraction (9) . DNA was also isolated from paraffin-embedded tumor tissues using the QIAmp Tissue kit (Qiagen, Hilden, Germany). About 100 ng of total cellular DNA were used for PCR.

Free DNA in serum was extracted according to the method described (10) with minor modifications. Briefly, serum (250 µl) was mixed with 0.5 M EDTA (20 µl) and sterile water (730 µl). The serum proteins were removed by phenol extraction followed by centrifugation at 10,000 x g for 5 min. DNA in the aqueous layer was precipitated by addition of sodium acetate and absolute ethanol, followed by incubation at -70°C for 10 min. The DNA was pelleted by centrifugation at 20,000 x g for 10 min, washed once with 70% ethanol, air dried and resuspended in sterile water (50 µl). Without measuring the DNA amount (because of low quantity), 5-µl samples of serum DNA extract were used for subsequent PCR assay.

PCR Amplification, Nucleotide Sequence Analysis of the D-Loop Region, and Classification of mtDNA Mutations.
The D-loop region (spanning np 16024 to 576) was amplified by PCR from tissue extracts under standard conditions. After purification (CONCERT rapid PCR kit; Life Technologies, Inc.), PCR products were then sequenced using a dRhodamine sequencing kit (Applied Biosystems), and sequences were read using a single capillary ABI 310 automatic sequencer (Perkin-Elmer). The DNA sequences were compared with the published Cambridge sequence (4) using DNAsis software. Sequence variants were then recorded. Those sequence variants found at a particular location in both tumor and matched normal mtDNA were classified as polymorphisms. Each was checked in the Mitomap database,³ and those not found in that database were classified as new polymorphisms, whereas others already there were classified as reported polymorphisms. If the DNA sequence at a particular location in tumor mtDNA differed from the matched normal mtDNA, this was defined as a somatic mutation. To confirm the DNA changes found in frozen tissues, the D-loop sequence within DNA extracted from paraffin-embedded tissues and serum from the corresponding individuals were also analyzed.

Sequence Analysis of Complete mtDNA Genomes.
Overlapping fragments of 1–3 kb in length were amplified by PCR to cover the entire mtDNA genome. After purification, the PCR products were used as templates for sequencing. Similar to the procedures described above, the reported polymorphisms, new polymorphisms, and somatic mutations were recorded. New polymorphisms and somatic mutations were reconfirmed in paraffin DNA and serum DNA. Details of PCR primers and sequencing primers are available upon request from the authors.

	Results and Discussion

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Sequence Variants in D-Loop.
Because the D-loop region is highly polymorphic and it contains two hypervariable regions that are believed to represent mutational hotspots (11) , we initially focused on the occurrence of mutations of this particular segment of mtDNA. From 15 cases of primary ovarian carcinomas, 71 sequence variants were found; each was classified according to "Materials and Methods" above. Fifty-four variants were reported polymorphisms, 8 were new polymorphisms (Table 1) , and 9 were somatic mutations found in 3 cases, OV12, OV22 and OV88 (Table 2) . Thus, 20% (3 of 15) of cases of ovarian carcinomas carried somatic mtDNA mutations in the D-loop. Most somatic mutations were homoplasmic, except one in OV22 and one in OV88. Sequencing details of the heteroplasmic mutation in OV22 are illustrated in Fig. 1A . The normal sequence is a microsatellite DNA containing a stretch of six CA repeats. In the tumor, the sequence represented a mixture of five and six CA repeats in approximately the ratio of 3:1. Interestingly, in OV88, a total of seven somatic mutations were found. The mutations in these three ovarian carcinomas were confirmed by analysis of mtDNA in paraffin and serum, if available (Table 2) .

View larger version (49K): [in this window] [in a new window] [Download PPT slide]   Fig. 1. Detection of mtDNA mutations in ovarian carcinomas by sequencing. A, portion of sequence data from OV22. The normal sequence (commencing at np 514, arrows) is a microsatellite DNA containing a stretch of six CA repeats. In the tumor, it was observed as a mixture of five and six CA repeats in approximately the ratio of 3:1. B, portion of sequence data from OV38. The mtDNA sequence found in the normal tissue contained a mixture of molecules carrying a consecutive stretch of C residues, comprising C7, C8, and C9 (commencing at np 303, arrows). In the tumor, mtDNA was observed as homoplasmic containing C7 sequence only. Sequence numbers in the figure refer to the printed output form the ABI310 automatic sequencer.

View larger version (13K): [in this window] [in a new window] [Download PPT slide]   Fig. 2. Location of somatic mtDNA mutations in various cancers. The locations of each such mutation, according to tissue source, are indicated by arrows (positions not drawn exactly to scale). COX, cytochrome c oxidase; ND, NADH dehydrogenase, Cyt b, cytochrome b; ATPase, ATP synthase. Gaps between genes indicate the positions of tRNAs. The mtDNA schematic is linearized as shown to enable the D-loop region to be displayed as a continuous segment. For ovarian cancer (the present work), data were obtained from complete mtDNA genome sequencing; in addition, 3 ovarian carcinomas were found to have mutations in the D-loop by specific analysis of PCR products from that region (asterisks), including seven mutations in a single tissue sample (thick arrow). Data for colon (5) and pancreas (7) were derived from complete mtDNA genome sequencing, whereas data for head and neck, bladder, and lung (6) were from extensive (80%) mtDNA genome sequencing. Data for papillary thyroid carcinomas (8) were obtained from a mutational scanning analysis of 25% of np in the mtDNA genome (sampling was spread across the entire genome), followed by DNA sequencing analysis.

A total of six mutations occur within a span of barely 3 kb encompassing the 16S and 12S rRNA genes, the D-loop, and the cytochrome b gene (Fig. 2) . This region, representing only about one-fifth of the mitochondrial genome, may represent a zone of preferred somatic mutations in human ovarian cancer. Certainly, to confirm whether this is a mutational "hotspot" region, analysis of a large number of samples would need to be carried out.

Significance of Mutations in 16S rRNA.
The distribution on the mtDNA genome of somatic mtDNA mutations found in this study and others (5, 6, 7, 8) are indicated in Fig. 2 . Although over seventy mutations were found, no one single somatic mtDNA mutation could be detected in more than one type of cancer. Nevertheless, mutations in the 16S rRNA gene were commonly found in different cancers, except those of the thyroid. Whether mutations in this gene contribute to a common mechanism of cancer growth and development or the results to date simply represent a coincidence is unknown. To assess the significance of these mutations and their association with carcinogenesis, functional analysis of mutated mtDNA in relation to cell behavior and mtDNA propagation is warranted. This could be done by repopulating rho⁰ cells (lacking mtDNA) with mitochondria carrying a cancer-derived variant mutant mtDNA genome followed by subsequent cell growth analysis (13) . Moreover, cell fusion tests (5) or heteroplasmic segregation tests (14) would enable examination of the proliferative drive of such mutant mtDNA. Jones et al. (7) have considered two interesting alternative possibilities whereby the homoplasmic state of the somatic mtDNA mutations arises in cancer tissues, i.e., by selection of mtDNA molecules for their enhanced replication or segregation (perhaps also by functional selection at the cellular level), or by random genetic drift during the 1000 or more cell divisions leading to a frank tumor mass.

High Mutational Rate of mtDNA.
Consistent with other studies, we have identified a large number of mtDNA polymorphisms. Most of the polymorphisms are TC or GA transitions. This indicates that mtDNA is highly susceptible to mutation, probably by oxidative stress (15) . It has been proposed that these mtDNA variants, together with somatic mtDNA mutations, would create an environment with a slight elevation of levels of reactive oxygen species inside mitochondria (5) . From consequential signal transduction, cell proliferation may be augmented. Again, the study of the functional impact of these variants on cell behavior may elucidate the role of mitochondria in carcinogenesis.

Application of Serum DNA in Cancer Management.
Many studies have demonstrated the detection of tumor DNA in plasma/serum (16) . It has been proposed that plasma/serum DNA might be a useful tool for the development of noninvasive diagnostic, prognostic, and follow-up tests for cancer (16 , 17) . In the present study, tumor mtDNA mutations were not detectable in sera of patients carrying somatic mtDNA mutations in their corresponding tissues. This may arise from the low sensitivity of detection by DNA sequencing. More sensitive methods, such as allele-specific PCR (18) , or DNA chip technology (19 , 20) could be used to detect tumor DNA in a background of normal DNA. It should be worthwhile to follow up these patients if tumor mtDNA mutations could be detectable in serum during metastasis. The feasibility of using serum or plasma DNA as a tool for the management of cancer needs further investigation. Nevertheless, analysis of the serum samples in this study has confirmed the nature of the germ-line mtDNA sequences to this stage, enabling confirmation of the authenticity of the observed somatic mtDNA mutations.

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom requests for reprints should be addressed, at Department of Obstetrics and Gynecology, University of Hong Kong, 6/Fl., Professorial Block, Queen Mary Hospital, Pokfulam Road, Hong Kong. Phone: 852-28554518; Fax: 852-28550947; E-mail: hysngan{at}hkucc.hku.hk

² The abbreviations used are: mtDNA, mitochondrial DNA; np, nucleotide position; rRNA, ribosomal RNA; tRNA, transfer RNA.

³ Internet address: http://www.gen.emory.edu/mitomap.html.

Received 5/15/01. Accepted 7/ 3/01.

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