Loss of heteroplasmy in the displacement loop of brain mitochondrial DNA in astrocytic tumors

Kirches, Elmar; Michael, Matthias; Woy, Cornelia; Schneider, Thomas; Warich-Kirches, Michaela; Schneider‐Stock, Regine; Winkler, Kirstin; Wittig, Holger; Dietzmann, Knut

doi:10.1002/(sici)1098-2264(199909)26:1<80::aid-gcc11>3.0.co;2-4

Cited by 27 publications

(23 citation statements)

References 4 publications

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“…After controlling products on silver-stained polyacrylamide gels, samples were digested with HaeIII, creating a blunt end at np 333 immediately behind the polycytosine tract of interest. Using cloned and sequenced HVR2 fragments from an earlier study 21 and known HVR2 blood sequences, we could clearly determine the absolute length of the polycytosine tracts on a 373A sequencer (Applied Biosystems, Foster City, CA) by comparison with known sequences. Mixing experiments of known variants revealed that a certain proportion of 2 variants always resulted in the same proportion of both peaks in the sequencing gels.…”

Section: Microdissection and Fragment Length Analysismentioning

confidence: 99%

High frequency of mitochondrial DNA mutations in glioblastoma multiforme identified by direct sequence comparison to blood samples

et al. 2001

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In an earlier study, we showed that heteroplasmy in the mitochondrial genome of gliomas sometimes occurs in a D-loop polycytosine tract. We extended this study by pairwise comparisons between glioma samples and adjacent brain tissue of 55 patients (50 glioblastomas, 1 astrocytoma WHO grade III, 4 astrocytomas WHO grade II). We used a combination of laser microdissection and PCR to detect and quantify variations in the polycytosine tract. New length variants undetectable in the adjacent brain tissue were observed in 5 glioblastomas (9%). In 2 of these cases, samples from a lower tumor stage (WHO grade II) could be analyzed and revealed the early occurrence of these mutations in both cases. Since the mitochondrial D-loop contains additional repeats and highly polymorphic non-coding sequences, we compared 17 glioblastomas with the corresponding blood samples of the same patients by direct sequencing of the complete D-loop. In 6 of these tumors (35%), instability was detected in 1 or 2 of 3 repeat regions; in 1 of these repeats, the instability was linked to a germline T-to-C transition. Furthermore, of 2 tumors (12%) 1 carried 1 and the other 9 additional transitions. In the latter patient, 6.7 kb of the protein coding mtDNA sequence were analyzed. Six silent transitions and 2 missense mutations (transitions) were found. All base substitutions appeared to be homoplasmic upon sequencing, and 89% occurred at known polymorphic sites in humans. Our data suggest that the same mechanisms that generate inherited mtDNA polymorphisms are strongly enhanced in gliomas and produce somatic mutations.

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Section: Microdissection and Fragment Length Analysismentioning

confidence: 99%

High frequency of mitochondrial DNA mutations in glioblastoma multiforme identified by direct sequence comparison to blood samples

et al. 2001

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“…Chinnery et al (2002) suggested that random genetic drift is powerful enough to explain the fixation of rare mtDNA mutations during ageing, mtDNA disease, and cancer. In brain tumors, Kirches et al (1999) found high sequence variability in astrocytic brain cancers, as well as a loss of the heteroplasmy present in normal cells. In 2001, the same group extended the study of the HVS-II poly-C tract to 55 gliomas, detecting instability in five (9%) of them.…”

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confidence: 99%

mtDNA mutations in tumors of the central nervous system reflect the neutral evolution of mtDNA in populations

et al. 2003

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Mitochondrial DNA (mtDNA) instability has been observed in different types of cancer, including colorectal, breast, and gastric cancer. The relationship between the occurrence of such alteration and the nuclear microsatellite instability (nMI) status of the neoplastic cells remains controversial. In an attempt to clarify this issue, we sequenced the first and second mtDNA hypervariable regions, and typed the mitochondrial (CA) n dinucleotide polymorphism in 69 patients with primary tumors of the central nervous system (CNS), previously screened for nMI. Tumor samples showed 27 D-loop sequence changes (39.1%) compared to the corresponding blood samples. Microsatellite homoplasmic allele mutations were detected in four cases (5.8%). We did not find significant associations of the mtDNA instability status with clinicopathological parameters including sex, age, tumor size, and duration of clinical course. Neither did we find any association between mtDNA and nuclear instabilities, indicating that, at least in CNS tumors, they respond to different DNA repair mechanisms. We have also compiled the mtDNA instabilities previously reported by other authors for several types of tumors, comparing them to mtDNA polymorphisms in human populations. Most of the tumor-associated changes are common human polymorphisms and mutational hotspots. To explain the molecular behavior of mtDNA instability in tumors, we propose a model also common to other biological situations.

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“…According to the electrophoretic mobility of cloned and sequenced reference DNA in the gels, the peaks in the diagrams could be labelled with their absolute c-tract length. It is known12 and is supported by our own sequencing data10 that usually only the first half of the incomplete HVR2 c-tract exhibits length variability (fig 1). Therefore, the peak designations in fig 2 reflect only the number of cytosine residues within this region.…”

Section: Resultsmentioning

confidence: 60%

“…After controlling the products on silver stained PAGE gels, the samples were digested with Hae III, which creates a blunt end at np 333 immediately behind the c-tract of interest. Using cloned and sequenced HVR2 fragments from an earlier study10 and known HVR2 blood sequences, we could clearly determine the absolute c-tract length on a 373A sequencer (Applied Biosystems, Foster City, CA) by comparison with known sequences. Mixing experiments of known variants showed that a certain proportion of two variants always resulted in the same proportion of both peaks in the sequencing gels.…”

Section: Methodsmentioning

confidence: 99%

Heterogeneous tissue distribution of a mitochondrial DNA polymorphism in heteroplasmic subjects without mitochondrial disorders

Kirches

Michael²,

Warich-Kirches³

et al. 2001

Journal of Medical Genetics

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Results-DiVerences were found between organs or groups of organs within subjects, pointing towards somatic segregation of mtDNA. In addition, marked diVerences of this organ distribution occurred between subjects, which cannot be explained by tissue specific selection. Conclusions-The observed interperson diVerences can be explained by somatic segregation, which occurs randomly at various developmental stages. Besides tissue specific selection, this process might participate in the distribution of pathogenic mtDNA mutations. (J Med Genet 2001;38:312-317)

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Loss of heteroplasmy in the displacement loop of brain mitochondrial DNA in astrocytic tumors

Cited by 27 publications

References 4 publications

High frequency of mitochondrial DNA mutations in glioblastoma multiforme identified by direct sequence comparison to blood samples

High frequency of mitochondrial DNA mutations in glioblastoma multiforme identified by direct sequence comparison to blood samples

mtDNA mutations in tumors of the central nervous system reflect the neutral evolution of mtDNA in populations

Heterogeneous tissue distribution of a mitochondrial DNA polymorphism in heteroplasmic subjects without mitochondrial disorders

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