Summary
Mitochondrial DNA was found to be highly mutated in colorectal cancer cells. One of the key molecules involved in the maintenance of the mitochondrial genome is the nuclear‐encoded polymerase ...gamma. The aim of our study was to determine if there is a link between polymorphisms within the polymerase gamma gene (POLG) and somatic mutations within the mitochondrial genome in cancer cells. We investigated POLG sequence variability in 50 colorectal cancer patients whose complete mitochondrial genome sequences were determined. Relative mtDNA copy number was also determined. We identified 251 sequence variants in the POLG gene. Most of them were germline‐specific (∼92%). Twenty‐one somatic changes in POLG were found in 10 colorectal cancer patients. We have found no association between the occurrence of mtDNA somatic mutations and the somatically occurring variants in POLG. MtDNA content was reduced in patients carrying somatic variants in POLG or germline nucleotide variants located in the region encoding the POLG polymerase domain, but the difference did not reach statistical significance. Our findings suggest that somatic mtDNA mutations occurring in colorectal cancer are not a consequence of somatic mutations in POLG. Nevertheless, POLG nucleotide variants may lead to a decrease in mtDNA content, and consequently result in mitochondrial dysfunction.
Numerous studies of mitochondrial DNA (mtDNA) in cancer have shown differences between mtDNA sequences in tumor and normal tissue and at various stages of cancer treatment in the same patient. ...However, there is little data on acute lymphoblastic leukemia (ALL), the most common type of leukemia in children. In this study we compared mitochondrial sequence variation in the D-loop region and in 5 genes of mtDNA in bone marrow samples of 6 pediatric patients with ALL at various stages of therapy. We found several common polymorphisms and one variant at position 3688 whose level varied during leukemia treatment. Our results suggest that mitochondrial DNA mutations, whose levels change during patient treatment, could be potential biomarkers for monitoring treatment efficacy and disease progression.
Sex, death and the (nerve) cell Tonska, Katarzyna; Bartnik, Ewa
Frontiers in bioscience (Elite edition),
01/2012, Volume:
4, Issue:
5
Journal Article
Peer reviewed
Men and women not only look different, but they have different risks of multiple diseases like migraine, neurodegenerative disorders or numerous cancers. Even the nerve cells may die in different ...ways and exhibit different sensitivity to pro-apoptotic factors. Some of the differences can be explained by the action of sex hormones, but the experiments on four core genotype mouse model, in which XX and XY mice can be of either sex showed that not all differences are due to hormones. An example of a disease with no simple explanation of sex bias is Leber hereditary optic neuropathy, a mitochondrial disease with about 4:1 male to female ratio. The apoptotic death of retinal ganglion cells forming an optic disc is a proposed mechanism of the disease pathophysiology. The mechanisms causing different sensitivity of the nerve cells of male and female subjects may be responsible for the gender bias in LHON and merit further studies.
In this consensus paper resulting from a meeting that involved representatives from more than 20 European partners, we recommend the foundation of an expert group (European Steering Committee) to ...assess the potential benefits and draw-backs of genome editing (off-targets, mosaicisms, etc.), and to design risk matrices and scenarios for a responsible use of this promising technology. In addition, this European steering committee will contribute in promoting an open debate on societal aspects prior to a translation into national and international legislation.
Diseases related to DNA polymerase gamma dysfunction comprise of heterogeneous clinical presentations with variable severity and age of onset. Molecular screening for the common POLG variants: ...p.Ala467Thr, p.Trp748Ser, p.Gly848Ser, and p.Tre251Ile has been conducted in a large population cohort (n = 3123) and in a clinically heterogeneous group of 1289 patients. Recessive pathogenic variants, including six novel ones were revealed in 22/26 patients. Infantile Alpers-Huttenlocher syndrome and adulthood ataxia spectrum were the most common found in our group. Distinct molecular profile identified in the Polish patients with significant predominance of p.Trp748Ser variant (50% of mutant alleles) reflected strikingly low population frequency of the three remaining variants and slightly higher p.Trp748Ser allele frequency in the general Polish population as compared to the non-Finish European population.
Cancer is a major health problem and cause of death worldwide that accounted for 7.6 million deaths in 2008, which is projected to continue rising with an estimated 13.1 million deaths in 2030 ...according to WHO. Breast cancer is the leading cause of cancer-based death among women around the world and its incidence is increasing annually with a similar tendency. In contrast, renal cell carcinoma accounts for only 3% of total human malignancies but it is still the most common type of urological cancer with a high prevalence in elderly men (>60 years of age). There are several factors linked with the development of renal cell cancer only, while others are connected only with breast cancer. Genetic risk factors and smoking are the factors which contribute to carcinogenesis in general. Some evidence exists indicating that vitamin D receptor (VDR) gene polymorphisms are associated with both breast and renal cancer; therefore, we put forward the hypothesis that polymorphisms in the VDR gene may influence both the occurrence risks of these cancers and their prognosis. However, the relationship between VDR polymorphisms and these two specific cancers remains a controversial hypothesis, and consequently needs further confirmation via clinical research together with genetic investigations. Here, we aimed to assess the correlation between the different alleles of VDR gene polymorphisms and renal cell cancer and breast cancer risks separately through a systematic review of the present literature. In contrast, this analysis has revealed that some VDR gene polymorphisms, such as: Bsm1, poly(A), Taq1, Apa1, are to some extent associated with breast cancer risk. Other polymorphisms were found to be significantly associated with renal cell cancer. Namely, they were Fok1, Bsm1, Taq1 and Apa1, which encode proteins participating mainly in proliferation, apoptosis and cell cycle regulation. However, data concerning renal cancer are not sufficient to firmly establish the VDR gene polymorphism association.
Perturbations of mitochondrial function, which may be caused by mutations in both nuclear and mitochondrial DNA, cause many human diseases. We describe the most frequent mitochondrial diseases, ...especially those caused by mutations in the nuclear genome, attempts to treat these diseases and possible ways of preventing the transmission of diseases caused by mutations in mitochondrial DNA to successive generations.
Huntington disease (HD) is an inherited neurodegenerative disorder caused by mutations in the huntingtin gene. Involvement of mitochondrial dysfunctions in, and especially influence of the level of ...mitochondrial DNA (mtDNA) on, development of this disease is unclear. Here, samples of blood from 84 HD patients and 79 controls, and dermal fibroblasts from 10 HD patients and 9 controls were analysed for mtDNA levels. Although the type of mitochondrial haplogroup had no influence on the mtDNA level, and there was no correlation between mtDNA level in leukocytes in HD patients and various parameters of HD severity, some considerable differences between HD patients and controls were identified. The average mtDNA/nDNA relative copy number was significantly higher in leukocytes, but lower in fibroblasts, of symptomatic HD patients relative to the control group. Moreover, HD women displayed higher mtDNA levels in leukocytes than HD men. Because this is the largest population analysed to date, these results might contribute to explanation of discrepancies between previously published studies concerning levels of mtDNA in cells of HD patients. We suggest that the size of the investigated population and type of cells from which DNA is isolated could significantly affect results of mtDNA copy number estimation in HD. Hence, these parameters should be taken into consideration in studies on mtDNA in HD, and perhaps also in other diseases where mitochondrial dysfunction occurs.
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