Mitochondrial DNA Polymerase γ Mutations and Their Implications in mtDNA Alterations in Colorectal Cancer

Linkowska, Katarzyna; Jawień, Arkadiusz; Marszałek, Andrzej; Malyarchuk, B. A.; Tońska, Katarzyna; Bartnik, Ewa; Skonieczna, Katarzyna; Grzybowski, Tomasz

doi:10.1111/ahg.12111

Cited by 22 publications

(19 citation statements)

References 46 publications

(57 reference statements)

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“…Nevertheless, the occurrence of such mutations may not have the same molecular background as the nuclear ones, as previous studies have shown lack of any association between the occurrence of mitochondrial and nuclear microsatellite instability (Venderbosch et al., ). It was previously proposed that polymerase gamma may be involved in mitochondrial length variation in D310 sequence in cancer (Skonieczna et al., ), but such associations were not observed for colorectal cancer patients (Linkowska et al., ). Thus, further studies are necessary to uncover molecular mechanisms underlying mitochondrial microsatellite instability in colorectal cancer.…”

Section: Discussionmentioning

confidence: 98%

Mitogenomic differences between the normal and tumor cells of colorectal cancer patients

et al. 2018

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So far, a reliable spectrum of mitochondrial DNA mutations in colorectal cancer cells is still unknown, and neither is their significance in carcinogenesis. Indeed, it remains debatable whether mtDNA mutations are "drivers" or "passengers" of colorectal carcinogenesis. Thus, we analyzed 200 mitogenomes from normal and cancer tissues of 100 colorectal cancer patients. Minority variant mutations were detected at the 1% level. We showed that somatic mutations frequently occur in colorectal cancer cells (75%) and are randomly distributed across the mitochondrial genome. Mutational signatures of somatic mitogenome mutations suggest that they might arise through nucleotide deamination due to oxidative stress. The majority of somatic mutations localized within the coding region (in positions not known from the human phylogeny) and was potentially pathogenic to cell metabolism. Further analysis suggested that the relaxation of negative selection in the mitogenomes of colorectal cancer cells may allow accumulation of somatic mutations. Thus, a shift in glucose metabolism from oxidative phosphorylation to glycolysis may create advantageous conditions for accumulation of mtDNA mutations. Considering the fact that the presence of somatic mtDNA mutations was not associated with any clinicopathological features, we suggested that mtDNA somatic mutations are "passengers" rather than the cause of colorectal carcinogenesis.

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Section: Discussionmentioning

confidence: 98%

Mitogenomic differences between the normal and tumor cells of colorectal cancer patients

et al. 2018

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“…In a study of 65 colorectal cancers, it has been suggested that hypomethylation of specific sites on CpG islands of the D-loop promoter may be involved in the regulation of mtDNA copy numbers [56]. Moreover, it has been reported that polymorphisms within the nuclear-encoded polymerase gamma gene (POLG), which codifies for a key component of the mitochondrial genome maintenance machinery, may lead to a decrease in mtDNA content and mitochondrial dysfunction [57]. Curiously, a homozygous polymorphic insertion (AluYb8MUTYH) in the 15th intron of the MUTYH base excision repair gene has been associated with a significant reduction of the type 1 MUTYH protein that localizes to mitochondria as well as lowered mtDNA content in age-related diseases [58].…”

Section: Mtdna Copy Number Alterationsmentioning

confidence: 99%

Mitochondrial DNA Variations in Tumors: Drivers or Passengers?

Errichiello¹,

Venesio²

2018

Mitochondrial DNA - New Insights

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Mitochondrial DNA alterations, including point mutations, deletions, inversions and copy number variations, have been widely reported in many age-related degenerative diseases and tumors. However, numerous studies investigating their pathogenic role in cancer have provided inconsistent evidence. Furthermore, biological impacts of mitochondrial DNA variants vary tremendously, depending on the proportion of mutant DNA molecules carried by the neoplastic cells (the so-called heteroplasmy). The recent discovery of inter-genomic crosstalk between nucleus and mitochondria has reinforced the role of mitochondrial DNA variants in perturbing this essential signaling pathway and thus indirectly targeting nuclear genes involved in tumorigenic and invasive phenotype. Therefore, mitochondrial dysfunction is currently considered a crucial hallmark of carcinogenesis as well as a promising target for anticancer therapy. This chapter describes the role of different types of mitochondrial DNA alterations by mainly considering the paradigmatic model of colorectal carcinogenesis and, in particular, it revisits the issue of whether mitochondrial mutations are causative cancer drivers or simply genuine passenger events. The advent of high-throughput next-generation sequencing techniques, as well as the development of genetic and pharmaceutical interventions for the treatment of mitochondrial dysfunction in cancer, are also discussed.

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“…2 Nevertheless, our previous study excluded the possibility that somatic mtDNA mutations arose in CC cells as a result of POLG gene mutations. 3 Thus, it remains to be determined whether other genes involved in mtDNA repair are associated with the accumulation of somatic mtDNA mutations in CC cells.…”

Section: Introductionmentioning

confidence: 99%

TP53 somatic mutations are associated with somatic mitogenome substitutions but not indels in colorectal cancer cells

Skonieczna

Jawień

Marszałek

et al. 2019

The Journal of Gene Medicine

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Background p53 is a tumour suppressor protein that is involved in many cancer‐related processes. Growing evidence suggests that p53 also plays an important role in mitochondrial (mtDNA) maintenance. Somatic mitogenome mutations are frequently observed in colorectal cancer (CC) cells. Thus, it was important to determine whether somatic mtDNA changes are associated with TP53 mutational status. Methods In the present study, we analysed the TP53 gene in 67 CC patients, for whom mitogenome haplotypes were previously described. In total, 134 TP53 sequences (of cancer and matched normal specimens) were determined using the dideoxy method. Results Nine hereditary polymorphisms in the TP53 gene were detected in normal colon cells. None of them (neither alleles, nor genotypes) was associated with somatic mitogenome mutations in CC cells. Moreover, 42 somatic TP53 mutations were found in approximately 36% of CC tissues. These somatic changes were significantly more frequent in CC cells with somatic mtDNA mutations (p = 0.0069). Furthermore, we show that only mitochondrial somatic substitutions (p = 0.0017), but not indels (p > 0.05), were associated with somatic TP53 mutations. Conclusions The results of the present study suggest that changes in TP53 may modify p53 properties, which may result in the accumulation of somatic substitutions in CC mitogenomes.

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Mitochondrial DNA Polymerase γ Mutations and Their Implications in mtDNA Alterations in Colorectal Cancer

Cited by 22 publications

References 46 publications

Mitogenomic differences between the normal and tumor cells of colorectal cancer patients

Mitogenomic differences between the normal and tumor cells of colorectal cancer patients

Mitochondrial DNA Variations in Tumors: Drivers or Passengers?

TP53 somatic mutations are associated with somatic mitogenome substitutions but not indels in colorectal cancer cells

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