Mitochondrial DNA Alterations in Cancer

Copeland, William C.; Wachsman, J. T.; Johnson, F. M.; Penta, John S.

doi:10.1002/chin.200301269

Cited by 28 publications

(41 citation statements)

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“…27,28 Numerous reports have demonstrated that mtDNA is mutated and the mtDNA copy number is increased or decreased in human tumor tissues, depending on the specific tumor type. [29][30][31][32][33][34][35][36][37] A classic twin study estimated that the leukocyte mtDNA copy number has a heritability rate of 65%. 17 Several recent studies have indicated that the leukocyte mtDNA copy number is associated with altered cancer risks in a cancer type-specific manner.…”

Section: Introductionmentioning

confidence: 99%

“…17 Several recent studies have indicated that the leukocyte mtDNA copy number is associated with altered cancer risks in a cancer type-specific manner. 17,22,38,39 In terms of GC, several studies have reported mtDNA mutation or depletion in tumor tissue 32,36,37 ; and, in a recent prospective study in a Chinese population, a significant association was observed between a low leukocyte mtDNA copy number and an increased risk of GC in blood drawn within 2 years before cancer diagnosis. 40 Hispanics are the largest nonwhite ethnic group in the United States and account for approximately 17% of the US population.…”

Section: Introductionmentioning

confidence: 99%

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Genetic and intermediate phenotypic susceptibility markers of gastric cancer in Hispanic Americans: A case‐control study

Sun

Ajani

et al. 2014

Cancer

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BACKGROUND: Hispanics are the largest nonwhite ethnic group in the US population, and they have higher incidence and mortality rates for gastric cancer (GC) than whites and Asians. Studies have identified several genetic susceptibility loci and intermediate phenotypic biomarkers for GC in whites and Asians. No studies have evaluated genetic susceptibility and intermediate phenotypic biomarkers in Hispanics. METHODS: In a case-control study of 132 Hispanic patients with GC (cases) and a control group of 125 Hispanics (controls), the authors evaluated the association of 5 single nucleotide polymorphisms (SNPs) that predispose whites and=or Asians to GC and of 2 intermediate phenotypic markers in peripheral blood leukocytes, ie, telomere length and mitochondrial DNA (mtDNA) copy number, with the GC risk. RESULTS: The variant C allele of the reference SNP rs2294008 in the PSCA gene was associated with a significantly reduced risk of GC (per allele-adjusted odds ratio [aOR], 0.51; 95% confidence interval [CI], 0.33-0.77; P 5.002). Leukocyte mtDNA copy numbers were significantly lower in GC cases (mean 6 standard deviation, 0.91 6 0.28) than in controls (1.29 6 0.42; P <.001). When individuals were dichotomized into high and low mtDNA copy number groups based on the median mtDNA copy number value in the controls, those who had a low mtDNA copy number had a significantly increased risk of GC (aOR, 11.00; 95% CI, 4.79-25.23; P <.001) compared with those who had a high mtDNA copy number. Telomere length was not associated significantly with the risk of GC (aOR, 1.21; 95% CI, 0.65-2.27; P 5.551). CONCLUSIONS: Hispanics share certain genetic susceptibility loci and intermediate phenotypic GC biomarkers with whites and Asians and may also have distinct genetic susceptibility factors.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genetic and intermediate phenotypic susceptibility markers of gastric cancer in Hispanic Americans: A case‐control study

Sun

Ajani

et al. 2014

Cancer

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“…Malfunction of the respiratory chain subsequent to mtDNA mutations may in turn cause increased generation of ROS, leading to further DNA damage, genetic instability, and cancer progression (Pelicano et al, 2004;Singh, 2004). Indeed, increased mutations in mtDNA have been observed in cancer cells of various tissue origins (Wallace, 1999;Carew and Huang, 2002;Copeland et al, 2002;Nomoto et al, 2002;Carew et al, 2003). Since maintenance of mtDNA integrity is crucial to the normal functioning of the cell, and since mtDNA mutations are frequently observed in human cancers, a thorough understanding of the mechanisms by which cells maintain the stability of their mitochondrial genome is essential.…”

Section: Introductionmentioning

confidence: 99%

Novel role of p53 in maintaining mitochondrial genetic stability through interaction with DNA Pol γ

Achanta

Sasaki

et al. 2005

EMBO J

262

241

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Mitochondrial DNA (mtDNA) mutations and deletions are frequently observed in cancer, and contribute to altered energy metabolism, increased reactive oxygen species (ROS), and attenuated apoptotic response to anticancer agents. The mechanisms by which cells maintain mitochondrial genomic integrity and the reason why cancer cells exhibit more frequent mtDNA mutations remain unclear. Here, we report that the tumor suppressor molecule p53 has a novel role in maintaining mitochondrial genetic stability through its ability to translocate to mitochondria and interact with mtDNA polymerase c (pol c) in response to mtDNA damage induced by exogenous and endogenous insults including ROS. The p53 protein physically interacts with mtDNA and pol c, and enhances the DNA replication function of pol c. Loss of p53 results in a significant increase in mtDNA vulnerability to damage, leading to increased frequency of in vivo mtDNA mutations, which are reversed by stable transfection of wildtype p53. This study provides a mechanistic explanation for the accelerating genetic instability and increased ROS stress in cancer cells associated with loss of p53.

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“…Numerous mtDNA mutations have now been reported in cancer (1,16). mtDNA mutations could either arise in the female germ line and predispose to cancer (oncogenic germline mutations), or arise in the mtDNAs of the tissues (tumor-specific somatic mutations) and participate in the tumor progression process (17)(18)(19)(20)(21).…”

Section: Mitochondrial Dna Mutations In Cancermentioning

confidence: 99%

“…By virtue of the clonal nature of mitochondria and high copy number, mitochondrial mutations may provide a powerful molecular biomarker for the detection of cancer. It has been suggested that the extent of mitochondrial DNA (mtDNA) mutations might be useful in the prognosis of cancer outcome and ⁄ or the response to certain therapies (1).…”

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confidence: 99%

Current Understanding of Mitochondrial DNA in Breast Cancer

et al. 2009

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The recent surge in mitochondrial research has been driven by the identification of mitochondria-associated diseases and the role of mitochondria in apoptosis and aging. Mitochondrial DNA (mtDNA) has been proposed to be involved in carcinogenesis because of its high susceptibility to mutations and limited repair mechanisms in comparison to nuclear DNA. As mtDNA lacks introns, it has been suggested that most mutations will occur in coding sequences. The subsequent accumulation of mutations may lead to tumor formation. By virtue of their clonal nature, high copy number and high frequent mutations may provide a powerful molecular biomarker for the detection of cancer. It has been suggested that the extent of mtDNA mutations might be useful in the prognosis of cancer outcome and/or the response to certain therapies. In this review article, we aim to provide a brief summary of our current understanding of mitochondrial genetics and biology, review the mtDNA alterations reported in breast cancer, and offer some perspectives as to the emergence of mtDNA mutations, including their functional consequences in cancer development, diagnostic criteria, and therapeutic implications.

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Mitochondrial DNA Alterations in Cancer

Abstract: For Abstract see ChemInform Abstract in Full Text.

Cited by 28 publications

References 1 publication

Genetic and intermediate phenotypic susceptibility markers of gastric cancer in Hispanic Americans: A case‐control study

Genetic and intermediate phenotypic susceptibility markers of gastric cancer in Hispanic Americans: A case‐control study

Novel role of p53 in maintaining mitochondrial genetic stability through interaction with DNA Pol γ

Current Understanding of Mitochondrial DNA in Breast Cancer

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