New Haplotypes of the ATP Synthase Subunit 6 Gene of Mitochondrial DNA are Associated with Acute Lymphoblastic Leukemia in Saudi Arabia

Yacoub, Haitham A.; Mahmoud, Wafaa; El-Baz, Hatim A.; Eid, Ola M.; El-Fayoumi, Refaat Ibrahim; Mahmoud, Maged Mostafa; Harakeh, Steve; Abuzinadah, Osama H. A.

doi:10.7314/apjcp.2014.15.23.10433

Cited by 10 publications

(9 citation statements)

References 19 publications

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“…Haplogroups reflect specific ancestral populations and are the result of sequential accumulation of mitochondrial mutations through maternal lineages; hence, they present continent-specific distributions. The molecular mechanisms underlying the association between mtDNA haplogroups and cancer development remains unclear and controversial results between populations have been reported (65)(66)(67)(68)(69)(70)(71)(72)(73). However, specific mtDNA haplogroups have been associated with the risk of prostate cancer, BC, CC, nasopharyngeal cancer, gastric cancer, myelodysplastic syndromes (MS), acute lymphoblastic leukemia, etc.…”

Section: Mitochondria Variants and Cancermentioning

confidence: 99%

“…However, specific mtDNA haplogroups have been associated with the risk of prostate cancer, BC, CC, nasopharyngeal cancer, gastric cancer, myelodysplastic syndromes (MS), acute lymphoblastic leukemia, etc. (65)(66)(67)(68)(69)(70)(71)(72)74). For example, an over-representation of haplogroup I in Polish cancer patients has been reported (75), haplogroup U has been shown to be associated with an increased risk of developing renal and prostate cancers (65), and haplogroup JT has been shown to be associated with MS susceptibility in North American caucasion subjects (70).…”

Section: Mitochondria Variants and Cancermentioning

confidence: 99%

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Overview of mitochondrial germline variants and mutations in human disease: Focus on breast cancer (Review)

et al. 2018

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High lactate production in cells during growth under oxygen-rich conditions (aerobic glycolysis) is a hallmark of tumor cells, indicating the role of mitochondrial function in tumorigenesis. In fact, enhanced mitochondrial biogenesis and impaired quality control are frequently observed in cancer cells. Mitochondrial DNA (mtDNA) encodes 13 subunits of oxidative phosphorylation (OXPHOS), is present in thousands of copies per cell, and has a very high mutation rate. Mutations in mtDNA and nuclear DNA (nDNA) genes encoding proteins that are important players in mitochondrial biogenesis and function are involved in oncogenic processes. A wide range of germline mtDNA polymorphisms, as well as tumor mtDNA somatic mutations have been identified in diverse cancer types. Approximately 72% of supposed tumor-specific somatic mtDNA mutations reported, have also been found as polymorphisms in the general population. The ATPase 6 and NADH dehydrogenase subunit genes of mtDNA are the most commonly mutated genes in breast cancer (BC). Furthermore, nuclear genes playing a role in mitochondrial biogenesis and function, such as peroxisome proliferators-activated receptor gamma coactivator-1 (PGC-1), fumarate hydratase (FH) and succinate dehydrogenase (SDH) are frequently mutated in cancer. In this review, we provide an overview of the mitochondrial germline variants and mutations in cancer, with particular focus on those found in BC.

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Section: Mitochondria Variants and Cancermentioning

confidence: 99%

Section: Mitochondria Variants and Cancermentioning

confidence: 99%

Overview of mitochondrial germline variants and mutations in human disease: Focus on breast cancer (Review)

et al. 2018

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“…In another study, somatic mutations in the D-loop were identified in a cohort of Chinese squamous cell carcinomas, but they did not correlate with prognosis or survival [217]. There are also D-Loop mutations in acute lymphoblastic leukemia (ALL) cases, with 89 G insertions, 95 G insertions, 182 C/T substitutions, 308 C insertions, and 311 C insertions, making a total of 132 mutations at 25 locations [397]. In a comprehensive study involving 54 hepatocellular carcinomas, 31 gastric cancers, 31 lung cancers, and 25 colorectal cancers, the incidence of somatic D-loop mutations in cancers of later stages was higher than that of early-stage cancers [203].…”

Section: Disparities At the Mitochondrial Genome Level And Their Rmentioning

confidence: 99%

Mitochondrial determinants of cancer health disparities

Choudhury

Singh

2017

Seminars in Cancer Biology

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Mitochondria are involved in the generation of energy, cell growth and differentiation, cellular signaling, cell cycle control, and cell death. To date, the mitochondrial basis of cancer disparities is unknown. The goal of this review is to provide an understanding and a framework of mitochondrial determinants that may contribute to cancer disparities in racially different populations. Mitochondria, which are multi-functional, have been implicated in the initiation and progression of cancers in relation to metabolic alterations in transformed cells. Due to ethnic-based diversity, the mitochondrial genome (mtDNA) could be a basis for inherited racial disparities and for acquired somatic mutations during tumorigenesis. In African Americans, several germline, population-specific haplotype variants in mtDNA as well as depletion of mtDNA have been linked to cancer predisposition and cancer disparities. Indeed, depletion of mtDNA and mutations in mtDNA or nuclear genome (nDNA)-encoded mitochondrial proteins lead to mitochondrial dysfunction and promote resistance to apoptosis, the epithelial-to-mesenchymal transition, and metastatic disease, which in turn can contribute to cancer disparity and tumor aggressiveness related to racial disparities. Ethnic differences at the level of expression or genetic variations in nDNA encoding the mitochondrial proteome, including mitochondria-localized mtDNA replication and repair proteins, miRNA, transcription factors, kinases and phosphatases, and tumor suppressors and oncogenes may underlie susceptibility to high-risk and aggressive cancers found in African Americans and other ethnicities. The mitochondrial retrograde signaling that alters the expression profile of nuclear genes in response to dysfunctional mitochondria is a mechanism for tumorigenesis. In ethnic populations, differences in mitochondrial function may alter the cross talk between mitochondria and the nucleus at epigenetic and genetic levels, which can also contribute to cancer health disparities. Targeting mitochondrial determinants and mitochondrial retrograde signaling could provide a promising strategy for the development of selective anticancer therapy for dealing with cancer disparities. Further, agents that restore mitochondrial function to optimal levels should permit sensitivity to anticancer agents for the treatment of aggressive tumors that occur in racially diverse populations and hence help in reducing racial disparities.

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“…As the main cytotoxic component of HAMLET is the oleic acid rather than the protein, the binding of HAMLET protein to ATP synthase protein subunits is likely a result of the unfolded HAMLET protein, no longer partially folded around its oleic acid cargo, binding to the ATP synthase subunits that are in proximity to HAMLET and are themselves now dissociated. Mutations in ATP synthase subunits are associated with some cancers (137)(138)(139).…”

Section: Binding To Nucleotide-binding Proteinsmentioning

confidence: 99%

Structure and Potential Cellular Targets of HAMLET-like Anti-Cancer Compounds made from Milk Components

et al. 2015

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-The HAMLET family of compounds (Human Alpha-lactalbumin Made Lethal to Tumours) was discovered during studies on the properties of human milk, and is a class of protein-lipid complexes having broad spectrum anti-cancer, and some specific anti-bacterial properties. The structure of HAMLETlike compounds consists of an aggregation of partially unfolded protein making up the majority of the compound's mass, with fatty acid molecules bound in the hydrophobic core. This is a novel protein-lipid structure and has only recently been derived by small-angle X-ray scattering analysis. The structure is the basis of a novel cytotoxicity mechanism responsible for anti-cancer activity to all of the around 50 different cancer cell types for which the HAMLET family has been trialled. Multiple cytotoxic mechanisms have been hypothesised for the HAMLET-like compounds, but it is not yet clear which of those are the initiating cytotoxic mechanism(s) and which are subsequent activities triggered by the initiating mechanism(s). In addition to the studies into the structure of these compounds, this review presents the state of knowledge of the anti-cancer aspects of HAMLET-like compounds, the HAMLET-induced cytotoxic activities to cancer and non-cancer cells, and the several prospective cell membrane and intracellular targets of the HAMLET family. The emerging picture is that HAMLET-like compounds initiate their cytotoxic effects on what may be a cancer-specific target in the cell membrane that has yet to be identified.

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New Haplotypes of the ATP Synthase Subunit 6 Gene of Mitochondrial DNA are Associated with Acute Lymphoblastic Leukemia in Saudi Arabia

Cited by 10 publications

References 19 publications

Overview of mitochondrial germline variants and mutations in human disease: Focus on breast cancer (Review)

Overview of mitochondrial germline variants and mutations in human disease: Focus on breast cancer (Review)

Mitochondrial determinants of cancer health disparities

Structure and Potential Cellular Targets of HAMLET-like Anti-Cancer Compounds made from Milk Components

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