The Uprising of Mitochondrial DNA Biomarker in Cancer
Advances in predictive #diagnostic and #precisionmedicine, can lead to powerful discoveries and treatments for patients. #Cancer cells acquire functional capabilities to survive, proliferate, and circulate due to an enabling characteristic called genomic instability. Genomic maintenance systems have the ability to spot and repair any #DNA defects, while cancer cells increase the rates of mutation that orchestrate tumorigenesis. Chromosomal instability (CIN) is one of the most frequent changes observed in cancer cells, which often results from aberrations in chromosome structures and numbers. The second section of the paper focuses on #biomarkers, which are substances, structures, or processes that can influence or predict the incidence and outcome of a disease. There are three classifications of biomarkers: exposure, effect, and susceptibility. Biomarkers of exposure measure exogenous chemicals or their metabolites within an organism, while biomarkers of effect measure alterations of endogenous factors caused by exposure to an exogenous agent. Biomarkers of susceptibility measure genetic polymorphism predisposition of individuals and their external multifactorial influencers. Surrogate endpoints are often used to substitute clinical endpoints, and biomarkers can be used as a screening tool for an early indicator of #malignancy-risk development. They can also be used as diagnostic aids and prognostic biomarkers, as well as predictive biomarkers to identify the sensitivity and/or resistance of cancer patients towards specific agents or #medical product exposure.
The communication between the nucleus and mitochondria of a cell is known as intergenomic #crosstalk and it is bidirectional, meaning it can go both ways. It is important for regulating energy metabolism and tumor suppression. The communication is achieved by pathways such as anterograde #signaling and retrograde signaling. Anterograde signaling is when the nucleus controls gene transcription and cytoplasmic mRNA translation in response to external signals. Retrograde signaling is when mitochondrial dysfunction or loss of mitochondrial #membrane potential triggers communication with the nuclear genetic compartment. This communication is important for #homeostasis adaptation and can detect any nuclear damage or nuclear stress.
#Mitochondria are organelles found in cells that are responsible for producing energy. They are believed to have originated from a #singlecell-ed organism and are made up of two membranes. They contain their own genetic material, called #mtDNA, which is made up of 16569 nucleotide base pairs. mtDNA mutations can lead to mitochondrial dysfunction, which can cause #onco-genic events, such as #tumor cell reprogramming and metabolic shifts. #Mitoepigenetics is the study of how #epigenetics mechanisms regulate mtDNA transcription and replication, and it is believed to be involved in cancer progression.
The interconnection between #carcinogenesis (the development of cancer) and mitochondria (the energy-producing organelles in cells) was first proposed in 1973. Since then, there have been many studies done on this topic, using DNA scanning technologies to detect mutations and deletions. Mitochondrial DNA (mtDNA) is beneficial for carcinogenic studies because it consists of 37 genes with no introns, meaning most mutations will occur in coding regions. Additionally, mtDNA has a small size, is easy to extract, has no genetic rearrangements, and has fast mutation rates, which makes it useful for molecular research. It also has a high copy number, meaning only minimal #tissue samples are needed for analysis. Large-scale deletions are commonly known to be responsible for mitochondrial diseases, and are thought to be the cause of various diseases and cancers.
Two types of mtDNA deletions, 3.4 kb and 4977 bp are associated with various types of cancer. The 3.4 kb deletion was patented by Parr et al. [97] and is used to detect cancer in individuals. It is also used to determine different #prostate tissue types, either benign, malignant, or proximal to malignant [100]. The 4977 bp deletion is primarily associated with #aging and is a common deletion with missing mtDNA nucleotide sequences starting at 8470 to 13447 np [106]. It has been studied in various types of cancer, such as #breastcancer, #colorectal, gastric, hepatocellular, and #brain tumors, and is thought to be associated with external environmental factors, genetic predisposition, and ethnicity.
The text is discussing different types of deletions in mtDNA (mitochondrial DNA) that are associated with cancer. The 5.1.3 section is talking about the 3895 bp deletion, which was first observed in 1991 in two patients with progressive external #ophthalmoplegia. It was then found to be 10 times less frequent than the 4977 bp deletion. A study involving 104 age-matched subjects showed that the 3895 bp deletion was more frequent in those with usually sun-exposed skin and nonmelanoma skin cancer. The 4576 bp deletion was then discussed, which was found to be an indicator for breast cancer in a study involving 39 breast cancer patients. The 4576 bp deletion was not found in 23 normal patients without breast cancer. The text then moves on to discuss mtDNA copy number, which is the amount of mtDNA in each cell. It is suggested that mtDNA copy number changes may lead to mitochondrial instability and regulate energy metabolism, which can initiate #tumorigenesis. Studies have also shown that mtDNA copy number changes can be used as a predictive biomarker for #chemotherapy response.
Cell-free mtDNA (cf-mtDNA) is a type of mitochondrial DNA that is released into the #blood circulation due to disruption of the normal mitochondrial life cycle. It is believed to activate the Toll-like receptor 9 (TLR9) pathway, which can cause #inflammation and potentially lead to cancer. It has been used to diagnose cancer and sepsis, and as a biomarker for metabolic syndrome and predicting the risk of future diabetes. It is also being studied as a #noninvasive liquid #biopsy for cancer, as higher levels of cf-mtDNA have been found in cancer patients compared to healthy controls. Research is being conducted to find the potential link between cf-mtDNA and various cancers, as it is a preferable biomarker due to its higher mtDNA copy number, simpler structure, and shorter length.
Mitochondrial Microsatellite Instability (#mtMSI) is a type of genetic mutation that occurs in the mitochondrial genome. It is caused by short tandem repeats (mononucleotide or dinucleotide) of 1 to 6 base pairs that are scattered throughout the mitochondrial genome. These variations can lead to frameshift mutations, which can be caused by DNA polymerase γ, an enzyme that is responsible for oxidative damage. Mammalian mitochondria also have an inefficient mismatch repair system, which can lead to mtMSI formation. The most commonly reported mtMSI is located in the D-loop region, which is a mutational hotspot in primary tumors. It is a highly polymorphic homopolymeric C stretch, which is involved in R-loop formation, a stable RNA-DNA hybrid that triggers mtDNA replication. D310 alteration has been suggested as a new cancer detection tool and a potential early premalignant cancer marker. Another potential marker is D16184, which is located in the hypervariable region I and is involved in mtDNA biogenesis. Studies have reported the presence of D16184 in various cancer types, such as gastric and endometrial carcinoma. Somatic mtDNA alterations have also been correlated to cancer, with evidence showing that mtDNA changes can contribute to the development or progression of cancer. One example of a somatic mtDNA alteration is A12308G, which is located in the variable loop next to the anticodon stem of tRNA Leu (CUN). This alteration has been suggested as a potential diagnostic tool for #colorectalcancer and as a risk factor for prostate and #renalcancer. A10398G has also been studied in relation to cancer, although the results have been conflicting.
Mitochondrial biomarkers are molecules that can be used to detect cancer in its early stages. A commercial kit (PCMT) has been developed to help with this detection. However, even if cancer is detected early, it can still be difficult to treat if the symptoms have not yet developed. Therefore, researchers are looking into gene therapy and other mitochondrial interventions as potential treatments for cancer. They can use current advancements in vitro mitochondrial intervention to identify the pathogenicity and therapeutic potential of a particular mtDNA mutation. One method proposed is to transfer artificial healthy mitochondria to remove damaged mtDNA without genetic manipulation. Other studies have looked at the levels of mtDNA biomarkers in cancerous and non-cancerous samples, as well as the levels of mtDNA methylation and mtRNA in cancerous tissues.
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