Somatic Evolution In Cancer
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Somatic Evolution In Cancer
Somatic evolution is the accumulation of mutations and epimutations in somatic cells (the cells of a body, as opposed to germ plasm and stem cells) during a lifetime, and the effects of those mutations and epimutations on the fitness of those cells. This evolutionary process has first been shown by the studies of Bert Vogelstein in colon cancer. Somatic evolution is important in the process of aging as well as the development of some diseases, including cancer. Natural selection in cancer Cells in pre-malignant and malignant neoplasms (tumors) evolve by natural selection. This accounts for how cancer develops from normal tissue and why it has been difficult to cure. There are three necessary and sufficient conditions for natural selection, all of which are met in a neoplasm: # There must be variation in the population. Neoplasms are mosaics of different mutant cells with both genetic and epigenetic changes that distinguish them from normal cells. # The variable traits must be h ...
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Mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosis, or meiosis or other types of damage to DNA (such as pyrimidine dimers caused by exposure to ultraviolet radiation), which then may undergo error-prone repair (especially microhomology-mediated end joining), cause an error during other forms of repair, or cause an error during replication (translesion synthesis). Mutations may also result from insertion or deletion of segments of DNA due to mobile genetic elements. Mutations may or may not produce detectable changes in the observable characteristics (phenotype) of an organism. Mutations play a part in both normal and abnormal biological processes including: evolution, cancer, and the development of the immune system, including junctional diversity. Mutation is the ultimate source o ...
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Therapeutic Resistance
A therapy or medical treatment (often abbreviated tx, Tx, or Tx) is the attempted remediation of a health problem, usually following a medical diagnosis. As a rule, each therapy has indications and contraindications. There are many different types of therapy. Not all therapies are effective. Many therapies can produce unwanted adverse effects. ''Medical treatment'' and ''therapy'' are generally considered synonyms. However, in the context of mental health, the term ''therapy'' may refer specifically to psychotherapy. History Before the creating of therapy as a formal procedure, people told stories to one another to inform and assist about the world. The term "healing through words" was used over 3,500 years ago in Greek and Egyptian writing. The term psychotherapy was invented in the 19th century, and psychoanalysis was founded by Sigmund Freud under a decade later. Semantic field The words ''care'', ''therapy'', ''treatment'', and ''intervention'' overlap in a sem ...
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MSH2
DNA mismatch repair protein Msh2 also known as MutS homolog 2 or MSH2 is a protein that in humans is encoded by the ''MSH2'' gene, which is located on chromosome 2. MSH2 is a tumor suppressor gene and more specifically a caretaker gene that codes for a DNA mismatch repair (MMR) protein, MSH2, which forms a heterodimer with MSH6 to make the human MutSα mismatch repair complex. It also dimerizes with MSH3 to form the MutSβ DNA repair complex. MSH2 is involved in many different forms of DNA repair, including transcription-coupled repair, homologous recombination, and base excision repair. Mutations in the MSH2 gene are associated with microsatellite instability and some cancers, especially with hereditary nonpolyposis colorectal cancer (HNPCC). At least 114 disease-causing mutations in this gene have been discovered. Clinical significance Hereditary nonpolyposis colorectal cancer (HNPCC), sometimes referred to as Lynch syndrome, is inherited in an autosomal dominant fashion, ...
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MLH1
DNA mismatch repair protein Mlh1 or MutL protein homolog 1 is a protein that in humans is encoded by the MLH1 gene located on chromosome 3. It is a gene commonly associated with hereditary nonpolyposis colorectal cancer. Orthologs of human MLH1 have also been studied in other organisms including mouse and the budding yeast ''Saccharomyces cerevisiae''. Function This gene was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer. It is a human homolog of the ''E. coli'' DNA mismatch repair gene, mutL, which mediates protein-protein interactions during mismatch recognition, strand discrimination, and strand removal. Defects in MLH1 are associated with the microsatellite instability observed in hereditary nonpolyposis colon cancer. Alternatively spliced transcript variants encoding different isoforms have been described, but their full-length natures have not been determined. Role in DNA mismatch repair MLH1 protein is one component of a system of seve ...
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PMS2
Mismatch repair endonuclease PMS2 is an enzyme that in humans is encoded by the ''PMS2'' gene. Function This gene is one of the PMS2 gene family members which are found in clusters on chromosome 7. Human PMS2 related genes are located at bands 7p12, 7p13, 7q11, and 7q22. Exons 1 through 5 of these homologues share high degree of identity to human PMS2 The product of this gene is involved in DNA mismatch repair. The protein forms a heterodimer with MLH1 and this complex interacts with MSH2 bound to mismatched bases. Defects in this gene are associated with hereditary nonpolyposis colorectal cancer, with Turcot syndrome, and are a cause of supratentorial primitive neuroectodermal tumors. Alternatively spliced transcript variants have been observed. Mismatch repair and endonuclease activity PMS2 is involved in mismatch repair and is known to have latent endonuclease activity that depends on the integrity of the meta-binding motif in MutL homologs. As an endonuclease, PMS2 intro ...
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O-6-methylguanine-DNA Methyltransferase
''O''6-alkylguanine DNA alkyltransferase (also known as AGT, MGMT or AGAT) is a protein that in humans is encoded by the ''O''6-methylguanine DNA methyltransferase (''MGMT'') gene. O6-methylguanine DNA methyltransferase is crucial for genome stability. It repairs the naturally occurring mutagenic DNA lesion O6-methylguanine back to guanine and prevents mismatch and errors during DNA replication and transcription. Accordingly, loss of ''MGMT'' increases the carcinogenic risk in mice after exposure to alkylating agents. The two bacterial isozymes are Ada and Ogt. Function and mechanism Although alkylating mutagens preferentially modify the guanine base at the N7 position, ''O''6-alkyl-guanine is a major carcinogenic lesion in DNA. This DNA adduct is removed by the repair protein ''O''6-alkylguanine DNA alkyltransferase through an SN2 mechanism. This protein is not a true enzyme since it removes the alkyl group from the lesion in a stoichiometric reaction and the active enzyme ...
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Promotor (biology)
In genetics, a promoter is a sequence of DNA to which proteins bind to initiate transcription of a single RNA transcript from the DNA downstream of the promoter. The RNA transcript may encode a protein (mRNA), or can have a function in and of itself, such as tRNA or rRNA. Promoters are located near the transcription start sites of genes, upstream on the DNA (towards the 5' region of the sense strand). Promoters can be about 100–1000 base pairs long, the sequence of which is highly dependent on the gene and product of transcription, type or class of RNA polymerase recruited to the site, and species of organism. Promoters control gene expression in bacteria and eukaryotes. RNA polymerase must attach to DNA near a gene for transcription to occur. Promoter DNA sequences provide an enzyme binding site. The -10 sequence is TATAAT. -35 sequences are conserved on average, but not in most promoters. Artificial promoters with conserved -10 and -35 elements transcribe more slowly. All D ...
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CpG Site
The CpG sites or CG sites are regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide in the linear sequence of bases along its 5' → 3' direction. CpG sites occur with high frequency in genomic regions called CpG islands (or CG islands). Cytosines in CpG dinucleotides can be methylated to form 5-methylcytosines. Enzymes that add a methyl group are called DNA methyltransferases. In mammals, 70% to 80% of CpG cytosines are methylated. Methylating the cytosine within a gene can change its expression, a mechanism that is part of a larger field of science studying gene regulation that is called epigenetics. Methylated cytosines often mutate to thymines. In humans, about 70% of promoters located near the transcription start site of a gene (proximal promoters) contain a CpG island. CpG characteristics Definition ''CpG'' is shorthand for ''5'—C—phosphate—G—3' '', that is, cytosine and guanine separated by only one phosphate group; phosphate ...
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Genome Instability
Genome instability (also genetic instability or genomic instability) refers to a high frequency of mutations within the genome of a cellular lineage. These mutations can include changes in nucleic acid sequences, chromosomal rearrangements or aneuploidy. Genome instability does occur in bacteria. In multicellular organisms genome instability is central to carcinogenesis, and in humans it is also a factor in some neurodegenerative diseases such as amyotrophic lateral sclerosis or the neuromuscular disease myotonic dystrophy. The sources of genome instability have only recently begun to be elucidated. A high frequency of externally caused DNA damage can be one source of genome instability since DNA damage can cause inaccurate translesion DNA synthesis past the damage or errors in repair, leading to mutation. Another source of genome instability may be epigenetic or mutational reductions in expression of DNA repair genes. Because endogenous (metabolically-caused) DNA damage is very fr ...
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Immortal DNA Strand Hypothesis
The immortal DNA strand hypothesis was proposed in 1975 by John Cairns as a mechanism for adult stem cells to minimize mutations in their genomes. This hypothesis proposes that instead of segregating their DNA during mitosis in a random manner, adult stem cells divide their DNA asymmetrically, and retain a distinct template set of DNA strands (parental strands) in each division. By retaining the same set of template DNA strands, adult stem cells would pass mutations arising from errors in DNA replication on to non-stem cell daughters that soon terminally differentiate (end mitotic divisions and become a functional cell). Passing on these replication errors would allow adult stem cells to reduce their rate of accumulation of mutations that could lead to serious genetic disorders such as cancer. Although evidence for this mechanism exists, whether it is a mechanism acting in adult stem cells in vivo is still controversial. Methods Two main assays are used to detect immortal DNA s ...
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Armitage–Doll Multistage Model Of Carcinogenesis
The Armitage–Doll model is a statistical model of carcinogenesis, proposed in 1954 by Peter Armitage and Richard Doll, in which a series of discrete mutations result in cancer.Armitage, P. and Doll, R. (1954"The Age Distribution of Cancer and a Multi-Stage Theory Of Carcinogenesis" ''British Journ. of Cancer'', 8 (1), 1-12. Reprinted (2004)reprint ''British Journal of Cancer'', 91, 1983–1989. The original paper has recently been reprinted with a set of commentary articles. The model The rate of incidence and mortality from a wide variety of common cancers follows a power law: someone's risk of developing a cancer increases with a power of their age. The model is very simple, and reads \mathrm = \frac t^ in Ashley's notation.Ashley, D. J. B., Brit. J. Cancer, 23, 313 (1969) Their interpretation was that a series of r mutations were required to initiate a tumour. This is now widely accepted, and part of the mainstream view of carcinogenesis. In their original paper, they ...
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Theodor Boveri
Theodor Heinrich Boveri (12 October 1862 – 15 October 1915) was a German zoologist, comparative anatomist and co-founder of modern cytology. He was notable for the first hypothesis regarding cellular processes that cause cancer, and for describing ''chromatin diminution in nematodes''. Boveri was married to the American biologist Marcella O'Grady (1863–1950). Their daughter Margret Boveri (1900–1975) became one of the best-known journalists in post-World War II Germany. Work Using an optical microscope, Boveri examined the processes involved in the fertilization of the animal egg cell; his favorite research objects were the nematode ''Parascaris'' and sea urchins. Boveri's work with sea urchins showed that it was necessary to have all chromosomes present in order for proper embryonic development to take place. This discovery was an important part of the Boveri–Sutton chromosome theory. He also discovered, in 1888, the importance of the centrosome for the formation of th ...
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