<unk> s are<unk> used by a series of mutations. Each mutation alters the behavior of the cell somewhat. Genetics<unk>  is fundamentally a disease of tissue growth regulation. In order for a normal cell to transform into a<unk>  cell, the genes that regulate cell growth and differentiation must be altered. The affected genes are divided into two broad<unk> tegories. Oncogenes are genes that promote cell growth and reproduction. Tumor suppressor genes are genes that inhibit cell division and survival. Malignant transformation<unk> n occur through the formation of novel oncogenes, the inappropriate over-expression of normal oncogenes, or by the under-expression or disabling of tumor suppressor genes. Typically, changes in multiple genes are required to transform a normal cell into a<unk>  cell. Genetic changes<unk> n occur at different levels and by different mechanisms. The gain or loss of an entire chromosome<unk> n occur through errors in mitosis. More common are mutations, which are changes in the nucleotide sequence of genomic DNA. Large-scale mutations involve the deletion or gain of a portion of a chromosome. Genomic amplification occurs when a cell gains copies (often 20 or more) of a small chromosomal locus, usually containing one or more oncogenes and adjacent genetic material. Translocation occurs when two separate chromosomal regions become abnormally fused, often at a characteristic location. A well-known example of this is the Philadelphia chromosome, or translocation of chromosomes 9 and 22, which occurs in chronic myelogenous leukemia and results in production of the BCR-abl fusion protein, an oncogenic tyrosine kinase. Small-scale mutations include point mutations, deletions, and insertions, which may occur in the promoter region of a gene and affect its expression, or may occur in the gene's coding sequence and alter the function or stability of its protein product. Disruption of a single gene may also result from integration of genomic material from a DNA virus or retrovirus, leading to the expression of viral oncogenes in the affected cell and its descendants. Replication of the data contained within the DNA of living cells will probabilistically result in some errors (mutations). Complex error correction and prevention is built into the process and safeguards the cell against<unk> . If a significant error occurs, the damaged cell<unk> n self-destruct through programmed cell death, termed apoptosis. If the error control processes fail, then the mutations will survive and be passed along to daughter cells. Some environments make errors more likely to arise and propagate. Such environments<unk> n include the presence of disruptive substances<unk> lled<unk> rcinogens, repeated physical injury, heat, ionising radiation or hypoxia. The errors that<unk> use<unk>  are self-amplifying and compounding, for example: * A mutation in the error-correcting machinery of a cell might<unk> use that cell and its children to accumulate errors more rapidly. * A further mutation in an oncogene might<unk> use the cell to reproduce more rapidly and more frequently than its normal counterparts. * A further mutation may<unk> use loss of a tumor suppressor gene, disrupting the apoptosis signaling pathway and immortalizing the cell. * A further mutation in the signaling machinery of the cell might send error-causing signals to nearby cells. The transformation of a normal cell into<unk>  is akin to a chain reaction<unk> used by initial errors, which compound into more severe errors, each progressively allowing the cell to escape more controls that limit normal tissue growth. This rebellion-like scenario is an undesirable survival of the fittest, where the driving forces of evolution work against the body's design and enforcement of order. Once<unk>  has begun to develop, this ongoing process, termed clonal evolution, drives progression towards more invasive stages. Clonal evolution leads to intra-tumour heterogeneity<unk>  cells with heterogeneous mutations) that complicates designing effective treatment strategies and requires an evolutionary approach to designing treatment. Characteristic abilities developed by<unk> s are divided into<unk> tegories, specifically evasion of apoptosis, self-sufficiency in growth signals, insensitivity to anti-growth signals, sustained angiogenesis, limitless replicative potential, metastasis, reprogramming of energy metabolism and evasion of immune destruction. Epigenetics The central role of DNA damage and epigenetic defects in DNA repair genes in<unk> rcinogenesis The classical view of<unk>  is a set of diseases that are driven by progressive genetic abnormalities that include mutations in tumor-suppressor genes and oncogenes and chromosomal abnormalities. Later epigenetic alterations' role was identified. Epigenetic alterations are functionally relevant modifications to the genome that do not change the nucleotide sequence. Examples of such modifications are changes in DNA methylation (hypermethylation and hypomethylation), histone modification and changes in chromosomal architecture <unk> used by inappropriate expression of proteins such as HMGA2 or HMGA1). Each of these alterations regulates gene expression without altering the underlying DNA sequence. These changes may remain through cell divisions, last for multiple generations and<unk> n be considered to be epimutations (equivalent to mutations). Epigenetic alterations occur frequently in<unk> s. As an example, one study listed protein coding genes that were frequently altered in their methylation in association with colon<unk> . These included 147 hypermethylated and 27 hypomethylated genes. Of the hypermethylated genes, 10 were hypermethylated in 100% of colon<unk> s and many others were hypermethylated in more than 50% of colon<unk> s. While epigenetic alterations are found in<unk> s, the epigenetic alterations in DNA repair genes,<unk> using reduced expression of DNA repair proteins, may be of particular importance. Such alterations are thought to occur early in progression to<unk>  and to be a likely<unk> use of the genetic instability characteristic of<unk> s. Reduced expression of DNA repair genes disrupts DNA repair. This is shown in the figure at the 4th level from the top. (In the figure, red wording indicates the central role of DNA damage and defects in DNA repair in progression to<unk> .) When DNA repair is deficient DNA damage remains in cells at a higher than usual level (5th level) and<unk> use increased frequencies of mutation and/or epimutation (6th level). Mutation rates increase substantially in cells defective in DNA mismatch repair or in homologous recombinational repair (HRR). Chromosomal rearrangements and aneuploidy also increase in HRR defective cells. Higher levels of DNA damage<unk> use increased mutation (right side of figure) and increased epimutation. During repair of DNA double strand breaks, or repair of other DNA damage, incompletely cleared repair sites<unk> n<unk> use epigenetic gene silencing. Deficient expression of DNA repair proteins due to an inherited mutation<unk> n increase<unk>  risks. Individuals with an inherited impairment in any of 34 DNA repair genes (see article DNA repair-deficiency disorder) have increased<unk>  risk, with some defects ensuring a 100% lifetime chance of<unk>  (e.g. p53 mutations). Germ line DNA repair mutations are noted on the figure's left side. However, such germline mutations (which<unk> use highly penetrant<unk>  syndromes) are the<unk> use of only about 1 percent of<unk> s. In sporadic<unk> s, deficiencies in DNA repair are occasionally<unk> used by a mutation in a DNA repair gene but are much more frequently<unk> used by epigenetic alterations that reduce or silence expression of DNA repair genes. This is indicated in the figure at the 3rd level. Many studies of heavy metal-induced<unk> rcinogenesis show that such heavy metals<unk> use a reduction in expression of DNA repair enzymes, some through epigenetic mechanisms. DNA repair inhibition is proposed to be a predominant mechanism in heavy metal-induced<unk> rcinogenicity. In addition, frequent epigenetic alterations of the DNA sequences code for small RNAs<unk> lled microRNAs (or miRNAs). miRNAs do not code for proteins, but<unk> n "target" protein-coding genes and reduce their expression.<unk> s usually arise from an assemblage of mutations and epimutations that confer a selective advantage leading to clonal expansion (see Field defects in progression to<unk> . Mutations, however, may not be as frequent in<unk> s as epigenetic alterations. An average<unk>  of the breast or colon<unk> n have about 60 to 70 protein-altering mutations, of which about three or four may be "driver" mutations and the remaining ones may be "passenger" mutations. Metastasis Metastasis is the spread of<unk>  to other locations in the body. The dispersed tumors are<unk> lled metastatic tumors, while the original is<unk> lled the primary tumor. Almost all<unk> s<unk> n metastasize. Most<unk>  deaths are due to<unk>  that has metastasized. Metastasis is common in the late stages of<unk>  and it<unk> n occur via the blood or the lymphatic system or both. The typical steps in metastasis are local invasion, intravasation into the blood or lymph, circulation through the body, extravasation into the new tissue, proliferation and angiogenesis. Different types of<unk> s tend to metastasize to particular organs, but overall the most common places for metastases to occur are the lungs, liver, brain and the bones. Metabolism Normal cells typically generate only about 30% of energy from glycolysis, whereas most<unk> s rely on glycolysis for energy production (Warburg effect). But a minority of<unk>  types rely on oxidative phosphorylation as the primary energy source, including lymphoma, leukemia, and endometrial<unk> . Even in these<unk> ses, however, the use of glycolysis as an energy source rarely exceeds 60%. A few<unk> s use glutamine as the major energy source, partly because it provides nitrogen required for nucleotide (DNA,RNA) synthesis.<unk>  stem
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