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Oncogene 18 53 — Metabolic regulation by p53 family members. Cell Metab 18 5 — DNA damage response genes and the development of cancer metastasis. Radiat Res 2 — Li H, Jogl G. J Biol Chem 3 — Cancer Res 64 7 — Science —3. Tumor suppression in the absence of pmediated cell-cycle arrest, apoptosis, and senescence. These include propano-, etheno- and malondialdehyde-derived DNA adducts, base propenals, estrogen-DNA adducts, alkylated bases, deamination of each of cytosine, adenine and guanine to form uracil, hypoxanthine and xanthine, respectively and adducts formed with DNA by reactive carbonyl species [ 15 ].
Thus there is a steady state level of many DNA damages, reflecting the efficiencies of repair and the frequencies of occurrence. For instance, Helbock et al. Nakamura and Swenberg [ 17 ] determined the number of AP sites apurinc and apyrimidinic sites in normal tissues of the rat i. The data indicated that the number of AP sites ranged from about 50, per cell in liver, kidney and lung to about , per cell in the brain.
These steady state numbers of AP sites in genomic DNA were considered to represent the balance between formation and repair of AP sites. DNA repair pathways are usually able to keep up with the endogenous damages in replicating cells, in part by halting DNA replication at the site of damage until repair can occur [ 28 , 29 ]. In contrast, non-replicating cells have a build-up of DNA damages, causing aging [ 30 , 31 ]. However, some exogenous DNA damaging agents, such as those in tobacco smoke, discussed below, may overload the repair pathways, either with higher levels of the same type of DNA damages as those occurring endogenously or with novel types of damage that are repaired more slowly.
In addition, if DNA repair pathways are deficient, due to inherited mutations or sporadic somatic epimutations in DNA repair genes in replicating somatic cells, unrepaired endogenous and exogenous damages will increase due to insufficient repair. Increased DNA damages would likely give rise to increased errors of replication past the damages by trans-lesion synthesis or increased error prone repair e. Increased mutations that activate oncogenes, inactivate tumor suppressor genes, cause genomic instability or give rise to other driver mutations in replicating cells would increase the risk of cancer.
Cancer incidence, in different areas of the world, varies considerably. Thus, the incidence of colon cancer among Black Native-Africans is less than 1 person out of , , while among male Black African-Americans it is Rates of colon cancer incidence among populations migrating from lower-incidence to higher-incidence countries change rapidly, and within one generation can reach the rate in the higher-incidence country. This is observed, for instance, in migrants from Japan to Hawaii [ 34 ].
The most common cancers for men and women and their rates of incidence per , , averaged over the more developed areas and less developed areas of the world, are shown in Table 2 from [ 35 ]. Overall, worldwide, cancer incidence in all organs combined is The differences in cancer incidence between more developed areas of the world and less developed areas are likely due, in large part, to differences in exposure to exogenous carcinogenic factors.
The lowest rates of cancers in a given organ Table 2 may be due, at least in part, to endogenous DNA damages as described in the previous section that cause errors of replication trans-lesion synthesis or error prone repair e. The higher rates Table 2 are likely largely attributable to exogenous factors, such as higher rates of tobacco use or diets higher in saturated fats that directly, or indirectly, increase the incidence of DNA damage.
It is interesting to note in Table 2 that, in cases where cancers occur in the same organs of men and women, men consistently have a higher rate of cancer than women. The basis for this is currently unknown.
Incidence and mortality rates for the most common cancers in age standardized rates per , excluding non-melanoma skin cancer Adapted from Jemal et al. Often such exogenous factors have been shown to cause DNA damage, as described below. In both developed and undeveloped countries, lung cancer is the most frequent cause of cancer mortality Table 2 , data for men and women combined. Tobacco smoke is a complex mixture of over 5, identified chemicals, of which are known to have specific toxicological properties see partial summary by Cunningham [ 37 ].
This quantitative-type of measurement is based on published dose response data for mutagenicity or carcinogenicity and the concentrations of these components in tobacco smoke Table 3.
The adducts formed by acrolein are a major type of DNA damage caused by tobacco smoke, and acrolein has been found to be mutagenic [ 38 ].
Benzo[a]pyrene has long been thought to be an important carcinogen in tobacco smoke [ 39 ]. As reviewed by Alexandrov et al. The other agents in Table 3 cause DNA damages in different ways. These cross-links, in turn, cause mutagenic deletions or other small-scale chromosomal rearrangements [ 40 ] and may also cause mutations through single-nucleotide insertions [ 41 ].
The fourth agent in Table 3 , 1, 3-butadiene, causes genotoxicity both directly by forming a DNA adduct as well as indirectly by causing global loss of DNA methylation and histone methylation leading to epigenetic alterations [ 44 ]. The sixth agent in Table 3 , ethylene oxide, forms mutagenic hydroxyethyl DNA adducts with adenine and guanine [ 46 ]. The seventh agent in Table 3 , isoprene, is normally produced endogenously by humans, and is the main hydrocarbon of non-smoking human breath [ 47 ].
Isoprene, after being metabolized to mono-epoxides, causes DNA damage measured as single and double strand breaks in DNA [ 49 ]. A large number of studies have been published in which the levels and characteristics of DNA adducts in the lung and bronchus of smokers and non-smokers have been compared, as reviewed by Phillips [ 50 ]. In most of these studies, significantly elevated levels of DNA adducts were detected in the peripheral lung, bronchial epithelium or bronchioalveolar lavage cells of the smokers, especially for total bulky DNA adducts.
As further discussed by Phillips [ 50 ], mean levels of DNA adducts in ex-smokers usually with at least a 1 year interval since smoking cessation are found generally to be intermediate between the levels of smokers and life-long non-smokers. Presumably tobacco smoke causes colon cancer due to the DNA damaging agents described above for lung cancer.
These agents may be taken up in the blood and carried to organs of the body. Reaction of acrolein with deoxyguanosine. Four different classes of colonic mutagenic compounds were analysed by de Kok and van Maanen [ 52 ] and evaluated for fecal mutagenicity.
These included 1 pyrolysis compounds from food heterocyclic aromatic amines and polycyclic aromatic hydrocarbons , 2 N -nitroso-compounds from high meat diets, from drinking water with high nitrates or produced during ulcerative colitis , 3 fecapentaenes produced by the colonic bacteria Bacteriodes in the presence of bile acids and 4 bile acids increased in the colon in response to a high fat diet and metabolized to genotoxic form by bacteria in the colon.
Many of these diet-related mutagenic compounds were analysed by Pearson et al. Evidence in both of these studies was insufficient to evaluate the colorectal cancer risk as a result of specific exposures in quantitative terms. However, substantial evidence implicates bile acids the 4 th possibility above in colon caner. Bernstein et al. In addition to causing DNA damage, bile acids may also generate genomic instability by causing mitotic perturbations and reduced expression of spindle checkpoint proteins, giving rise to micro-nuclei, chromosome bridges and other structures that are precursors to aneuploidy [ 55 ].
Furthermore, at high physiological concentrations, bile acids cause frequent apoptosis, and those cells in the exposed populations with reduced apoptosis capability tend to survive and selectively proliferate [ 54 , 56 ]. Cells with reduced ability to undergo apoptosis in response to DNA damage would tend to accumulate mutations when replication occurs past those damages, and such cells may give rise to colon cancers.
In addition, 7 epidemiological studies between and reviewed by Bernstein et al. A similar epidemiological study showed that concentrations of fecal LCA and DCA, respectively, were 4-fold and 5-fold higher in a population at fold higher risk of colon cancer compared to a population at lower risk of colon cancer [ 32 ].
Dietary total fat intake and dietary saturated fat intake is significantly related to incidence of colon cancer [ 57 ]. This supplement raised the level of DCA in the feces of mice from the standard-diet fed mouse level of 0.
This directly indicates that DCA, a DNA damaging agent, at levels present in humans after a high fat diet, can cause colorectal cancer. It is beyond the scope of this chapter to detail the evidence implicating DNA damaging agents as etiologic agents in all of the significant cancers.
Therefore, in Table 4 we indicate with a single reference the major DNA damaging agent in five additional prevalent cancers, in order to illustrate the generality of exogenous DNA damaging agents as causes of cancer. In particular, we point out, as reviewed by Handa et al. Thus, H. In the case of human papillomavirus HPV infection, Wei et al. Expression of DNA repair genes may be reduced by inherited germ line mutations or genetic polymorphisms, or by epigenetic alterations or mutations in somatic cells, and these reductions may substantially increase the risk of cancer.
In 2 overlapping databases [ 67 , 68 ] and human genes depending on the database are listed that are directly employed in DNA repair or influence DNA repair processes.
The lists were originally devised by Wood et al. Individuals with an inherited impairment in DNA repair capability are often at considerably increased risk of cancer. If an individual has a germ line mutation in a DNA repair gene or a DNA damage response gene that recognizes DNA damage and activates DNA repair , usually one abnormal copy of the gene is inherited from one of the parents and then the other copy is inactivated at some later point in life in a somatic cell.
The inactivation may be due, for example, to point mutation, deletion, gene conversion, epigenetic silencing or other mechanisms [ 72 ]. The protein encoded by the gene will either not be expressed or be expressed in a mutated form.
Consequently the DNA repair or DNA damage response function will be deficient or impaired, and damages will accumulate. Such DNA damages can cause errors during DNA replication or inaccurate repair, leading to mutations that can give rise to cancer. Increased oxidative DNA damages also cause increased gene silencing by CpG island hypermethylation, a form of epimutation. These oxidative DNA damages induce formation and relocalization of a silencing complex that may result in cancer-specific aberrant DNA methylation and transcriptional silencing [ 73 ].
If silencing of genes necessary for DNA repair occurs, the repair of further DNA damages will be deficient and more damages will accumulate. Such additional DNA damages will cause increased errors during DNA synthesis, leading to mutations that can give rise to cancer.
Table 6 lists 36 genes for which an inherited mutation results in an increased risk of cancer. The proteins encoded by 35 of these genes are involved in DNA repair and in some cases also in other aspects of the DNA damage response such as cell cycle arrest and apoptosis. Thus defects in DNA repair cause progression to cancer. In addition to mutations in genes that may substantially raise lifetime cancer risk, there appear to be many weakly effective genetically inherited polymorphisms [single nucleotide polymophisms SNPs and copy number variants CNVs ].
However the added risk of cancer by these SNPs is usually small, i. The differences in monozygotic and dizygotic rates of paired cancer were not significant for the other 24 types of cancer evaluated in this study.
While germ line familial mutations in DNA repair genes cause a high risk of cancer, somatic mutations in DNA repair genes are rarely found in sporadic non-familial cancers [ 4 ]. Much more often, DNA repair genes are found to have epigenetic alterations in cancers. Truninger et al. Of these, were deficient in protein expression of MLH1 , with 68 of these cancers being sporadic the remaining MLH1 deficient cancers were due to germ line mutations.
Deficient protein expression of MLH1 may also have been caused, in the remaining 3 sporadic MLH1 protein-deficient cancers which did not have germ line mutations , by over expression of the microRNA miR When miR was transfected into cells it caused reduced expression of MLH1 [ 77 ]. Overexpression of miR was found in colon cancers in which protein expression of MLH1 was deficient and the MLH1 gene was neither mutated nor hypermethylated in its CpG island [ 77 ].
Another example of the epigenetic down-regulation of a DNA repair gene in cancer comes from studies of the direct reversal of methylated guanine bases by methyl guanine methyl transferase MGMT. Zhang et al. Almost all DNA repair deficiencies found, so far, in sporadic cancers, and in precancerous tissues surrounding cancers field defects are due to epigenetic changes. Examples of such epigenetic alterations in DNA repair genes in different types of cancer are shown in Table 7.
A recent review [ 80 ] lists 41 reports mostly not overlapping with those listed in Table 7 indicating methylation of 20 DNA repair genes in various cancers. In Table 7 data are also shown on DNA repair gene deficiencies for the field defects associated with colorectal, gastric, laryngeal and non-small cell lung cancer.
As summarized above, epimutations can result from oxidative DNA damages. Such damages cause formation and relocalization of a silencing complex that in turn causes increased gene silencing by CpG island hypermethylation [ 73 ]. Epigenetic nucleosome remodeling during DNA repair can also silence gene expression [ 11 ]. When CpG island methylation or nucleosome remodeling or other types of epigenetic alterations e. Thus epigenetic deficiencies in DNA repair genes can have a cascading effect a mutator phenotype , leading to genomic instability and accumulation of mutations and epimutations that can give rise to cancer.
Examples of epigenetic alterations epimutations of DNA repair genes in cancers and in field defects, with mechanisms indicated where known. Deficiencies in DNA repair genes cause increased mutation rates. Chromosomal rearrangements and aneuploidy also increase in HRR defective cells [ 84 ]. Thus, deficiency in DNA repair causes genomic instability and genomic instability is the likely main underlying cause of the genetic alterations leading to tumorigenesis. Deficient DNA repair permits the acquisition of a sufficient number of alterations in tumor suppressor genes and oncogenes to fuel carcinogenesis.
Deficiencies in DNA repair appear to be central to the genomic and epigenomic instability characteristic of cancer. Figure 3 illustrates the chain of consequences of exposure of cells to endogenous and exogenous DNA damaging agents that lead to cancer.
The role of germ line defects in DNA repair genes in familial cancer are also indicated. The roles of germ line mutation and directly induced somatic mutation in sporadic cancer are indicated as well. As discussed above, over-expression of miR causes reduced expression of DNA repair protein MLH1, and miR is overexpressed in colon cancers [ 77 ] curved arrow in Figure 3.
Schnekenburger and Diederich [ 7 ] list miR as one of a long list of mi-RNAs whose expression is increased by hypomythylation in colorectal cancers. Wan et al. Of these, all but miRa were identified by Schnekenburger and Diederich [ 7 ], and Malumbres [ ] further identified miRa and miRa as being among miRNAs whose expression is subject to epigenetic alteration in tumors.
Their expression levels in adult tissues are kept low by the actions of specific miRNAs. As reviewed by Resar [ ], all HMG proteins share an acidic carboxyl terminus and associate with chromatin. Baldassarre et al. HGMA1 was almost undetectable in normal breast tissue, highly expressed in the tumor samples, and BRCA1 protein was strongly diminished in tumor samples. In Figure 3 , one of two dotted lines is used to indicate possible repression of ERCC1 by epigenetically induced chromatin remodeling.
Resar [ ] and Baldassarre et al. Palmieri et al. The promoter regions associated with miR, miRa2 and Let-7a miRNAs are epimutated by hypomethylation [ 7 , ] while Sampath et al. In this recent study, among the 18 miRNAs with reduced expression, the reduced expression of miRb, miRb, miR and miR was known to be due to epigenetic alteration [ 7 , ]. Suzuki et al. Activating marks are alterations on histones that cause transcriptional activation of the genes associated with those altered histones reviewed by Tchou-Wong et al.
In particular, the nucleosome, the fundamental subunit of chromatin, is composed of bp of DNA wrapped around an octamer of four core histone proteins H3, H4, H2A, and H2B. Posttranslational modifications i. These specific histone modifications, and their combinations, are translated, through protein interactions, into distinct effects on nuclear processes, such as activation or inhibition of transcription.
In eukaryotes, methylation of lysine 4 in histone H3 H3K4 , which interacts with the promoter region of genes, is linked to transcriptional activation.
There is a strong positive correlation between trimethylation of H3K4, transcription rates, active polymerase II occupancy and histone acetylation. Thus trimethylation of H3K4 is an activating mark. In addition to pri-miRNAs being regulated by activating marks, some miRNAs appear to be directly regulated by these histone modifications. As summarized by Sampath et al. Sampath et al. In Figure 3 , histone modification and chromatin remodeling are indicated as epigentically altering the expression of many genes in progression to cancer, and specifically causing reduced BRCA1 and possibly as indicated by one dotted line reduced expression of ERCC1.
Klase et al. Recent research indicates a mechanism by which an early driver mutation may cause subsequent epigenetic alterations or mutations in pathways leading to cancer. Wang et al.
A gene frequently mutated in cancer is considered to be a driver mutation [ 4 ] so that mutations in IDH1 and IDH2 would be driver mutations. As shown in Figure 3 , a driver mutation in IDH1 can cause a feedback loop leading to increased DNA repair deficiency, further mutations and epimutations, and consequent accelerated tumor progression. Work by Turcan et al. Carillo et al. Other initial driver mutations can cause progression to glioblastoma as well.
As pointed out above, increased levels of miRd also cause reduced expression of MGMT protein in glioblastoma. Nelson et al. Patients with a glioblastoma that does not harbor an IDH1 mutation have an overall fairly short survival time, while patients with both mutated IDH1 and methylated MGMT have a subtype of glioblastoma with a much longer survival time implying a different pathway of cancer progression [ ].
An IDH1 mutation that gives rise to a CpG island methylator phenotype that causes promoter hypermethylation and concomitant silencing of MGMT also causes promoter silencing of other genes as well. In addition to silencing of genes, the CpG island methylator phenotype can cause methylation of the promoter regions of long interspersed nuclear element-1 LINE-1 DNA sequences.
Ohka et al. This phenotype, likely associated with methylation of the MGMT promoter, in turn, indicates whether treatment with the DNA alkylating agent temozolomide will be beneficial in treatment of a patient with a glioblastoma, since MGMT removes the alkyl groups added to guanine by temozolomide. Field defects have been described in many types of gastrointestinal cancers [ ]. A field defect arises when an epimutation or mutation occurs in a stem cell that causes that stem cell to give rise to a number of daughter stem cells that can out-compete neighboring stem cells.
These initial mutated cells form a patch of somewhat more rapidly growing cells an initial field defect. That patch then enlarges at the expense of neighboring cells, followed by, at some point, an additional mutation or epimutation arising in one of the field defect stem cells so that this new stem cell with two advantageous mutations can generate daughter stem cells that can out-compete the surrounding field defect of cells that have just one advantageous mutation.
As illustrated in Figure 4 , this process of expanding sub-patches within earlier patches will occur multiple times until a particular constellation of mutations results in a cancer represented by the small dark patch in Figure 4. It should also be noted that a cancer, once formed, continues to evolve and continues to produce sub clones. Schematic of a field defect in progression to cancer.
Colon resection including a colon cancer. Dashed arrows indicate grossly unremarkable colonic mucosa. Ulcerated hemorrhagic mass represents a moderately differentiated invasive adenocarcinoma. Solid arrow indicates the heaped up edge of the malignant ulcer. Figure 5 shows an opened resected segment of a human colon that has a colon cancer. As illustrated by Bernstein et al. The resection shown in Figure 5 has an area of about 6.
Thus this area has about 1. There are stem cells at the base of each colonic crypt [ , ]. Therefore there are likely about 15 million stem cells in the grossly unremarkable colonic mucosal epithelium shown in Figure 5. Figure 4. References and Recommended Reading Branze, D.
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