Cancer epigenetics is the study of epigenetic modifications to the genome of cancer cells that do not involve a change in the nucleotide sequence. Epigenetic alterations are as important as genetic mutations in a cell’s transformation to cancer. Mechanisms of epigenetic silencing of tumor suppressor genes and activation of oncogenes include: alteration in CpG island methylation patterns, histone modifications, and dysregulation of DNA binding proteins. Understanding epigenetic mechanisms holds great promise for cancer prevention, detection, and therapy.
- 1 DNA methylation
- 2 Histone modifications
- 3 MicroRNA gene silencing
- 4 Epigenetic DNA repair deficiencies in cancer
- 5 Cancer subtype specific epigenetic modifications
- 6 Current therapeutics
- 7 Tools for identification
- 8 Diagnostic and prognostic uses
- 9 References
DNA methylation is probably the most well researched epigenetic mark that differs between normal cells and tumor cells in humans. The "normal" CpG methylation profile is often inverted in cells that become tumorigenic. In normal cells, CpG islands preceding gene promoters are generally unmethylated, while other individual CpG dinucleotides throughout the genome tend to be methylated. However, in cancer cells, CpG islands preceding tumor suppressor gene promoters are often hypermethylated, while CpG methylation of oncogene promoter regions and parasitic repeat sequences is often decreased.
Hypermethylation of gene promoters can result in silencing of those genes. This type of epigenetic mutation is dangerous when genes that regulate the cell cycle are silenced, allowing cells to grow and reproduce uncontrollably, leading to tumorigenesis. Genes commonly found to be transcriptionally silenced due to promoter hypermethylation include: Cyclin-dependent kinase inhibitor p16, a cell-cycle inhibitor; p53, a tumor suppressor gene; MGMT, a DNA repair gene; APC, a cell cycle regulator; MLH1, a DNA-repair gene; and BRCA1, another DNA-repair gene. Indeed, cancer cells can become addicted to the transcriptional silencing, due to promoter hypermethylation, of some key tumor suppressor genes, a process known as epigenetic addiction
Hypomethylation of CpG dinucleotides in other parts of the genome leads to chromosome instability due to mechanisms such as loss of imprinting and reactivation of transposable elements. Loss of imprinting of insulin-like growth factor gene (IGF2) increases risk of colorectal cancer and is associated with Beckwith-Wiedemann syndrome which significantly increases the risk of cancer for newborns. In healthy cells, CpG dinucleotides of lower densities are found within coding and non-coding intergenic regions. Parasitic repetitive sequences, centromeres and oncogenes are often repressed through methylation.
The entire genome of a cancerous cell contains significantly less methylcytosine than the genome of a healthy cell. In fact, cancer cell genomes have 20-50% less methylation at individual CpG dinucleotides across the genome. In cancer cells “global hypomethylation” due to disruption in DNA methyltransferases (DNMTs) may promote mitotic recombination and chromosome rearrangement, ultimately resulting in aneuploidy when the chromosomes fail to separate properly during mitosis.
CpG island methylation is important in regulation of gene expression, yet cytosine methylation can lead directly to destabilizing genetic mutations and a precancerous cellular state. Methylated cytosines make hydrolysis of the amine group and spontaneous conversion to thymine more favorable. They can cause aberrant recruitment of chromatin proteins. Cytosine methylations change the amount of UV light absorption of the nucleotide base, creating pyrimidine dimers. When mutation results in loss of heterozygosity at tumor suppressor gene sites, these genes may become inactive. Single base pair mutations during replication can also have detrimental effects.
Eukaryotic DNA has a complex structure. It is generally wrapped around special proteins called histones to form a structure called a nucleosome. A nucleosome consists of 2 sets of 4 histones: H2A, H2B, H3, and H4. Additionally, histone H1 contributes to DNA packaging outside of the nucleosome. Certain histone modifying enzymes can add or remove functional groups to the histones, and these modifications influence the level of transcription of the genes wrapped around those histones and the level of DNA replication. Therefore, one might expect the histone modification profiles of healthy and cancerous cells to differ.
In comparison to healthy cells, cancerous cells have been seen to exhibit decreased monoacetylated and trimethylated forms of histone H4 (decreased H4ac and H4me3). In mouse models, scientists have noticed that the loss of histone H4 acetylation and trimethylation actually increases as tumor growth continues. Interestingly, loss of histone H4 Lysine 16 acetylation (H4K16ac), which is a mark of aging at the telomeres, specifically loses its acetylation. Some scientists hope this particular loss of histone acetylation might be battled with a histone deacetylase (HDAC) inhibitor specific for SIRT1, an HDAC specific for H4K16.
Other histone marks associated with tumorigenesis include increased deacetylation (decreased acetylation) of histones H3 and H4, decreased trimethylation of histone H3 Lysine 4 (H3K4me3), and increased monomethylation of histone H3 Lysine 9 (H3K9me) and trimethylation of histone H3 Lysine 27 (H3K27me3). These histone modifications can silence tumor suppressor genes despite the drop in methylation of the gene’s CpG island (an event that normally activates genes).
Some research has focused on blocking the action of BRD4 on acetylated histones, which has been shown to increase the expression of the Myc protein, implicated in several cancers. The development process of the drug to bind to BRD4 is noteworthy for the collaborative, open approach the team is taking.
The tumor suppressor gene p53 regulates DNA repair and can induce apoptosis in dysregulated cells. E Soto-Reyes and F Recillas-Targa elucidated the importance of the CTCF protein in regulating p53 expression. CTCF, or CCCTC binding factor, is a zinc finger protein that insulates the p53 promoter from accumulating repressive histone marks. In certain types of cancer cells, the CTCF protein does not bind normally, and the p53 promoter accumulates repressive histone marks, causing p53 expression to decrease.
Mutations in the epigenetic machinery itself may occur as well, potentially responsible for the changing epigenetic profiles of cancerous cells. For example, the decrease in H4K16ac may be caused by either a decrease in activity of a histone acetyltransferases (HATs) or an increase in deacetylation by SIRT1. Likewise, an inactivating frameshift mutation in HDAC2, a histone deacetylase that acts on many histone-tail lysines, has been associated with cancers showing altered histone acetylation patterns. These findings indicate a promising mechanism for altering epigenetic profiles through enzymatic inhibition or enhancement.
DNA damage, caused by UV light, ionizing radiation, environmental toxins, and metabolic chemicals, can also lead to genomic instability and cancer. The DNA damage response to double strand DNA breaks (DSB) is mediated in part by histone modifications. At a DSB, MRE11-RAD50-NBS1 (MRN) protein complex recruits ataxia telangiectasia mutated (ATM) kinase which phosphorylates Serine 129 of Histone 2A. MDC1, mediator of DNA damage checkpoint 1, binds to the phosphopeptide, and phosphorylation of H2AX may spread by a positive feedback loop of MRN-ATM recruitment and phosphorylation. TIP60 acetylates the γH2AX, which is then polyubiquitylated. RAP80, a subunit of the DNA repair breast cancer type 1 susceptibility protein complex (BRCA1-A), binds ubiquitin attached to histones. BRCA1-A activity arrests the cell cycle at the G2/M checkpoint, allowing time for DNA repair, or apoptosis may be initiated.
MicroRNA gene silencing
In mammals, microRNA (miRNA) regulates around 60% of the transcriptional activity of protein-encoding genes. Some miRNAs have also been found to undergo methylation-associated silencing in cancerous cells. Let-7 and miR15/16 play important roles in down-regulating RAS and BCL2 oncogenes, and their silencing has been found in cancer cells. A decrease in expression of miR-125b1, a miRNA that functions as a tumor suppressor, was observed in prostate, ovarian, breast and glial cell cancers. In vitro experiments have shown that miR-125b1 targets two genes, HER2/neu and ESR1, that are linked to breast cancer. DNA methylation, specifically hypermethylation, is one of the main ways that the miR-125b1 is epigenetically silenced. In patients with breast cancer, hypermethylation of CpG islands located proximal to the transcription start site was observed. Loss of CTCF binding and an increase in repressive histone marks, H3K9me3 and H3K27me3, correlates with DNA methylation and miR-125b1 silencing. Mechanistically, CTCF may function as a boundary element to stop the spread of DNA methylation. Results from experiments conducted by Soto-Reyes indicate a negative effect of methylation on the function and expression of miR-125b1, therefore Soto-Reyes and his team were able to conclude that DNA methylation has a part in silencing the gene. Furthermore, results show that some miRNA’s are epigenetically silenced early on in breast cancer, and therefore these miRNA’s could potentially be useful as tumor markers.
miRNA, DNA repair and cancer
DNA damage is considered to be the primary underlying cause of cancer. If DNA repair is deficient, damage tends to accumulate in DNA. Such DNA damage can cause mutational errors during DNA replication due to error-prone translesion synthesis. Accumulated DNA damage can also cause epigenetic alterations due to errors during DNA repair. Such mutations and epigenetic alterations can give rise to cancer (see malignant neoplasms).
Germ line mutations in DNA repair genes cause only 2–5% of colon cancer cases. However, altered expression of microRNAs, causing DNA repair deficiencies, are frequently associated with cancers and may be an important causal factor for these cancers.
Among 68 sporadic colon cancers with reduced expression of the DNA mismatch repair protein MLH1, most were found to be deficient due to epigenetic methylation of the CpG island of the MLH1 gene. However, up to 15% of the MLH1-deficiencies in sporadic colon cancers appeared to be due to over-expression of the microRNA miR-155, which represses MLH1 expression.
In 29–66% of glioblastomas, DNA repair is deficient due to epigenetic methylation of the MGMT gene, which reduces protein expression of MGMT. However, for 28% of glioblastomas, the MGMT protein is deficient but the MGMT promoter is not methylated. In the glioblastomas without methylated MGMT promoters, the level of microRNA miR-181d is inversely correlated with protein expression of MGMT and the direct target of miR-181d is the MGMT mRNA 3’UTR (the three prime untranslated region of MGMT mRNA). Thus, in 28% of glioblastomas, increased expression of miR-181d and reduced expression of DNA repair enzyme MGMT may be a causal factor.
HMGA proteins (HMGA1a, HMGA1b and HMGA2) are implicated in cancer, and expression of these proteins is regulated by microRNAs. HMGA expression is almost undetectable in differentiated adult tissues but is elevated in many cancers. HGMA proteins are polypeptides of ~100 amino acid residues characterized by a modular sequence organization. These proteins have three highly positively-charged regions, termed AT hooks, that bind the minor groove of AT-rich DNA stretches in specific regions of DNA. Human neoplasias, including thyroid, prostatic, cervical, colorectal, pancreatic and ovarian carcinoma, show a strong increase of HMGA1a and HMGA1b proteins. Transgenic mice with HMGA1 targeted to lymphoid cells develop aggressive lymphoma, showing that high HMGA1 expression is not only associated with cancers, but that the HMGA1 gene can act as an oncogene to cause cancer. Baldassarre et al., showed that HMGA1 protein binds to the promoter region of DNA repair gene BRCA1 and inhibits BRCA1 promoter activity. They also showed that while only 11% of breast tumors had hypermethylation of the BRCA1 gene, 82% of aggressive breast cancers have low BRCA1 protein expression, and most of these reductions were due to chromatin remodeling by high levels of HMGA1 protein.
HMGA2 protein specifically targets the promoter of ERCC1, thus reducing expression of this DNA repair gene. ERCC1 protein expression was deficient in 100% of 47 evaluated colon cancers (though the extent to which HGMA2 was involved is unknown). Palmieri et al. showed that, in normal tissues, HGMA1 and HMGA2 genes are targeted (and thus strongly reduced in expression) by miR-15, miR-16, miR-26a, miR-196a2 and Let-7a. However, each of these HMGA-targeting miRNAs are drastically reduced in almost all human pituitary adenomas studied, when compared with the normal pituitary gland. Consistent with the down-regulation of these HMGA-targeting miRNAs, an increase in the HMGA1 and HMGA2-specific mRNAs was observed. Three of these microRNAs (miR-16, miR-196a and Let-7a) have methylated promoters and therefore low expression in colon cancer. For two of these, miR-15 and miR-16, the coding regions are epigenetically silenced in cancer due to histone deacetylase activity. When these microRNAs are expressed at a low level, then HMGA1 and HMGA2 proteins are expressed at a high level. HMGA1 and HMGA2 target (reduce expression of) BRCA1 and ERCC1 DNA repair  genes. Thus DNA repair can be reduced, likely contributing to cancer progression.
In contrast to the previous example, where under-expression of miRNAs indirectly caused reduced expression of DNA repair genes, in some cases over-expression of certain miRNAs may directly reduce expression of specific DNA repair proteins. Wan et al. referred to 6 DNA repair genes that are directly targeted by the miRNAs indicated in parenthese: ATM (miR-421), RAD52 (miR-210, miR-373), RAD23B (miR-373), MSH2 (miR-21), BRCA1 (miR-182) and P53 (miR-504, miR-125b). More recently, Tessitore et al. listed further DNA repair genes that are directly targeted by additional miRNAs, including ATM (miR-18a, miR-101), DNA-PK (miR-101), ATR (miR-185), Wip1 (miR-16), MLH1, MSH2 and MSH6 (miR-155), ERCC3 and ERCC4 (miR-192) and UNG2 (mir-16, miR-34c and miR-199a). Of these miRNAs, miR-16, miR-18a, miR-21, miR-34c, miR-125b, miR-101, miR-155, miR-182, miR-185 and miR-192 are among those identified by Schnekenburger and Diederich as over-expressed in colon cancer through epigenetic hypomethylation. Over expression of any one of these miRNAs can cause reduced expression of its target DNA repair gene.
Epigenetic DNA repair deficiencies in cancer
Cancers have high levels of genome instability, associated with a high frequency of mutations. A high frequency of genomic mutations increases the likelihood of particular mutations occurring that activate oncogenes and inactivate tumor suppressor genes, leading to carcinogenesis.
On the basis of whole genome sequencing, cancers are found to have thousands to hundreds of thousands of mutations in their whole genomes. (Also see Mutation frequencies in cancers.) By comparison, the mutation frequency in the whole genome between generations for humans (parent to child) is about 70 new mutations per generation.
Deficiencies in DNA repair genes cause increased mutation rates. Mutation rates are strongly increased in cells defective in DNA mismatch repair or in homologous recombinational repair (HRR). Individuals with inherited mutations in any of 34 DNA repair genes are at increased risk of cancer (see DNA repair defects and increased cancer risk.) . However, such germ line mutations (which cause highly penetrant cancer syndromes) are the cause of only about 1 percent of cancers.
In sporadic cancers, a deficiency in DNA repair is occasionally found to be due to a mutation in a DNA repair gene, but much more frequently reduced or absent expression of DNA repair genes is due to epigenetic alterations that reduce or silence gene expression. For example, for 113 colorectal cancers examined in sequence, only four had a missense mutation in the DNA repair gene MGMT, while the majority had reduced MGMT expression due to methylation of the MGMT promoter region (an epigenetic alteration). Similarly, out of 119 cases of mismatch repair-deficient colorectal cancers that lacked DNA repair gene PMS2 expression, PMS2 protein was deficient in 6 due to mutations in the PMS2 gene, while in 103 cases PMS2 expression was deficient because its pairing partner MLH1 was repressed due to promoter methylation (PMS2 protein is unstable in the absence of MLH1). In the other 10 cases, loss of PMS2 expression was likely due to epigenetic overexpression of the microRNA, miR-155, which down-regulates MLH1.
Epigenetic defects in DNA repair genes are frequent in cancers. In the Table, multiple cancers were evaluated for reduced or absent expression of the DNA repair gene of interest, and the frequency shown is the frequency with which the cancers had an epigenetic deficiency of gene expression. Such epigenetic deficiencies are likely early-arising defects in the path to carcinogenesis, since they are also frequently found (though at somewhat lower frequency) in the field defect surrounding the cancer from which the cancer likely arose (see Table).
|Cancer||Gene||Frequency in Cancer||Frequency in Field Defect||Ref.|
|Head and Neck||MGMT||54%||38%|||
|Head and Neck||MLH1||33%||25%|||
|Head and Neck||MLH1||31%||20%|||
Epigenetic defects in DNA repair pathways
Epigenetic control of expression has been shown for at least 26 DNA repair genes, shown in the chart in red. The chart in this section shows some frequent DNA damaging agents, examples of DNA lesions they cause, and the pathways that deal with these DNA damages. At least 169 enzymes are either directly employed in DNA repair or influence DNA repair processes. Of these, 83 are directly employed in the 5 types of DNA repair processes illustrated in the chart. Forty seven of the most well studied genes central to these repair processes are also shown in the chart. As indicated by the DNA repair genes shown in red, many of the genes in these repair pathways are regulated by epigenetic mechanisms, and the expressions of these genes are frequently reduced or silent in various cancers (marked by an asterisk). Two review articles. and two broad experimental survey articles document most of these epigenetic DNA repair deficiencies.
It appears that cancers may frequently be initiated by epigenetic reductions(s) in expression of one or more DNA repair enzymes. For instance, simultaneous epigenetic deficiency of DNA repair enzymes in two DNA repair pathways (nucleotide excision repair and mismatch repair) were found in the majority of 49 colon cancers evaluated in one report. Reduced DNA repair likely allows accumulation of DNA damages. Error prone translesion synthesis past some of these DNA damages may give rise to a mutation with a selective advantage. A clonal patch with a selective advantage may grow and out-compete neighboring cells, forming a field defect. While there is no obvious selective advantage for a cell to have reduced DNA repair, the epimutation of the DNA repair gene may be carried along as a passenger when the cells with the selectively advantageous mutation are replicated. In the cells carrying both the epimutation of the DNA repair gene and the mutation with the selective advantage, further DNA damages will accumulate, and these could, in turn, give rise to further mutations with still greater selective advantages. Epigenetic defects in DNA repair may thus contribute to the characteristic high frequency of mutations in the genomes of cancers, and cause their carcinogenic progression.
While DNA damages may give rise to mutations through error prone translesion synthesis, DNA damages can also give rise to epigenetic alterations during faulty DNA repair processes. The DNA damages that accumulate due to epigenetic DNA repair defects can be a source of the increased epigenetic alterations found in many genes in cancers, and some of these epigenetic alterations may further contribute to cancer progression.
Cancer subtype specific epigenetic modifications
Prostate cancer kills around 35,000 men yearly, and about 220,000 men are diagnosed with prostate cancer per year, in North America alone. Prostate cancer is the second leading cause of cancer-caused fatalities in men, and within a man’s lifetime, one in six men will have the disease. Prostate cancer has been associated with gene silencing by CpG island hypermethylation. The GSTP1 gene has been found to defend prostate cells against genomic damage that is caused by different oxidants or carcinogens. This suggests that the silencing of this gene will permit genetic damage to the prostate by oxidants and carcinogens. Methylation of cytosines within a CpG island is a causative factor in gene silencing. Modern epigenetics have correlated CpG island hypermethylation with unexpressed genes. Hypermethylation of the CpG island within the promoter region of the GSTP1 gene has been found to occur in more than 90% of prostate cancers. The high percentage of occurrence demonstrates that hypermethylation of the CpG island within the promoter region of the GSTP1 gene is a highly causative factor of prostate carcinogenesis. In prostate cancer, many other genes have been found to be hypermethylated. An experiment using quantitative real-time methylation-specific polymerase chain reaction (PCR) viewed 16 different genes of prostate cancer that were hypermethylated in high frequencies of the CpG islands in GSTP1, APC, RASSF1a, PTGS2, and MDRI[clarification needed], but in normal prostate tissues almost no methylation was found. Polymerase chain reaction shows the fragment sizes of DNA of interest. Hypermethylation of the genes were shown to be unexpressed. This demonstrates that the hypermethylation of the 16 different genes show no expression of these genes in prostate cancer, and that these genes are necessary for a normal functioning disease-free prostate.
The second most common malignant tumor in women is invasive cervical cancer (ICC) and more than 50% of all invasive cervical cancer (ICC) is caused by oncongenic human papillomavirus 16 (HPV16). Furthermore, cervix intraepithelial neoplasia (CIN) is primarily caused by oncogenic HPV16. As in many cases, the causative factor for cancer does not always take a direct route from infection to the development of cancer. Genomic methylation patterns have been associated with invasive cervical cancer. Within the HPV16L1 region, 14 tested CpG sites have significantly higher methylation in CIN3+ than in HPV16 genomes of women without CIN3. Only 2/16 CpG sites tested in HPV16 upstream regulatory region were found to have association with increased methylation in CIN3+. This suggests that the direct route from infection to cancer is sometimes detoured to a precancerous state in cervix intraepithelial neoplasia. Additionally, increased CpG site methylation was found in low levels in most of the five host nuclear genes studied, including 5/5 TERT, 1/4 DAPK1, 2/5 RARB, MAL, and CADM1. Furthermore, 1/3 of CpG sites in mitochondrial DNA were associated with increased methylation in CIN3+. Thus, a correlation exists between CIN3+ and increased methylation of CpG sites in the HPV16 L1 open reading frame. This could be a potential biomarker for future screens of cancerous and precancerous cervical disease.
Drugs that specifically target the inverted methylation pattern of cancerous cells include the DNA methyltransferase inhibitor 5-aza-2’-deoxycytidine. This hypomethylating agent has been used to treat myelodysplastic syndrome, a blood cancer produced by abnormal bone marrow stem cells. An inhibitor for all three types of active DNA methyltransferases, 5-azaC, previously thought to be highly toxic for human trials, proves to be an effective therapeutics in clinical trials when apply in low dosage, reducing progression of myelodysplastic syndrome to leukaemia, and increasing survival rate of patients with cancer.
Histone deacetylase (HDAC) inhibitors have undergone many clinical trials. With significant efficacy in treating T cell lymphoma, two HDAC inhibitors, vorinostat and romidepsin, have recently been approved by the Food and Drug Administration. However, since these HDAC inhibitors alter the acetylation state of many proteins in addition to the histone of interest, knowledge of the underlying mechanism at the molecular level of patient response is required to enhance the efficiency of using such inhibitors as treatment. A histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA) has had some success in clinical trials. Epigenetic therapeutics are taken in combination and concurrently with traditional cancer treatments, such as chemotherapy and immunotherapy. There is much crosstalk between CpG island methylation and histone modifications. Treatment with HDAC inhibitors has been found to promote gene reactivation after DNA methyl-transferases inhibitors have repressed transcription.
Tools for identification
Previously, epigenetic profiles were limited to individual genes under scrutiny by a particular research team. Recently, however, scientists have been moving toward a more genomic approach to determine an entire genomic profile for cancerous versus healthy cells.
Popular approaches for measuring CpG methylation in cells include:
- Bisulfite sequencing
- Combined bisulfite restriction analysis (COBRA)
- Restriction landmark genomic scanning
- Arbitrary primed PCR
- HELP assay (HpaII tiny fragment enrichment by ligation-mediated PCR)
- Chromatin immunoprecipitation ChIP-Chip using antibodies specific for methyl-CpG binding domain proteins
- Methylated DNA immunoprecipitation Methyl-DIP
- Gene-expression profiles via DNA microarray : comparing mRNA levels from cancer cell lines before and after treatment with a demethylating agent
Since bisulfite sequencing is considered the gold standard for measuring CpG methylation, when one of the other methods is used, results are usually confirmed using bisulfite sequencing. Popular approaches for determining histone modification profiles in cancerous versus healthy cells include:
- Mass spectrometry
- Chromatin Immunoprecipitation Assay
Diagnostic and prognostic uses
Researchers are hoping to identify specific epigenetic profiles of various types and subtypes of cancer with the goal of using these profiles as tools to diagnose individuals more specifically and accurately. Since epigenetic profiles change, scientists would like to use the different epigenomic profiles to determine the stage of development or level of aggressiveness of a particular cancer in patients. For example, hypermethylation of the genes coding for Death-Associated Protein Kinase (DAPK), p16, and Epithelial Membrane Protein 3 (EMP3) have been linked to more aggressive forms of lung, colorectal, and brain cancers. This type of knowledge can affect the way that doctors will diagnose and choose to treat their patients.
Another factor that will influence the treatment of patients is knowing how well they will respond to certain treatments. Personalized epigenomic profiles of cancerous cells can provide insight into this field. For example, MGMT is an enzyme that reverses the addition of alkyl groups to the nucleotide guanine. Alkylating guanine, however, is the mechanism by which several chemotherapeutic drugs act in order to disrupt DNA and cause cell death. Therefore, if the gene encoding MGMT in cancer cells is hypermethylated and in effect silenced or repressed, the chemotherapeutic drugs that act by methylating guanine will be more effective than in cancer cells that have a functional MGMT enzyme.
Epigenetic biomarkers can also be utilized as tools for molecular prognosis. In primary tumor and mediastinal lymph node biopsy samples, hypermethylation of both CDKN2A and CDH13 serves as the marker for increased risk of faster cancer relapse and higher death rate of patients.
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