View source for Biology:Cancer epigenetics

{{short description|Field of study in cancer research}}
'''Cancer epigenetics''' is the study of [[Biology:Epigenetics|epigenetic]] modifications to the DNA of [[Biology:Cancer cell|cancer cell]]s that do not involve a change in the nucleotide sequence, but instead involve a change in the way the genetic code is expressed. Epigenetic mechanisms are necessary to maintain normal sequences of tissue specific gene expression and are crucial for normal development.<ref>{{cite journal | vauthors = Sharma S, Kelly TK, Jones PA | title = Epigenetics in cancer | journal = Carcinogenesis | volume = 31 | issue = 1 | pages = 27–36 | date = January 2010 | pmid = 19752007 | pmc = 2802667 | doi = 10.1093/carcin/bgp220 }}</ref> They may be just as important, if not even more important, than [[Biology:Mutation|genetic mutations]] in a cell's transformation to cancer. The disturbance of epigenetic processes in cancers, can lead to a loss of [[Biology:Gene expression|expression of genes]] that occurs about 10 times more frequently by transcription silencing (caused by epigenetic promoter hypermethylation of [[Biology:CpG site#Methylation, silencing, cancer, and aging|CpG islands]]) than by mutations. As Vogelstein et al. points out, in a colorectal cancer there are usually about 3 to 6 driver mutations and 33 to 66 [[Biology:Genetic hitchhiking|hitchhiker]] or passenger mutations.<ref name="pmid23539594">{{cite journal | vauthors = Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Kinzler KW | title = Cancer genome landscapes | journal = Science | volume = 339 | issue = 6127 | pages = 1546–1558 | date = March 2013 | pmid = 23539594 | pmc = 3749880 | doi = 10.1126/science.1235122 | bibcode = 2013Sci...339.1546V }}</ref> However, in colon tumors compared to adjacent normal-appearing colonic mucosa, there are about 600 to 800 heavily methylated CpG islands in the promoters of genes in the tumors while these CpG islands are not methylated in the adjacent mucosa.<ref name=Illingworth>{{cite journal | vauthors = Illingworth RS, Gruenewald-Schneider U, Webb S, Kerr AR, James KD, Turner DJ, Smith C, Harrison DJ, Andrews R, Bird AP | display-authors = 6 | title = Orphan CpG islands identify numerous conserved promoters in the mammalian genome | journal = PLOS Genetics | volume = 6 | issue = 9 | pages = e1001134 | date = September 2010 | pmid = 20885785 | pmc = 2944787 | doi = 10.1371/journal.pgen.1001134 | doi-access = free }}</ref><ref name="pmid27493446">{{cite journal | vauthors = Wei J, Li G, Dang S, Zhou Y, Zeng K, Liu M | title = Discovery and Validation of Hypermethylated Markers for Colorectal Cancer | journal = Disease Markers | volume = 2016 | pages = 2192853 | year = 2016 | pmid = 27493446 | pmc = 4963574 | doi = 10.1155/2016/2192853 | doi-access = free }}</ref><ref name=Beggs>{{cite journal | vauthors = Beggs AD, Jones A, El-Bahrawy M, El-Bahwary M, Abulafi M, Hodgson SV, Tomlinson IP | title = Whole-genome methylation analysis of benign and malignant colorectal tumours | journal = The Journal of Pathology | volume = 229 | issue = 5 | pages = 697–704 | date = April 2013 | pmid = 23096130 | pmc = 3619233 | doi = 10.1002/path.4132 }}</ref> Manipulation of epigenetic alterations holds great promise for cancer prevention, detection, and therapy.<ref name="Novak">{{cite journal | vauthors = Novak K | title = Epigenetics changes in cancer cells | journal = MedGenMed | volume = 6 | issue = 4 | pages = 17 | date = December 2004 | pmid = 15775844 | pmc = 1480584 }}</ref><ref name="pmid22735547">{{cite journal | vauthors = Banno K, Kisu I, Yanokura M, Tsuji K, Masuda K, Ueki A, Kobayashi Y, Yamagami W, Nomura H, Tominaga E, Susumu N, Aoki D | display-authors = 6 | title = Epimutation and cancer: a new carcinogenic mechanism of Lynch syndrome (Review) | journal = International Journal of Oncology | volume = 41 | issue = 3 | pages = 793–797 | date = September 2012 | pmid = 22735547 | pmc = 3582986 | doi = 10.3892/ijo.2012.1528 }}</ref> In different types of cancer, a variety of epigenetic mechanisms can be perturbed, such as the silencing of [[Biology:Tumor suppressor gene|tumor suppressor gene]]s and [[Biology:Regulation of gene expression|activation]] of [[Biology:Oncogene|oncogene]]s by altered CpG island [[Biology:DNA methylation|methylation]] patterns, [[Biology:Histone|histone]] modifications, and dysregulation of DNA binding proteins. There are several medications which have epigenetic impact, that are now used in a number of these diseases. 
[[File:Normal-cancer-epigenome.png|thumb|right|Epigenetics patterns in a normal and cancer cells]]

[[File:Epigenetic alterations in tumour progression.svg|thumb|right|Epigenetic alterations in tumour progression]]

==Mechanisms==

===DNA methylation===
{{main|Biology:DNA methylation in cancer}}
[[File:DNA methylation.jpg|thumb|right|A [[Biology:DNA|DNA]] molecule fragment that is methylated at two cytosines]]
In somatic cells, patterns of DNA methylation are in general transmitted to daughter cells with high fidelity.<ref name="pmid11782440">{{cite journal | vauthors = Bird A | title = DNA methylation patterns and epigenetic memory | journal = Genes & Development | volume = 16 | issue = 1 | pages = 6–21 | date = January 2002 | pmid = 11782440 | doi = 10.1101/gad.947102 | doi-access = free }}</ref> Typically, this methylation only occurs at cytosines that are located 5' to guanosine in the CpG dinucleotides of higher order eukaryotes.<ref>{{cite journal | vauthors = Herman JG, Graff JR, Myöhänen S, Nelkin BD, Baylin SB | title = Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 18 | pages = 9821–9826 | date = September 1996 | pmid = 8790415 | pmc = 38513 | doi = 10.1073/pnas.93.18.9821 | doi-access = free | bibcode = 1996PNAS...93.9821H }}</ref> However, epigenetic [[Biology:DNA methylation|DNA methylation]] differs between normal cells and tumor cells in humans. The "normal" [[Biology:CpG site|CpG]] methylation profile is often inverted in cells that become tumorigenic.<ref name="Esteller2007" /> In normal cells, CpG islands preceding gene promoters are generally unmethylated, and tend to be transcriptionally active, while other individual CpG dinucleotides throughout the genome tend to be methylated. However, in cancer cells, CpG islands preceding [[Biology:Tumor suppressor gene|tumor suppressor gene]] promoters are often hypermethylated, while CpG methylation of oncogene promoter regions and parasitic repeat sequences is often decreased.<ref name= CraigJMWongNC>{{cite book |vauthors=Wong NC, Craig JM | title=Epigenetics: A Reference Manual | publisher=Caister Academic Press | location=Norfolk, England | year=2011 | isbn=978-1-904455-88-2  }}</ref>

Hypermethylation of tumor suppressor gene promoter regions can result in silencing of those genes. This type of epigenetic mutation allows cells to grow and reproduce uncontrollably, leading to tumorigenesis.<ref name="Esteller2007" /> The addition of methyl groups to cytosines causes the DNA to coil tightly around the histone proteins, resulting in DNA that can not undergo transcription (transcriptionally silenced DNA). Genes commonly found to be transcriptionally silenced due to promoter hypermethylation include: Cyclin-dependent kinase inhibitor p16, a cell-cycle inhibitor; [[Biology:O-6-methylguanine-DNA methyltransferase|MGMT]], a [[Biology:DNA repair|DNA repair]] gene; [[Biology:Adenomatous polyposis coli|APC]], a cell cycle regulator; MLH1, a DNA-repair gene; and [[Biology:BRCA1|BRCA1]], another DNA-repair gene.<ref name="Esteller2007" /><ref name="Jones 2002" /> 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.<ref name="De Carvalho et al 2012">{{cite journal | vauthors = De Carvalho DD, Sharma S, You JS, Su SF, Taberlay PC, Kelly TK, Yang X, Liang G, Jones PA | display-authors = 6 | title = DNA methylation screening identifies driver epigenetic events of cancer cell survival | journal = Cancer Cell | volume = 21 | issue = 5 | pages = 655–667 | date = May 2012 | pmid = 22624715 | pmc = 3395886 | doi = 10.1016/j.ccr.2012.03.045 }}</ref>

Hypomethylation of CpG dinucleotides in other parts of the genome leads to [[Biology:Chromosome instability|chromosome instability]] due to mechanisms such as loss of imprinting and reactivation of [[Biology:Transposable element|transposable element]]s.<ref name="HermanBaylin2003" /><ref name="FeinbergTycko2004" /><ref name="EggerLiangAparicio2004" /><ref name="Esteller2005" /> Loss of imprinting of [[Biology:Insulin-like growth factor|insulin-like growth factor]] gene (IGF2) increases risk of [[Medicine:Colorectal cancer|colorectal cancer]] and is associated with Beckwith-Wiedemann syndrome which significantly increases the risk of cancer for newborns.<ref name="BaylinJones 2011" /> In healthy cells, CpG dinucleotides of lower densities are found within coding and non-coding intergenic regions. Expression of some repetitive sequences and meiotic recombination at [[Biology:Centromere|centromere]]s are repressed through methylation <ref>{{cite journal | vauthors = Ellermeier C, Higuchi EC, Phadnis N, Holm L, Geelhood JL, Thon G, Smith GR | title = RNAi and heterochromatin repress centromeric meiotic recombination | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 19 | pages = 8701–8705 | date = May 2010 | pmid = 20421495 | pmc = 2889303 | doi = 10.1073/pnas.0914160107 | doi-access = free | bibcode = 2010PNAS..107.8701E }}</ref>

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.<ref name="HermanBaylin2003" /><ref name="FeinbergTycko2004" /><ref name="EggerLiangAparicio2004" /><ref name="Esteller2005" /> CpG islands found in promoter regions are usually protected from DNA methylation. In cancer cells CpG islands are hypomethylated <ref>{{cite journal | vauthors = Esteller M | title = Cancer epigenomics: DNA methylomes and histone-modification maps | language = En | journal = Nature Reviews. Genetics | volume = 8 | issue = 4 | pages = 286–298 | date = April 2007 | pmid = 17339880 | doi = 10.1038/nrg2005 | s2cid = 4801662 }}</ref> The regions flanking CpG islands called CpG island shores are where most DNA methylation occurs in the CpG dinucleotide context. Cancer cells are deferentially methylated at CpG island shores. In cancer cells, hypermethylation in the CpG island shores move into CpG islands, or hypomethylation of CpG islands move into CpG island shores eliminating sharp epigenetic boundaries between these genetic elements.<ref>{{cite journal | vauthors = Timp W, Feinberg AP | title = Cancer as a dysregulated epigenome allowing cellular growth advantage at the expense of the host | language = En | journal = Nature Reviews. Cancer | volume = 13 | issue = 7 | pages = 497–510 | date = July 2013 | pmid = 23760024 | pmc = 4636434 | doi = 10.1038/nrc3486 }}</ref> In cancer cells "global hypomethylation" due to disruption in [[Biology:DNA methyltransferase|DNA methyltransferase]]s (DNMTs) may promote [[Biology:Mitotic recombination|mitotic recombination]] and chromosome rearrangement, ultimately resulting in [[Medicine:Aneuploidy|aneuploidy]] when the chromosomes fail to separate properly during [[Biology:Mitosis|mitosis]].<ref name="HermanBaylin2003" /><ref name="FeinbergTycko2004" /><ref name="EggerLiangAparicio2004" /><ref name="Esteller2005" />

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 [[Chemistry:Hydrolysis|hydrolysis]] of the amine group and spontaneous conversion to [[Chemistry:Thymine|thymine]] more favorable. They can cause aberrant recruitment of [[Biology:Chromatin|chromatin]] proteins. Cytosine methylations change the amount of UV light absorption of the nucleotide base, creating [[Biology:Pyrimidine dimer|pyrimidine dimer]]s. 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.<ref name="Jones 2002" />

===Histone modification===
[[Biology:Chromatin|Eukaryotic DNA]] has a complex structure. It is generally wrapped around special proteins called [[Biology:Histone|histone]]s to form a structure called a [[Biology:Nucleosome|nucleosome]]. A nucleosome consists of 2 sets of 4 histones: [[Biology:Histone H2A|H2A]], [[Biology:Histone H2B|H2B]], H3, and [[Biology:Histone H4|H4]]. Additionally, [[Biology:Histone H1|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. Histone modification profiles of healthy and cancerous cells tend to differ.

In comparison to healthy cells, cancerous cells exhibit decreased monoacetylated and trimethylated forms of [[Biology:Histone H4|histone H4]] (decreased H4ac and H4me3).<ref name="Fraga et al 2005" /> Additionally, mouse models have shown that a decrease in histone H4R3 asymmetric dimethylation (H4R3me2a) of the p19ARF promoter is correlated with more advanced cases of tumorigenesis and metastasis.<ref name="aprelikova">{{cite journal | vauthors = Aprelikova O, Chen K, El Touny LH, Brignatz-Guittard C, Han J, Qiu T, Yang HH, Lee MP, Zhu M, Green JE | display-authors = 6 | title = The epigenetic modifier JMJD6 is amplified in mammary tumors and cooperates with c-Myc to enhance cellular transformation, tumor progression, and metastasis | journal = Clinical Epigenetics | volume = 8 | issue = 38 | pages = 38 | date = Apr 2016 | pmid = 27081402 | pmc = 4831179 | doi = 10.1186/s13148-016-0205-6 | doi-access = free }}</ref> In mouse models, the loss of histone H4 acetylation and trimethylation increases as tumor growth continues.<ref name="Fraga et al 2005" /> Loss of histone H4 Lysine 16 acetylation ([[Biology:H4K16ac|H4K16ac]]), which is a mark of aging at the [[Biology:Telomere|telomere]]s, specifically loses its acetylation. Some scientists hope this particular loss of histone acetylation might be battled with a [[Biology:Histone deacetylase|histone deacetylase]] (HDAC) inhibitor specific for SIRT1, an HDAC specific for H4K16.<ref name="Esteller2007" /><ref name="Dang et al 2009" />

Other histone marks associated with tumorigenesis include increased deacetylation (decreased acetylation) of histones H3 and H4, decreased trimethylation of histone H3 Lysine 4 ([[Biology:H3K4me3|H3K4me3]]), and increased monomethylation of histone H3 Lysine 9 (H3K9me1) and trimethylation of histone H3 Lysine 27 ([[Biology:H3K27me3|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).<ref name="Vire et al 2006" /><ref name="Richon et al 2000" />

Some research has focused on blocking the action of [[Biology:BRD4|BRD4]] on acetylated histones, which has been shown to increase the expression of the [[Biology:Myc|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.<ref>{{cite journal | vauthors = Maxmen A | title = Cancer research: Open ambition | journal = Nature | volume = 488 | issue = 7410 | pages = 148–150 | date = August 2012 | pmid = 22874946 | doi = 10.1038/488148a | doi-access = free | bibcode = 2012Natur.488..148M }}</ref>

The tumor suppressor gene [[Biology:P53|p53]] regulates [[Biology:DNA repair|DNA repair]] and can induce apoptosis in dysregulated cells. E Soto-Reyes and F Recillas-Targa elucidated the importance of the [[Biology:CTCF|CTCF]] protein in regulating p53 expression.<ref name="Soto-Reyes and Recillas-Targa 2010" /> CTCF, or CCCTC binding factor, is a [[Biology:Zinc finger|zinc finger]] protein that insulates the p53 [[Biology:Promoter (genetics)|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.<ref name="Soto-Reyes and Recillas-Targa 2010" />

Mutations in the epigenetic machinery itself may occur as well, potentially responsible for the changing epigenetic profiles of cancerous cells. The [[Biology:Histone|histone]] variants of the H2A family are highly conserved in mammals, playing critical roles in regulating many nuclear processes by altering [[Biology:Chromatin|chromatin]] structure. One of the key H2A variants, H2A.X, marks DNA damage, facilitating the recruitment of DNA repair proteins to restore genomic integrity. Another variant, H2A.Z, plays an important role in both gene activation and repression. A high level of H2A.Z expression is detected in many cancers and is significantly associated with cellular proliferation and genomic instability.<ref name="CraigJMWongNC"/> Histone variant macroH2A1 is important in the pathogenesis of many types of cancers, for instance in hepatocellular carcinoma.<ref>{{cite journal | vauthors = Rappa F, Greco A, Podrini C, Cappello F, Foti M, Bourgoin L, Peyrou M, Marino A, Scibetta N, Williams R, Mazzoccoli G, Federici M, Pazienza V, Vinciguerra M | display-authors = 6 | title = Immunopositivity for histone macroH2A1 isoforms marks steatosis-associated hepatocellular carcinoma | journal = PLOS ONE | volume = 8 | issue = 1 | pages = e54458 | year = 2013 | pmid = 23372727 | pmc = 3553099 | doi = 10.1371/journal.pone.0054458 | veditors = Folli F | doi-access = free | bibcode = 2013PLoSO...854458R }}</ref> Other mechanisms include a decrease in H4K16ac may be caused by either a decrease in activity of a [[Biology:Histone acetyltransferase|histone acetyltransferase]]s (HATs) or an increase in deacetylation by SIRT1.<ref name="Esteller2007" /> Likewise, an inactivating frameshift mutation in HDAC2, a [[Biology:Histone deacetylase|histone deacetylase]] that acts on many histone-tail [[Chemistry:Lysine|lysine]]s, has been associated with cancers showing altered histone acetylation patterns.<ref name="Ropero et al 2006" /> These findings indicate a promising mechanism for altering epigenetic profiles through enzymatic inhibition or enhancement. A new emerging field that captures toxicological epigenetic changes as a result of the exposure to different compounds (drugs, food, and environment) is toxicoepigenetics. In this field, there is growing interest in mapping changes in histone modifications and their possible consequences.<ref>{{Cite journal |last1=Verhelst |first1=Sigrid |last2=Van Puyvelde |first2=Bart |last3=Willems |first3=Sander |last4=Daled |first4=Simon |last5=Cornelis |first5=Senne |last6=Corveleyn |first6=Laura |last7=Willems |first7=Ewoud |last8=Deforce |first8=Dieter |last9=De Clerck |first9=Laura |last10=Dhaenens |first10=Maarten |date=2022-01-24 |title=A large scale mass spectrometry-based histone screening for assessing epigenetic developmental toxicity |url=https://www.nature.com/articles/s41598-022-05268-x |journal=Scientific Reports |language=en |volume=12 |issue=1 |pages=1256 |doi=10.1038/s41598-022-05268-x |pmid=35075221 |bibcode=2022NatSR..12.1256V |issn=2045-2322|hdl=1854/LU-8735551 |hdl-access=free }}</ref>

DNA damage, caused by UV light, [[Physics:Ionizing radiation|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 ([[Biology:BRCA1|BRCA1]]-A), binds [[Biology:Ubiquitin|ubiquitin]] attached to histones. BRCA1-A activity arrests the [[Biology:Cell cycle|cell cycle]] at the G2/M checkpoint, allowing time for DNA repair, or [[Biology:Apoptosis|apoptosis]] may be initiated.<ref name="Van Attikum Grasser 2009" />

===MicroRNA gene silencing===
In mammals, [[Biology:MicroRNA|microRNA]]s (miRNAs) regulate about 60% of the transcriptional activity of protein-encoding genes.<ref name="pmid18955434">{{cite journal | vauthors = Friedman RC, Farh KK, Burge CB, Bartel DP | title = Most mammalian mRNAs are conserved targets of microRNAs | journal = Genome Research | volume = 19 | issue = 1 | pages = 92–105 | date = January 2009 | pmid = 18955434 | pmc = 2612969 | doi = 10.1101/gr.082701.108 }}</ref> Some miRNAs also undergo methylation-associated silencing in cancer cells.<ref name="Saito et al 2006" /><ref name="Lujambio et al 2007" /> Let-7 and miR15/16 play important roles in down-regulating [[Biology:Ras subfamily|RAS]] and BCL2 oncogenes, and their silencing occurs in cancer cells.<ref name="BaylinJones 2011" /> Decreased expression of miR-125b1, a miRNA that functions as a [[Biology:Tumor suppressor|tumor suppressor]], was observed in prostate, [[Medicine:Ovarian cancer|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 [[Biology:CTCF|CTCF]] binding and an increase in repressive histone marks, H3K9me3 and H3K27me3, correlates with [[Biology:DNA methylation|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 et al.<ref name="Soto-Reyes et al 2012" /> indicate a negative effect of methylation on the function and expression of miR-125b1. Therefore, they concluded that DNA methylation has a part in silencing the gene. Furthermore, some miRNA's are epigenetically silenced early on in breast cancer, and therefore these miRNA's could potentially be useful as tumor markers.<ref name="Soto-Reyes et al 2012" /> The epigenetic silencing of miRNA genes by aberrant DNA methylation is a frequent event in cancer cells; almost one third of miRNA promoters active in normal mammary cells were found hypermethylated in breast cancer cells - that is a several fold greater proportion than is usually observed for protein coding genes.<ref>{{cite journal | vauthors = Vrba L, Muñoz-Rodríguez JL, Stampfer MR, Futscher BW | title = miRNA gene promoters are frequent targets of aberrant DNA methylation in human breast cancer | journal = PLOS ONE | volume = 8 | issue = 1 | pages = e54398 | year = 2013 | pmid = 23342147 | pmc = 3547033 | doi = 10.1371/journal.pone.0054398 | doi-access = free | bibcode = 2013PLoSO...854398V }}</ref> 

==Metabolic recoding of epigenetics in cancer==

Dysregulation of metabolism allows tumor cells to generate needed building blocks as well as to modulate epigenetic marks to support cancer initiation and progression. Cancer-induced metabolic changes alter the epigenetic landscape, especially modifications on histones and DNA, thereby promoting malignant transformation, adaptation to inadequate nutrition, and metastasis. In order to satisfy the biosynthetic demands of cancer cells, metabolic pathways are altered by manipulating oncogenes and tumor suppressive genes concurrently.<ref name="Metabolic recoding of epigenetics i">{{cite journal | vauthors = Wang YP, Lei QY | title = Metabolic recoding of epigenetics in cancer | journal = Cancer Communications | volume = 38 | issue = 1 | date = May 2018 | page = 25 | pmid = 29784032 | pmc = 5993135 | doi = 10.1186/s40880-018-0302-3 | doi-access = free }}</ref> The accumulation of certain metabolites in cancer can target epigenetic enzymes to globally alter the epigenetic landscape. Cancer-related metabolic changes lead to locus-specific recoding of epigenetic marks. Cancer epigenetics can be precisely reprogramed by cellular metabolism through 1) dose-responsive modulation of cancer epigenetics by metabolites; 2) sequence-specific recruitment of metabolic enzymes; and 3) targeting of epigenetic enzymes by nutritional signals.<ref name="Metabolic recoding of epigenetics i"/> In addition to modulating metabolic programming on a molecular level, there are microenvironmental factors that can influence and effect metabolic recoding. These influences include nutritional, inflammatory, and the immune response of malignant tissues.

==MicroRNA and DNA repair==
DNA damage appears to be the primary underlying cause of cancer.<ref name="pmid18403632">{{cite journal | vauthors = Kastan MB | title = DNA damage responses: mechanisms and roles in human disease: 2007 G.H.A. Clowes Memorial Award Lecture | journal = Molecular Cancer Research | volume = 6 | issue = 4 | pages = 517–524 | date = April 2008 | pmid = 18403632 | doi = 10.1158/1541-7786.MCR-08-0020 | doi-access = free }}</ref><ref name=BernsteinPrasad>{{cite book | vauthors = Bernstein C, Prasad AR, Nfonsam V, Bernstein H |year=2013 |chapter= Chapter 16: DNA Damage, DNA Repair and Cancer |title= New Research Directions in DNA Repair | veditors = Chen C |isbn=978-953-51-1114-6|page=413|publisher=BoD – Books on Demand }}</ref> If DNA repair is deficient, DNA damage tends to accumulate. Such excess DNA damage can increase mutational errors during [[Biology:DNA replication|DNA replication]] due to error-prone [[Biology:DNA repair#Translesion synthesis|translesion synthesis]]. Excess DNA damage can also increase [[Biology:Epigenetics|epigenetic]] alterations due to errors during DNA repair.<ref name=Hagan>{{cite journal | vauthors = O'Hagan HM, Mohammad HP, Baylin SB | title = Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island | journal = PLOS Genetics | volume = 4 | issue = 8 | pages = e1000155 | date = August 2008 | pmid = 18704159 | pmc = 2491723 | doi = 10.1371/journal.pgen.1000155 | doi-access = free }}</ref><ref name=Cuozzo>{{cite journal | vauthors = Cuozzo C, Porcellini A, Angrisano T, Morano A, Lee B, Di Pardo A, Messina S, Iuliano R, Fusco A, Santillo MR, Muller MT, Chiariotti L, Gottesman ME, Avvedimento EV | display-authors = 6 | title = DNA damage, homology-directed repair, and DNA methylation | journal = PLOS Genetics | volume = 3 | issue = 7 | pages = e110 | date = July 2007 | pmid = 17616978 | pmc = 1913100 | doi = 10.1371/journal.pgen.0030110 | doi-access = free }}</ref> Such mutations and epigenetic alterations can give rise to [[Medicine:Cancer|cancer]] (see [[Medicine:Neoplasm#Malignant neoplasms|malignant neoplasms]]).

Germ line mutations in DNA repair genes cause only 2–5% of colon cancer cases.<ref>{{cite journal | vauthors = Jasperson KW, Tuohy TM, Neklason DW, Burt RW | title = Hereditary and familial colon cancer | journal = Gastroenterology | volume = 138 | issue = 6 | pages = 2044–2058 | date = June 2010 | pmid = 20420945 | pmc = 3057468 | doi = 10.1053/j.gastro.2010.01.054 }}</ref> However, altered expression of microRNAs, causing DNA repair deficiencies, are frequently associated with cancers and may be an important [[Causality|causal]] factor for these cancers.

Over-expression of certain miRNAs may directly reduce expression of specific DNA repair proteins. Wan et al.<ref>{{cite journal | vauthors = Wan G, Mathur R, Hu X, Zhang X, Lu X | title = miRNA response to DNA damage | journal = Trends in Biochemical Sciences | volume = 36 | issue = 9 | pages = 478–484 | date = September 2011 | pmid = 21741842 | pmc = 3532742 | doi = 10.1016/j.tibs.2011.06.002 }}</ref> referred to 6 DNA repair genes that are directly targeted by the miRNAs indicated in parentheses: ''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.<ref name="pmid24616890">{{cite journal | vauthors = Tessitore A, Cicciarelli G, Del Vecchio F, Gaggiano A, Verzella D, Fischietti M, Vecchiotti D, Capece D, Zazzeroni F, Alesse E | display-authors = 6 | title = MicroRNAs in the DNA Damage/Repair Network and Cancer | journal = International Journal of Genomics | volume = 2014 | pages = 820248 | year = 2014 | pmid = 24616890 | pmc = 3926391 | doi = 10.1155/2014/820248 | doi-access = free }}</ref> 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<ref name=Schnekenburger /> 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.

Up to 15% of the MLH1-deficiencies in sporadic colon cancers appeared to be due to over-expression of the microRNA [[Biology:MiR-155|miR-155]], which represses MLH1 expression.<ref name="ReferenceA">{{cite journal | vauthors = Valeri N, Gasparini P, Fabbri M, Braconi C, Veronese A, Lovat F, Adair B, Vannini I, Fanini F, Bottoni A, Costinean S, Sandhu SK, Nuovo GJ, Alder H, Gafa R, Calore F, Ferracin M, Lanza G, Volinia S, Negrini M, McIlhatton MA, Amadori D, Fishel R, Croce CM | display-authors = 6 | title = Modulation of mismatch repair and genomic stability by miR-155 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 15 | pages = 6982–6987 | date = April 2010 | pmid = 20351277 | pmc = 2872463 | doi = 10.1073/pnas.1002472107 | doi-access = free | bibcode = 2010PNAS..107.6982V | jstor = 25665289 }}</ref> However, the majority of 68 sporadic colon cancers with reduced expression of the [[Biology:DNA mismatch repair|DNA mismatch repair]] protein MLH1 were found to be deficient due to epigenetic methylation of the CpG island of the ''MLH1'' gene.<ref name="Truninger K 2005">{{cite journal | vauthors = Truninger K, Menigatti M, Luz J, Russell A, Haider R, Gebbers JO, Bannwart F, Yurtsever H, Neuweiler J, Riehle HM, Cattaruzza MS, Heinimann K, Schär P, Jiricny J, Marra G | display-authors = 6 | title = Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer | journal = Gastroenterology | volume = 128 | issue = 5 | pages = 1160–1171 | date = May 2005 | pmid = 15887099 | doi = 10.1053/j.gastro.2005.01.056 | doi-access = free }}</ref>

In 28% of glioblastomas, the MGMT DNA repair protein is deficient but the ''MGMT'' promoter is not methylated.<ref name=Zhang /> 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 [[Biology:MRNA|mRNA]] 3'UTR (the [[Biology:Three prime untranslated region|three prime untranslated region]] of MGMT mRNA).<ref name=Zhang /> Thus, in 28% of glioblastomas, increased expression of miR-181d and reduced expression of DNA repair enzyme MGMT may be a causal factor. In 29–66%<ref name=Zhang>{{cite journal | vauthors = Zhang W, Zhang J, Hoadley K, Kushwaha D, Ramakrishnan V, Li S, Kang C, You Y, Jiang C, Song SW, Jiang T, Chen CC | display-authors = 6 | title = miR-181d: a predictive glioblastoma biomarker that downregulates MGMT expression | journal = Neuro-Oncology | volume = 14 | issue = 6 | pages = 712–719 | date = June 2012 | pmid = 22570426 | pmc = 3367855 | doi = 10.1093/neuonc/nos089 }}</ref><ref>{{cite journal | vauthors = Spiegl-Kreinecker S, Pirker C, Filipits M, Lötsch D, Buchroithner J, Pichler J, Silye R, Weis S, Micksche M, Fischer J, Berger W | display-authors = 6 | title = O6-Methylguanine DNA methyltransferase protein expression in tumor cells predicts outcome of temozolomide therapy in glioblastoma patients | journal = Neuro-Oncology | volume = 12 | issue = 1 | pages = 28–36 | date = January 2010 | pmid = 20150365 | pmc = 2940563 | doi = 10.1093/neuonc/nop003 }}</ref> of glioblastomas, DNA repair is deficient due to epigenetic methylation of the [[Biology:O-6-methylguanine-DNA methyltransferase|''MGMT'']] gene, which reduces protein expression of MGMT.

High mobility group A ([[Biology:HMGA|HMGA]]) proteins, characterized by an [[Biology:AT-hook|AT-hook]], are small, nonhistone, chromatin-associated proteins that can modulate transcription. MicroRNAs control the expression of [[Biology:HMGA|HMGA]] proteins, and these proteins ([[Biology:HMGA1|HMGA1]] and [[Biology:HMGA2|HMGA2]]) are architectural chromatin transcription-controlling elements. Palmieri et al.<ref name=Palmieri>{{cite journal | vauthors = Palmieri D, D'Angelo D, Valentino T, De Martino I, Ferraro A, Wierinckx A, Fedele M, Trouillas J, Fusco A | display-authors = 6 | title = Downregulation of HMGA-targeting microRNAs has a critical role in human pituitary tumorigenesis | journal = Oncogene | volume = 31 | issue = 34 | pages = 3857–3865 | date = August 2012 | pmid = 22139073 | doi = 10.1038/onc.2011.557 | doi-access = free }}</ref> showed that, in normal tissues, ''HGMA1'' and ''HMGA2'' genes are targeted (and thus strongly reduced in expression) by [[Biology:Mir-15 microRNA precursor family|miR-15]], [[Biology:Mir-15 microRNA precursor family|miR-16]], [[Biology:Mir-26 microRNA precursor family|miR-26a]], [[Biology:Mir-196 microRNA precursor family|miR-196a2]] and [[Biology:Let-7 microRNA precursor|Let-7a]].

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.<ref>{{cite journal | vauthors = Sgarra R, Rustighi A, Tessari MA, Di Bernardo J, Altamura S, Fusco A, Manfioletti G, Giancotti V | display-authors = 6 | title = Nuclear phosphoproteins HMGA and their relationship with chromatin structure and cancer | journal = FEBS Letters | volume = 574 | issue = 1–3 | pages = 1–8 | date = September 2004 | pmid = 15358530 | doi = 10.1016/j.febslet.2004.08.013 | s2cid = 28903539 }}</ref> 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.<ref>{{cite journal | vauthors = Xu Y, Sumter TF, Bhattacharya R, Tesfaye A, Fuchs EJ, Wood LJ, Huso DL, Resar LM | display-authors = 6 | title = The HMG-I oncogene causes highly penetrant, aggressive lymphoid malignancy in transgenic mice and is overexpressed in human leukemia | journal = Cancer Research | volume = 64 | issue = 10 | pages = 3371–3375 | date = May 2004 | pmid = 15150086 | doi = 10.1158/0008-5472.CAN-04-0044 | s2cid = 34111491 | doi-access =  }}</ref> Baldassarre et al.,<ref>{{cite journal | vauthors = Baldassarre G, Battista S, Belletti B, Thakur S, Pentimalli F, Trapasso F, Fedele M, Pierantoni G, Croce CM, Fusco A | display-authors = 6 | title = Negative regulation of BRCA1 gene expression by HMGA1 proteins accounts for the reduced BRCA1 protein levels in sporadic breast carcinoma | journal = Molecular and Cellular Biology | volume = 23 | issue = 7 | pages = 2225–2238 | date = April 2003 | pmid = 12640109 | pmc = 150734 | doi = 10.1128/MCB.23.7.2225-2238.2003 }}</ref> 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.<ref>{{cite journal | vauthors = Borrmann L, Schwanbeck R, Heyduk T, Seebeck B, Rogalla P, Bullerdiek J, Wisniewski JR | title = High mobility group A2 protein and its derivatives bind a specific region of the promoter of DNA repair gene ERCC1 and modulate its activity | journal = Nucleic Acids Research | volume = 31 | issue = 23 | pages = 6841–6851 | date = December 2003 | pmid = 14627817 | pmc = 290254 | doi = 10.1093/nar/gkg884 }}</ref> ERCC1 protein expression was deficient in 100% of 47 evaluated colon cancers (though the extent to which HGMA2 was involved is unknown).<ref name=Facista>{{cite journal | vauthors = Facista A, Nguyen H, Lewis C, Prasad AR, Ramsey L, Zaitlin B, Nfonsam V, Krouse RS, Bernstein H, Payne CM, Stern S, Oatman N, Banerjee B, Bernstein C | display-authors = 6 | title = Deficient expression of DNA repair enzymes in early progression to sporadic colon cancer | journal = Genome Integrity | volume = 3 | issue = 1 | pages = 3 | date = April 2012 | pmid = 22494821 | pmc = 3351028 | doi = 10.1186/2041-9414-3-3 | doi-access = free }}</ref>

Palmieri et al.<ref name=Palmieri /> showed that each of the miRNAs that target ''HMGA'' genes 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)<ref name=Schnekenburger>{{cite journal | vauthors = Schnekenburger M, Diederich M | title = Epigenetics Offer New Horizons for Colorectal Cancer Prevention | journal = Current Colorectal Cancer Reports | volume = 8 | issue = 1 | pages = 66–81 | date = March 2012 | pmid = 22389639 | pmc = 3277709 | doi = 10.1007/s11888-011-0116-z }}</ref><ref>{{cite journal | vauthors = Malumbres M | title = miRNAs and cancer: an epigenetics view | journal = Molecular Aspects of Medicine | volume = 34 | issue = 4 | pages = 863–874 | year = 2013 | pmid = 22771542 | pmc = 5791883 | doi = 10.1016/j.mam.2012.06.005 }}</ref> 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 [[Biology:Histone deacetylase|histone deacetylase]] activity.<ref>{{cite journal | vauthors = Sampath D, Liu C, Vasan K, Sulda M, Puduvalli VK, Wierda WG, Keating MJ | title = Histone deacetylases mediate the silencing of miR-15a, miR-16, and miR-29b in chronic lymphocytic leukemia | journal = Blood | volume = 119 | issue = 5 | pages = 1162–1172 | date = February 2012 | pmid = 22096249 | pmc = 3277352 | doi = 10.1182/blood-2011-05-351510 }}</ref> 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) ''[[Biology:BRCA1|BRCA1]]'' and ''ERCC1'' DNA repair genes. Thus DNA repair can be reduced, likely contributing to cancer progression.<ref name=BernsteinPrasad />

==DNA repair pathways==
[[File:DNA damage, repair, alteration of repair in cancer.png|thumb|400px|A chart of common DNA damaging agents, examples of lesions they cause in DNA, and pathways used to repair these lesions. Also shown are many of the genes in these pathways, an indication of which genes are epigenetically regulated to have reduced (or increased) expression in various cancers. It also shows genes in the error prone microhomology-mediated end joining pathway with increased expression in various cancers.]]

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.<ref>[http://sciencepark.mdanderson.org/labs/wood/dna_repair_genes.html Human DNA Repair Genes], 15 April 2014, MD Anderson Cancer Center, University of Texas</ref> Of these, 83 are directly employed in repairing the 5 types of DNA damages illustrated in the chart.

Some of the more well studied genes central to these repair processes are shown in the chart. The gene designations shown in red, gray or cyan indicate genes frequently epigenetically altered in various types of cancers. Wikipedia articles on each of the genes highlighted by red, gray or cyan describe the epigenetic alteration(s) and the cancer(s) in which these epimutations are found. Two broad experimental survey articles<ref>{{cite journal | vauthors = Krishnan K, Steptoe AL, Martin HC, Wani S, Nones K, Waddell N, Mariasegaram M, Simpson PT, Lakhani SR, Gabrielli B, Vlassov A, Cloonan N, Grimmond SM | display-authors = 6 | title = MicroRNA-182-5p targets a network of genes involved in DNA repair | journal = RNA | volume = 19 | issue = 2 | pages = 230–242 | date = February 2013 | pmid = 23249749 | pmc = 3543090 | doi = 10.1261/rna.034926.112 }}</ref><ref>{{cite journal | vauthors = Chaisaingmongkol J, Popanda O, Warta R, Dyckhoff G, Herpel E, Geiselhart L, Claus R, Lasitschka F, Campos B, Oakes CC, Bermejo JL, Herold-Mende C, Plass C, Schmezer P | display-authors = 6 | title = Epigenetic screen of human DNA repair genes identifies aberrant promoter methylation of NEIL1 in head and neck squamous cell carcinoma | journal = Oncogene | volume = 31 | issue = 49 | pages = 5108–5116 | date = December 2012 | pmid = 22286769 | doi = 10.1038/onc.2011.660 | doi-access = free }}</ref> also document most of these epigenetic DNA repair deficiencies in cancers.

Red-highlighted genes are frequently reduced or silenced by epigenetic mechanisms in various cancers. When these genes have low or absent expression, DNA damages can accumulate. Replication errors past these damages (see [[Biology:DNA repair#translesion synthesis|translesion synthesis]]) can lead to increased mutations and, ultimately, cancer. Epigenetic repression of DNA repair genes in ''accurate'' DNA repair pathways appear to be central to [[Biology:Carcinogenesis|carcinogenesis]].

The two gray-highlighted genes ''[[Biology:RAD51|RAD51]]'' and ''[[Biology:BRCA2|BRCA2]]'', are required for [[Biology:Homologous recombination|homologous recombination]]al repair. They are sometimes epigenetically over-expressed and sometimes under-expressed in certain cancers. As indicated in the Wikipedia articles on [[Biology:RAD51|RAD51]] and [[Biology:BRCA2|BRCA2]], such cancers ordinarily have epigenetic deficiencies in other DNA repair genes. These repair deficiencies would likely cause increased unrepaired DNA damages. The over-expression of ''RAD51'' and ''BRCA2'' seen in these cancers may reflect selective pressures for compensatory ''RAD51'' or ''BRCA2'' over-expression and increased homologous recombinational repair to at least partially deal with such excess DNA damages. In those cases where ''RAD51'' or ''BRCA2'' are under-expressed, this would itself lead to increased unrepaired DNA damages. Replication errors past these damages (see [[Biology:DNA repair#translesion synthesis|translesion synthesis]]) could cause increased mutations and cancer, so that under-expression of ''RAD51'' or ''BRCA2'' would be carcinogenic in itself.

Cyan-highlighted genes are in the [[Biology:Microhomology-mediated end joining|microhomology-mediated end joining]] (MMEJ) pathway and are up-regulated in cancer. MMEJ is an additional error-prone ''inaccurate'' repair pathway for double-strand breaks. In MMEJ repair of a double-strand break, an homology of 5-25 complementary base pairs between both paired strands is sufficient to align the strands, but mismatched ends (flaps) are usually present. MMEJ removes the extra nucleotides (flaps) where strands are joined, and then ligates the strands to create an intact DNA double helix. MMEJ almost always involves at least a small deletion, so that it is a mutagenic pathway.<ref name=Liang>{{cite journal | vauthors = Liang L, Deng L, Chen Y, Li GC, Shao C, Tischfield JA | title = Modulation of DNA end joining by nuclear proteins | journal = The Journal of Biological Chemistry | volume = 280 | issue = 36 | pages = 31442–31449 | date = September 2005 | pmid = 16012167 | doi = 10.1074/jbc.M503776200 | doi-access = free }}</ref> FEN1, the flap endonuclease in MMEJ, is epigenetically increased by promoter hypomethylation and is over-expressed in the majority of cancers of the breast,<ref name=Singh>{{cite journal | vauthors = Singh P, Yang M, Dai H, Yu D, Huang Q, Tan W, Kernstine KH, Lin D, Shen B | display-authors = 6 | title = Overexpression and hypomethylation of flap endonuclease 1 gene in breast and other cancers | journal = Molecular Cancer Research | volume = 6 | issue = 11 | pages = 1710–1717 | date = November 2008 | pmid = 19010819 | pmc = 2948671 | doi = 10.1158/1541-7786.MCR-08-0269 }}</ref> prostate,<ref name="pmid16879693">{{cite journal | vauthors = Lam JS, Seligson DB, Yu H, Li A, Eeva M, Pantuck AJ, Zeng G, Horvath S, Belldegrun AS | display-authors = 6 | title = Flap endonuclease 1 is overexpressed in prostate cancer and is associated with a high Gleason score | journal = BJU International | volume = 98 | issue = 2 | pages = 445–451 | date = August 2006 | pmid = 16879693 | doi = 10.1111/j.1464-410X.2006.06224.x | s2cid = 22165252 }}</ref> stomach,<ref name="pmid15701830">{{cite journal | vauthors = Kim JM, Sohn HY, Yoon SY, Oh JH, Yang JO, Kim JH, Song KS, Rho SM, Yoo HS, Yoo HS, Kim YS, Kim JG, Kim NS | display-authors = 6 | title = Identification of gastric cancer-related genes using a cDNA microarray containing novel expressed sequence tags expressed in gastric cancer cells | journal = Clinical Cancer Research | volume = 11 | issue = 2 Pt 1 | pages = 473–482 | date = January 2005 | pmid = 15701830 | doi = 10.1158/1078-0432.473.11.2 | doi-access = free }}</ref><ref name="pmid24590400">{{cite journal | vauthors = Wang K, Xie C, Chen D | title = Flap endonuclease 1 is a promising candidate biomarker in gastric cancer and is involved in cell proliferation and apoptosis | journal = International Journal of Molecular Medicine | volume = 33 | issue = 5 | pages = 1268–1274 | date = May 2014 | pmid = 24590400 | doi = 10.3892/ijmm.2014.1682 | doi-access = free }}</ref> neuroblastomas,<ref name="pmid15922863">{{cite journal | vauthors = Krause A, Combaret V, Iacono I, Lacroix B, Compagnon C, Bergeron C, Valsesia-Wittmann S, Leissner P, Mougin B, Puisieux A | display-authors = 6 | title = Genome-wide analysis of gene expression in neuroblastomas detected by mass screening | journal = Cancer Letters | volume = 225 | issue = 1 | pages = 111–120 | date = July 2005 | pmid = 15922863 | doi = 10.1016/j.canlet.2004.10.035 | s2cid = 44644467 | url = https://hal.archives-ouvertes.fr/hal-00157917/file/Cancer_Letters_2004.pdf }}</ref> pancreas,<ref name="pmid12651607">{{cite journal | vauthors = Iacobuzio-Donahue CA, Maitra A, Olsen M, Lowe AW, van Heek NT, Rosty C, Walter K, Sato N, Parker A, Ashfaq R, Jaffee E, Ryu B, Jones J, Eshleman JR, Yeo CJ, Cameron JL, Kern SE, Hruban RH, Brown PO, Goggins M | display-authors = 6 | title = Exploration of global gene expression patterns in pancreatic adenocarcinoma using cDNA microarrays | journal = The American Journal of Pathology | volume = 162 | issue = 4 | pages = 1151–1162 | date = April 2003 | pmid = 12651607 | pmc = 1851213 | doi = 10.1016/S0002-9440(10)63911-9 }}</ref> and lung.<ref name="pmid14562054">{{cite journal | vauthors = Sato M, Girard L, Sekine I, Sunaga N, Ramirez RD, Kamibayashi C, Minna JD | title = Increased expression and no mutation of the Flap endonuclease (FEN1) gene in human lung cancer | journal = Oncogene | volume = 22 | issue = 46 | pages = 7243–7246 | date = October 2003 | pmid = 14562054 | doi = 10.1038/sj.onc.1206977 | s2cid = 22443138 | doi-access =  }}</ref> PARP1 is also over-expressed when its promoter region [[Biology:ETS1|ETS]] site is epigenetically hypomethylated, and this contributes to progression to endometrial cancer,<ref name="pmid23762867">{{cite journal | vauthors = Bi FF, Li D, Yang Q | title = Hypomethylation of ETS transcription factor binding sites and upregulation of PARP1 expression in endometrial cancer | journal = BioMed Research International | volume = 2013 | pages = 946268 | year = 2013 | pmid = 23762867 | pmc = 3666359 | doi = 10.1155/2013/946268 | doi-access = free }}</ref> BRCA-mutated ovarian cancer,<ref name="pmid24448423">{{cite journal | vauthors = Li D, Bi FF, Cao JM, Cao C, Li CY, Liu B, Yang Q | title = Poly (ADP-ribose) polymerase 1 transcriptional regulation: a novel crosstalk between histone modification H3K9ac and ETS1 motif hypomethylation in BRCA1-mutated ovarian cancer | journal = Oncotarget | volume = 5 | issue = 1 | pages = 291–297 | date = January 2014 | pmid = 24448423 | pmc = 3960209 | doi = 10.18632/oncotarget.1549 }}</ref> and BRCA-mutated serous ovarian cancer.<ref name="pmid23442605">{{cite journal | vauthors = Bi FF, Li D, Yang Q | title = Promoter hypomethylation, especially around the E26 transformation-specific motif, and increased expression of poly (ADP-ribose) polymerase 1 in BRCA-mutated serous ovarian cancer | journal = BMC Cancer | volume = 13 | pages = 90 | date = February 2013 | pmid = 23442605 | pmc = 3599366 | doi = 10.1186/1471-2407-13-90 | doi-access = free }}</ref> Other genes in the [[Biology:Microhomology-mediated end joining|MMEJ]] pathway are also over-expressed in a number of cancers (see [[Biology:Microhomology-mediated end joining|MMEJ]] for summary), and are also shown in blue.

===Frequencies of epimutations in DNA repair genes===
Deficiencies in DNA repair proteins that function in accurate DNA repair pathways increase the risk of mutation. Mutation rates are strongly increased in cells with mutations in [[Biology:DNA mismatch repair|DNA mismatch repair]]<ref name=Narayanan>{{cite journal | vauthors = Narayanan L, Fritzell JA, Baker SM, Liskay RM, Glazer PM | title = Elevated levels of mutation in multiple tissues of mice deficient in the DNA mismatch repair gene Pms2 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 7 | pages = 3122–3127 | date = April 1997 | pmid = 9096356 | pmc = 20332 | doi = 10.1073/pnas.94.7.3122 | doi-access = free | bibcode = 1997PNAS...94.3122N | jstor = 41786 }}</ref><ref name=Hegan>{{cite journal | vauthors = Hegan DC, Narayanan L, Jirik FR, Edelmann W, Liskay RM, Glazer PM | title = Differing patterns of genetic instability in mice deficient in the mismatch repair genes Pms2, Mlh1, Msh2, Msh3 and Msh6 | journal = Carcinogenesis | volume = 27 | issue = 12 | pages = 2402–2408 | date = December 2006 | pmid = 16728433 | pmc = 2612936 | doi = 10.1093/carcin/bgl079 }}</ref> or in [[Biology:Homologous recombination|homologous recombination]]al repair (HRR).<ref name=Tutt>{{cite journal | vauthors = Tutt AN, van Oostrom CT, Ross GM, van Steeg H, Ashworth A | title = Disruption of Brca2 increases the spontaneous mutation rate in vivo: synergism with ionizing radiation | journal = EMBO Reports | volume = 3 | issue = 3 | pages = 255–260 | date = March 2002 | pmid = 11850397 | pmc = 1084010 | doi = 10.1093/embo-reports/kvf037 }}</ref> Individuals with inherited mutations in any of 34 DNA repair genes are at increased risk of cancer (see [[Medicine:DNA repair-deficiency disorder#DNA repair defects and increased cancer risk|DNA repair defects and increased cancer risk]]).

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 [[Biology:Missense mutation|missense mutation]] in the DNA repair gene [[Biology:O-6-methylguanine-DNA methyltransferase|''MGMT'']], while the majority had reduced ''MGMT'' expression due to methylation of the ''MGMT'' promoter region (an epigenetic alteration).<ref>{{cite journal | vauthors = Halford S, Rowan A, Sawyer E, Talbot I, Tomlinson I | title = O(6)-methylguanine methyltransferase in colorectal cancers: detection of mutations, loss of expression, and weak association with G:C>A:T transitions | journal = Gut | volume = 54 | issue = 6 | pages = 797–802 | date = June 2005 | pmid = 15888787 | pmc = 1774551 | doi = 10.1136/gut.2004.059535 }}</ref> 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).<ref name="Truninger K 2005"/> In the other 10 cases, loss of PMS2 expression was likely due to epigenetic overexpression of the microRNA, miR-155, which down-regulates MLH1.<ref name="ReferenceA"/>

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 likely arise early in [[Biology:Carcinogenesis|carcinogenesis]], since they are also frequently found (though at somewhat lower frequency) in the [[Medicine:Neoplasm#Field defects|field defect]] surrounding the cancer from which the cancer likely arose (see Table).  
{| class="wikitable sortable"
|+ Frequency of epigenetic reduction in DNA repair gene expression in sporadic cancers and in adjacent field defects
! Cancer !!Gene !!Frequency in Cancer !!Frequency in Field Defect!!Ref.
|-
!Colorectal
|''MGMT''|| 46%||34%||<ref name="pmid16174854">{{cite journal | vauthors = Shen L, Kondo Y, Rosner GL, Xiao L, Hernandez NS, Vilaythong J, Houlihan PS, Krouse RS, Prasad AR, Einspahr JG, Buckmeier J, Alberts DS, Hamilton SR, Issa JP | display-authors = 6 | title = MGMT promoter methylation and field defect in sporadic colorectal cancer | journal = Journal of the National Cancer Institute | volume = 97 | issue = 18 | pages = 1330–1338 | date = September 2005 | pmid = 16174854 | doi = 10.1093/jnci/dji275 | doi-access = free }}</ref>
|-
!Colorectal
|''MGMT''|| 47%||11%||<ref name="pmid21706233">{{cite journal | vauthors = Lee KH, Lee JS, Nam JH, Choi C, Lee MC, Park CS, Juhng SW, Lee JH | display-authors = 6 | title = Promoter methylation status of hMLH1, hMSH2, and MGMT genes in colorectal cancer associated with adenoma-carcinoma sequence | journal = Langenbeck's Archives of Surgery | volume = 396 | issue = 7 | pages = 1017–1026 | date = October 2011 | pmid = 21706233 | doi = 10.1007/s00423-011-0812-9 | s2cid = 8069716 }}</ref>
|-
!Colorectal
|''MGMT''|| 70%||60%||<ref name="Svrcek et al 2010">{{cite journal | vauthors = Svrcek M, Buhard O, Colas C, Coulet F, Dumont S, Massaoudi I, Lamri A, Hamelin R, Cosnes J, Oliveira C, Seruca R, Gaub MP, Legrain M, Collura A, Lascols O, Tiret E, Fléjou JF, Duval A | display-authors = 6 | title = Methylation tolerance due to an O6-methylguanine DNA methyltransferase (MGMT) field defect in the colonic mucosa: an initiating step in the development of mismatch repair-deficient colorectal cancers | journal = Gut | volume = 59 | issue = 11 | pages = 1516–1526 | date = November 2010 | pmid = 20947886 | doi = 10.1136/gut.2009.194787 | s2cid = 206950452 }}</ref>
|-
!Colorectal
|''[[Biology:MSH2|MSH2]]''|| 13%||5%|| <ref name="pmid21706233"/>
|-
!Colorectal
|''ERCC1''|| 100%||40%||<ref name=Facista />
|-
!Colorectal
|''PMS2''|| 88%||50%||<ref name=Facista />
|-
!Colorectal
|''XPF''|| 55%||40%||<ref name=Facista />
|-
!Head and Neck
|''MGMT''|| 54%||38%||<ref name="Jaroslaw et al 2011">{{cite journal | vauthors = Paluszczak J, Misiak P, Wierzbicka M, Woźniak A, Baer-Dubowska W | title = Frequent hypermethylation of DAPK, RARbeta, MGMT, RASSF1A and FHIT in laryngeal squamous cell carcinomas and adjacent normal mucosa | journal = Oral Oncology | volume = 47 | issue = 2 | pages = 104–107 | date = February 2011 | pmid = 21147548 | doi = 10.1016/j.oraloncology.2010.11.006 }}</ref>
|-
!Head and Neck
|''MLH1''|| 33%||25%||<ref name="Chunlai et al 2009">{{cite journal | vauthors = Zuo C, Zhang H, Spencer HJ, Vural E, Suen JY, Schichman SA, Smoller BR, Kokoska MS, Fan CY | display-authors = 6 | title = Increased microsatellite instability and epigenetic inactivation of the hMLH1 gene in head and neck squamous cell carcinoma | journal = Otolaryngology–Head and Neck Surgery | volume = 141 | issue = 4 | pages = 484–490 | date = October 2009 | pmid = 19786217 | doi = 10.1016/j.otohns.2009.07.007 | s2cid = 8357370 }}</ref>
|-
!Head and Neck
|''MLH1''|| 31%||20%||<ref name="Tawfik et al 2011">{{cite journal | vauthors = Tawfik HM, El-Maqsoud NM, Hak BH, El-Sherbiny YM | title = Head and neck squamous cell carcinoma: mismatch repair immunohistochemistry and promoter hypermethylation of hMLH1 gene | journal = American Journal of Otolaryngology | volume = 32 | issue = 6 | pages = 528–536 | year = 2011 | pmid = 21353335 | doi = 10.1016/j.amjoto.2010.11.005 }}</ref>
|-
!Stomach
|''MGMT''|| 88%||78%||<ref name="Zou et al 2009">{{cite journal | vauthors = Zou XP, Zhang B, Zhang XQ, Chen M, Cao J, Liu WJ | title = Promoter hypermethylation of multiple genes in early gastric adenocarcinoma and precancerous lesions | journal = Human Pathology | volume = 40 | issue = 11 | pages = 1534–1542 | date = November 2009 | pmid = 19695681 | doi = 10.1016/j.humpath.2009.01.029 }}</ref>
|-
!Stomach
|''MLH1''|| 73%||20%||<ref name="pmid23098428">{{cite journal | vauthors = Wani M, Afroze D, Makhdoomi M, Hamid I, Wani B, Bhat G, Wani R, Wani K | display-authors = 6 | title = Promoter methylation status of DNA repair gene (hMLH1) in gastric carcinoma patients of the Kashmir valley | journal = Asian Pacific Journal of Cancer Prevention | volume = 13 | issue = 8 | pages = 4177–4181 | year = 2012 | pmid = 23098428 | doi = 10.7314/APJCP.2012.13.8.4177 | doi-access = free }}</ref>
|-
!Stomach
|''ERCC1''||95-100%||14-65%||<ref name="pmid32143126">{{cite journal | vauthors = Raza Y, Ahmed A, Khan A, Chishti AA, Akhter SS, Mubarak M, Bernstein C, Zaitlin B, Kazmi SU | display-authors = 6 | title = Helicobacter pylori severely reduces expression of DNA repair proteins PMS2 and ERCC1 in gastritis and gastric cancer | journal = DNA Repair | volume = 89 | issue =  | pages = 102836 | date = May 2020 | pmid = 32143126 | doi = 10.1016/j.dnarep.2020.102836 | s2cid = 212622031 | doi-access = free }}</ref>
|-
!Stomach
|''PMS2''||95-100%||14-60%||<ref name="pmid32143126"/>
|-
!Esophagus
|''MLH1''|| 77%–100%||23%–79%||<ref name="Agarwal et al 2012">{{cite journal | vauthors = Agarwal A, Polineni R, Hussein Z, Vigoda I, Bhagat TD, Bhattacharyya S, Maitra A, Verma A | display-authors = 6 | title = Role of epigenetic alterations in the pathogenesis of Barrett's esophagus and esophageal adenocarcinoma | journal = International Journal of Clinical and Experimental Pathology | volume = 5 | issue = 5 | pages = 382–396 | year = 2012 | pmid = 22808291 | pmc = 3396065 }}</ref>
|}

It appears that cancers may frequently be initiated by an epigenetic reduction in expression of one or more DNA repair enzymes. Reduced DNA repair likely allows accumulation of DNA damages. Error prone [[Biology:DNA repair#Translesion synthesis|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 [[Medicine:Neoplasm#Field defects|field defect]]. While there is no obvious [[Biology:Natural selection#Cell and molecular biology|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.

Cancers have high levels of [[Biology:Genome instability|genome instability]], associated with a high frequency of [[Biology:Mutation|mutation]]s. A high frequency of genomic mutations increases the likelihood of particular mutations occurring that activate oncogenes and inactivate tumor suppressor genes, leading to [[Biology:Carcinogenesis|carcinogenesis]]. On the basis of [[Biology:Whole genome sequencing|whole genome sequencing]], cancers are found to have thousands to hundreds of thousands of mutations in their whole genomes.<ref name="pmid23178448">{{cite journal | vauthors = Tuna M, Amos CI | title = Genomic sequencing in cancer | journal = Cancer Letters | volume = 340 | issue = 2 | pages = 161–170 | date = November 2013 | pmid = 23178448 | pmc = 3622788 | doi = 10.1016/j.canlet.2012.11.004 }}</ref> (Also see [[Biology:Whole genome sequencing#Mutation frequencies|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.<ref>{{cite journal | vauthors = Roach JC, Glusman G, Smit AF, Huff CD, Hubley R, Shannon PT, Rowen L, Pant KP, Goodman N, Bamshad M, Shendure J, Drmanac R, Jorde LB, Hood L, Galas DJ | display-authors = 6 | title = Analysis of genetic inheritance in a family quartet by whole-genome sequencing | journal = Science | volume = 328 | issue = 5978 | pages = 636–639 | date = April 2010 | pmid = 20220176 | pmc = 3037280 | doi = 10.1126/science.1186802 | bibcode = 2010Sci...328..636R }}</ref><ref>{{cite journal | vauthors = Campbell CD, Chong JX, Malig M, Ko A, Dumont BL, Han L, Vives L, O'Roak BJ, Sudmant PH, Shendure J, Abney M, Ober C, Eichler EE | display-authors = 6 | title = Estimating the human mutation rate using autozygosity in a founder population | journal = Nature Genetics | volume = 44 | issue = 11 | pages = 1277–1281 | date = November 2012 | pmid = 23001126 | pmc = 3483378 | doi = 10.1038/ng.2418 }}</ref> In the protein coding regions of the genome, there are only about 0.35 mutations between parent/child generations (less than one mutated protein per generation).<ref>{{cite journal | vauthors = Keightley PD | title = Rates and fitness consequences of new mutations in humans | journal = Genetics | volume = 190 | issue = 2 | pages = 295–304 | date = February 2012 | pmid = 22345605 | pmc = 3276617 | doi = 10.1534/genetics.111.134668 }}</ref> Whole genome sequencing in blood cells for a pair of identical twin 100-year-old centenarians only found 8 somatic differences, though somatic variation occurring in less than 20% of blood cells would be undetected.<ref name="pmid24182360">{{cite journal | vauthors = Ye K, Beekman M, Lameijer EW, Zhang Y, Moed MH, van den Akker EB, Deelen J, Houwing-Duistermaat JJ, Kremer D, Anvar SY, Laros JF, Jones D, Raine K, Blackburne B, Potluri S, Long Q, Guryev V, van der Breggen R, Westendorp RG, 't Hoen PA, den Dunnen J, van Ommen GJ, Willemsen G, Pitts SJ, Cox DR, Ning Z, Boomsma DI, Slagboom PE | display-authors = 6 | title = Aging as accelerated accumulation of somatic variants: whole-genome sequencing of centenarian and middle-aged monozygotic twin pairs | journal = Twin Research and Human Genetics | volume = 16 | issue = 6 | pages = 1026–1032 | date = December 2013 | pmid = 24182360 | doi = 10.1017/thg.2013.73 | doi-access = free }}</ref>

While DNA damages may give rise to mutations through error prone [[Biology:DNA repair#Translesion synthesis|translesion synthesis]], DNA damages can also give rise to epigenetic alterations during faulty DNA repair processes.<ref name=Hagan /><ref name=Cuozzo /><ref name="pmid20550933">{{cite journal | vauthors = Shanbhag NM, Rafalska-Metcalf IU, Balane-Bolivar C, Janicki SM, Greenberg RA | title = ATM-dependent chromatin changes silence transcription in cis to DNA double-strand breaks | journal = Cell | volume = 141 | issue = 6 | pages = 970–981 | date = June 2010 | pmid = 20550933 | pmc = 2920610 | doi = 10.1016/j.cell.2010.04.038 }}</ref><ref name="pmid24137009">{{cite journal | vauthors = Morano A, Angrisano T, Russo G, Landi R, Pezone A, Bartollino S, Zuchegna C, Babbio F, Bonapace IM, Allen B, Muller MT, Chiariotti L, Gottesman ME, Porcellini A, Avvedimento EV | display-authors = 6 | title = Targeted DNA methylation by homology-directed repair in mammalian cells. Transcription reshapes methylation on the repaired gene | journal = Nucleic Acids Research | volume = 42 | issue = 2 | pages = 804–821 | date = January 2014 | pmid = 24137009 | pmc = 3902918 | doi = 10.1093/nar/gkt920 }}</ref> 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. In an early study, looking at a limited set of transcriptional promoters, Fernandez et al.<ref name="pmid21613409">{{cite journal | vauthors = Fernandez AF, Assenov Y, Martin-Subero JI, Balint B, Siebert R, Taniguchi H, Yamamoto H, Hidalgo M, Tan AC, Galm O, Ferrer I, Sanchez-Cespedes M, Villanueva A, Carmona J, Sanchez-Mut JV, Berdasco M, Moreno V, Capella G, Monk D, Ballestar E, Ropero S, Martinez R, Sanchez-Carbayo M, Prosper F, Agirre X, Fraga MF, Graña O, Perez-Jurado L, Mora J, Puig S, Prat J, Badimon L, Puca AA, Meltzer SJ, Lengauer T, Bridgewater J, Bock C, Esteller M | display-authors = 6 | title = A DNA methylation fingerprint of 1628 human samples | journal = Genome Research | volume = 22 | issue = 2 | pages = 407–419 | date = February 2012 | pmid = 21613409 | pmc = 3266047 | doi = 10.1101/gr.119867.110 }}</ref> examined the DNA methylation profiles of 855 primary tumors. Comparing each tumor type with its corresponding normal tissue, 729 CpG island sites (55% of the 1322 CpG sites evaluated) showed differential DNA methylation. Of these sites, 496 were hypermethylated (repressed) and 233 were hypomethylated (activated). Thus, there is a high level of epigenetic promoter methylation alterations in tumors. Some of these epigenetic alterations may contribute to cancer progression.

==Epigenetic carcinogens==

A variety of compounds are considered as epigenetic carcinogens—they result in an increased incidence of tumors, but they do not show mutagen activity (toxic compounds or pathogens that cause tumors incident to increased regeneration should also be excluded). Examples include [[Chemistry:Diethylstilbestrol|diethylstilbestrol]], [[Chemistry:Arsenite|arsenite]], [[Chemistry:Hexachlorobenzene|hexachlorobenzene]], and [[Chemistry:Nickel|nickel]] compounds.

Many [[Chemistry:Teratogen|teratogen]]s exert specific effects on the fetus by epigenetic mechanisms.<ref name="bishop97">{{cite journal | vauthors = Bishop JB, Witt KL, Sloane RA | title = Genetic toxicities of human teratogens | journal = Mutation Research | volume = 396 | issue = 1–2 | pages = 9–43 | date = December 1997 | pmid = 9434858 | doi = 10.1016/S0027-5107(97)00173-5 | url = https://zenodo.org/record/1259667 }}</ref><ref name="gurvich04">{{cite journal | vauthors = Gurvich N, Berman MG, Wittner BS, Gentleman RC, Klein PS, Green JB | title = Association of valproate-induced teratogenesis with histone deacetylase inhibition in vivo | journal = FASEB Journal | volume = 19 | issue = 9 | pages = 1166–1168 | date = July 2005 | pmid = 15901671 | doi = 10.1096/fj.04-3425fje | s2cid = 25874971 }}</ref> While epigenetic effects may preserve the effect of a teratogen such as [[Chemistry:Diethylstilbestrol|diethylstilbestrol]] throughout the life of an affected child, the possibility of birth defects resulting from exposure of fathers or in second and succeeding generations of offspring has generally been rejected on theoretical grounds and for lack of evidence.<ref name="smithells98">{{cite journal | vauthors = Smithells D | title = Does thalidomide cause second generation birth defects? | journal = Drug Safety | volume = 19 | issue = 5 | pages = 339–341 | date = November 1998 | pmid = 9825947 | doi = 10.2165/00002018-199819050-00001 | s2cid = 9014237 }}</ref> However, a range of male-mediated abnormalities have been demonstrated, and more are likely to exist.<ref name="friedler96">{{cite journal | vauthors = Friedler G | title = Paternal exposures: impact on reproductive and developmental outcome. An overview | journal = Pharmacology, Biochemistry, and Behavior | volume = 55 | issue = 4 | pages = 691–700 | date = December 1996 | pmid = 8981601 | doi = 10.1016/S0091-3057(96)00286-9 | s2cid = 2260876 | doi-access = free }}</ref> FDA label information for Vidaza, a formulation of 5-azacitidine (an unmethylatable analog of cytidine that causes hypomethylation when incorporated into DNA) states that "men should be advised not to father a child" while using the drug, citing evidence in treated male mice of reduced fertility, increased [[Biology:Embryo loss|embryo loss]], and abnormal embryo development.<ref>{{cite web | title = Vidaza (azacitidine for injectable suspension) package insert | url = http://www.fda.gov/cder/foi/label/2004/050794lbl.pdf | archive-url = https://web.archive.org/web/20040529163200/http://www.fda.gov/cder/foi/label/2004/050794lbl.pdf | archive-date = 29 May 2004 | work = Pharmion Corporation | publisher = U.S. Food and Drug Administration | date = 18 May 2004 }}</ref> In rats, endocrine differences were observed in offspring of males exposed to morphine.<ref name="cicero91">{{cite journal | vauthors = Cicero TJ, Adams ML, Giordano A, Miller BT, O'Connor L, Nock B | title = Influence of morphine exposure during adolescence on the sexual maturation of male rats and the development of their offspring | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 256 | issue = 3 | pages = 1086–1093 | date = March 1991 | pmid = 2005573 }}</ref> In mice, second generation effects of diethylstilbesterol have been described occurring by epigenetic mechanisms.<ref name="newbold06">{{cite journal | vauthors = Newbold RR, Padilla-Banks E, Jefferson WN | title = Adverse effects of the model environmental estrogen diethylstilbestrol are transmitted to subsequent generations | journal = Endocrinology | volume = 147 | issue = 6 Suppl | pages = S11–S17 | date = June 2006 | pmid = 16690809 | doi = 10.1210/en.2005-1164 | doi-access = free }}</ref>

==Cancer subtypes==

===Skin cancer===
[[Medicine:Melanoma|Melanoma]] is a deadly skin cancer that originates from melanocytes. Several epigenetic alterations are known to play a role in the transition of melanocytes to melanoma cells. This includes DNA methylation that can be inherited without making changes to the DNA sequence, as well as silencing the tumor suppressor genes in the epidermis that have been exposed to UV radiation for periods of time.<ref name="Katiyar-2012">{{cite journal | vauthors = Katiyar SK, Singh T, Prasad R, Sun Q, Vaid M | title = Epigenetic alterations in ultraviolet radiation-induced skin carcinogenesis: interaction of bioactive dietary components on epigenetic targets | journal = Photochemistry and Photobiology | volume = 88 | issue = 5 | pages = 1066–1074 | date = September 2012 | pmid = 22017262 | pmc = 3288155 | doi = 10.1111/j.1751-1097.2011.01020.x }}</ref> The silencing of tumor suppressor genes leads to photocarcinogenesis which is associated to epigenetic alterations in DNA methylation, DNA methyltransferases, and histone acetylation.<ref name="Katiyar-2012" /> These alterations are the consequence of deregulation of their corresponding enzymes. Several histone methyltransferases and demethylases are among these enzymes.<ref>{{cite journal | vauthors = Orouji E, Utikal J | title = Tackling malignant melanoma epigenetically: histone lysine methylation | journal = Clinical Epigenetics | volume = 10 | issue = 1 | pages = 145 | date = November 2018 | pmid = 30466474 | pmc = 6249913 | doi = 10.1186/s13148-018-0583-z | doi-access = free }}</ref>

===Prostate cancer===
[[Medicine:Prostate cancer|Prostate cancer]] kills around 35,000 men yearly, and about 220,000 men are diagnosed with prostate cancer per year, in North America alone.<ref name="Collins et al 2012" /> 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.<ref name="Collins et al 2012" /> Alterations in histone acetylation and DNA methylation occur in various genes influencing prostate cancer, and have been seen in genes involved in hormonal response.<ref name="Li2005">{{cite journal | vauthors = Li LC, Carroll PR, Dahiya R | title = Epigenetic changes in prostate cancer: implication for diagnosis and treatment | journal = Journal of the National Cancer Institute | volume = 97 | issue = 2 | pages = 103–115 | date = January 2005 | pmid = 15657340 | doi = 10.1093/jnci/dji010 | doi-access =  }}</ref> More than 90% of prostate cancers show [[Biology:Gene silencing|gene silencing]] by [[Biology:CpG island hypermethylation|CpG island hypermethylation]] of the GSTP1 gene [[Biology:Promoter (genetics)|promoter]], which protects [[Biology:Prostate|prostate]] cells from genomic damage that is caused by different oxidants or [[Biology:Carcinogen|carcinogen]]s.<ref name="Gurel et al 2008" /> Real-time methylation-specific [[Biology:Polymerase chain reaction|polymerase chain reaction]] (PCR) suggests that many other genes are also hypermethylated.<ref name="Gurel et al 2008" /> Gene expression in the prostate may be modulated by nutrition and lifestyle changes.<ref name="pmid18559852">{{cite journal | vauthors = Ornish D, Magbanua MJ, Weidner G, Weinberg V, Kemp C, Green C, Mattie MD, Marlin R, Simko J, Shinohara K, Haqq CM, Carroll PR | display-authors = 6 | title = Changes in prostate gene expression in men undergoing an intensive nutrition and lifestyle intervention | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 24 | pages = 8369–8374 | date = June 2008 | pmid = 18559852 | pmc = 2430265 | doi = 10.1073/pnas.0803080105 | doi-access = free | bibcode = 2008PNAS..105.8369O }}</ref>

===Cervical cancer===
The second most common malignant tumor in women is invasive [[Medicine:Cervical cancer|cervical cancer]] (ICC) and more than 50% of all [[Medicine:Cervical cancer|invasive cervical cancer]] (ICC) is caused by [[Biology:Oncogene|oncongenic]] human papillomavirus 16 (HPV16).<ref name="SunReimersBurk2011" /> Furthermore, cervix intraepithelial neoplasia (CIN) is primarily caused by oncogenic HPV16.<ref name="SunReimersBurk2011" /> 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.<ref name="SunReimersBurk2011" /> Only 2/16 CpG sites tested in HPV16 upstream regulatory region were found to have association with increased methylation in CIN3+.<ref name="SunReimersBurk2011" /> 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 [[Biology:DAPK1|DAPK1]], 2/5 [[Biology:Retinoic acid receptor beta|RARB]], MAL, and CADM1.<ref name="SunReimersBurk2011" /> Furthermore, 1/3 of CpG sites in [[Biology:Mitochondrial DNA|mitochondrial DNA]] were associated with increased methylation in CIN3+.<ref name="SunReimersBurk2011" /> Thus, a correlation exists between CIN3+ and increased methylation of CpG sites in the HPV16 L1 open reading frame.<ref name="SunReimersBurk2011" /> This could be a potential [[Biology:Biomarker|biomarker]] for future screens of cancerous and precancerous cervical disease.<ref name="SunReimersBurk2011" />

===Leukemia===
Recent studies have shown that the mixed-lineage leukemia (MLL) gene causes [[Medicine:Leukemia|leukemia]] by rearranging and fusing with other genes in different chromosomes, which is a process under epigenetic control.<ref name="pmid20236314">{{cite journal | vauthors = Mandal SS | title = Mixed lineage leukemia: versatile player in epigenetics and human disease | journal = The FEBS Journal | volume = 277 | issue = 8 | pages = 1789 | date = April 2010 | pmid = 20236314 | doi = 10.1111/j.1742-4658.2010.07605.x | s2cid = 37705117 | doi-access = free }}</ref> Mutations in MLL block the correct regulatory regions in leukemia associated translocations or insertions causing malignant transformation controlled by HOX genes.<ref>{{cite journal | vauthors = Nebbioso A, Tambaro FP, Dell'Aversana C, Altucci L | title = Cancer epigenetics: Moving forward | journal = PLOS Genetics | volume = 14 | issue = 6 | pages = e1007362 | date = June 2018 | pmid = 29879107 | pmc = 5991666 | doi = 10.1371/journal.pgen.1007362 | doi-access = free | veditors = Greally GM }}</ref> This is what leads to the increase in white blood cells. Leukemia related genes are managed by the same pathways that control epigenetics, signaling transduction, transcriptional regulation, and energy metabolism. It was indicated that infections, electromagnetic fields and increased birth weight can contribute to being the causes of leukemia.<ref>{{cite journal| vauthors = Butcher J |date=March 2001|title=Electromagnetic fields may cause leukaemia in children |journal=The Lancet |language=en |volume=357 |issue=9258 |pages=777 |doi=10.1016/S0140-6736(05)71207-1|s2cid=54400632}}</ref>

===Sarcoma===
There are about 15,000 new cases of sarcoma in the US each year, and about 6,200 people were projected to die of sarcoma in the US in 2014.<ref>{{cite web | url=http://www.cancer.gov/research/progress/snapshots/sarcoma | title=Soft Tissue Sarcoma | work = National Cancer Institute | publisher =  National Institutes of Health, U.S. Department of Health and Human Services | date=January 1980}}</ref> Sarcomas comprise a large number of rare, histogenetically heterogeneous mesenchymal tumors that, for example, include chondrosarcoma, Ewing's sarcoma, leiomyosarcoma, liposarcoma, osteosarcoma, synovial sarcoma, and (alveolar and embryonal) rhabdomyosarcoma. Several oncogenes and tumor suppressor genes are epigenetically altered in sarcomas. These include APC, CDKN1A, CDKN2A, CDKN2B, Ezrin, FGFR1, GADD45A, MGMT, STK3, STK4, PTEN, RASSF1A, WIF1, as well as several miRNAs.<ref>{{cite journal | vauthors = Bennani-Baiti IM | title = Epigenetic and epigenomic mechanisms shape sarcoma and other mesenchymal tumor pathogenesis | journal = Epigenomics | volume = 3 | issue = 6 | pages = 715–732 | date = December 2011 | pmid = 22126291 | doi = 10.2217/epi.11.93 }}</ref> Expression of epigenetic modifiers such as that of the BMI1 component of the PRC1 complex is deregulated in chondrosarcoma, Ewing's sarcoma, and osteosarcoma, and expression of the EZH2 component of the PRC2 complex is altered in Ewing's sarcoma and rhabdomyosarcoma. Similarly, expression of another epigenetic modifier, the LSD1 histone demethylase, is increased in chondrosarcoma, Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma. Drug targeting and inhibition of EZH2 in Ewing's sarcoma,<ref>{{cite journal | vauthors = Richter GH, Plehm S, Fasan A, Rössler S, Unland R, Bennani-Baiti IM, Hotfilder M, Löwel D, von Luettichau I, Mossbrugger I, Quintanilla-Martinez L, Kovar H, Staege MS, Müller-Tidow C, Burdach S | display-authors = 6 | title = EZH2 is a mediator of EWS/FLI1 driven tumor growth and metastasis blocking endothelial and neuro-ectodermal differentiation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 13 | pages = 5324–5329 | date = March 2009 | pmid = 19289832 | pmc = 2656557 | doi = 10.1073/pnas.0810759106 | doi-access = free | bibcode = 2009PNAS..106.5324R }}</ref> or of LSD1 in several sarcomas,<ref>{{cite journal | vauthors = Bennani-Baiti IM, Machado I, Llombart-Bosch A, Kovar H | title = Lysine-specific demethylase 1 (LSD1/KDM1A/AOF2/BHC110) is expressed and is an epigenetic drug target in chondrosarcoma, Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma | journal = Human Pathology | volume = 43 | issue = 8 | pages = 1300–1307 | date = August 2012 | pmid = 22245111 | doi = 10.1016/j.humpath.2011.10.010 }}</ref> inhibits tumor cell growth in these sarcomas.

=== Lung Cancer ===
Lung cancer is the second most common type of cancer and leading cause of death in men and women in the United States, it is estimated that there is about 216,000 new cases and 160,000 deaths due to lung cancer.<ref>{{Cite journal |last1=Tam |first1=Kit W. |last2=Zhang |first2=Wei |last3=Soh |first3=Junichi |last4=Stastny |first4=Victor |last5=Chen |first5=Min |last6=Sun |first6=Han |last7=Thu |first7=Kelsie |last8=Rios |first8=Jonathan J. |last9=Yang |first9=Chenchen |last10=Marconett |first10=Crystal N. |last11=Selamat |first11=Suhaida. A. |last12=Laird-Offringa |first12=Ite A. |last13=Taguchi |first13=Ayumu |last14=Hanash |first14=Samir |last15=Shames |first15=David |date=2013-11-01 |title=CDKN2A/p16 Inactivation Mechanisms and Their Relationship to Smoke Exposure and Molecular Features in Non–Small-Cell Lung Cancer |journal=Journal of Thoracic Oncology |language=en |volume=8 |issue=11 |pages=1378–1388 |doi=10.1097/JTO.0b013e3182a46c0c |pmid=24077454 |issn=1556-0864|pmc=3951422 }}</ref>

Initiation and progression of lung carcinoma is the result of the interaction between genetic, epigenetic and environmental factors. Most cases of lung cancer are because of genetic mutations in ''EGFR'', ''KRAS'', ''STK11'' (also known as ''LKB1''), ''TP53'' (also known as ''p53''), and ''CDKN2A'' (also known as ''p16'' or ''INK4a'')<ref>{{Cite web |last1=Hong |first1=Runyu |last2=Liu |first2=Wenke |last3=Fenyö |first3=David |date=2021 |title=Predicting and Visualizing STK11 Mutation in Lung Adenocarcinoma Histopathology Slides Using Deep Learning |url=http://dx.doi.org/10.1101/2020.02.20.956557 |access-date=2023-03-16 |doi=10.1101/2020.02.20.956557 }}</ref><ref>{{Cite book |first=Aamir |last=Ahmad |url=http://worldcat.org/oclc/1113687835 |title=Lung Cancer and Personalized Medicine: Novel Therapies and Clinical Management |date=2015 |publisher=Springer International Publishing |isbn=978-3-319-24932-2 |oclc=1113687835}}</ref><ref>{{Cite journal |last1=Iwakawa |first1=Reika |last2=Kohno |first2=Takashi |last3=Anami |first3=Yoichi |last4=Noguchi |first4=Masayuki |last5=Suzuki |first5=Kenji |last6=Matsuno |first6=Yoshihiro |last7=Mishima |first7=Kazuhiko |last8=Nishikawa |first8=Ryo |last9=Tashiro |first9=Fumio |last10=Yokota |first10=Jun |date=2008-06-15 |title=Association of p16 Homozygous Deletions with Clinicopathologic Characteristics and EGFR/KRAS/p53 Mutations in Lung Adenocarcinoma |url=http://dx.doi.org/10.1158/1078-0432.ccr-07-4552 |journal=Clinical Cancer Research |volume=14 |issue=12 |pages=3746–3753 |doi=10.1158/1078-0432.ccr-07-4552 |pmid=18559592 |s2cid=17931210 |issn=1078-0432}}</ref> with the most common type of lung cancer being an inactivation at p16. p16 is a tumor suppressor protein that occurs in mostly in humans the functional significance of the mutations was tested on many other species including mice, cats, dogs, monkeys and cows the identification of these multiple nonoverlapping clones was not entirely surprising since the reduced stringency hybridization of a zoo blot with the same probe also revealed 10-15 positive EcoRI fragments in all species tested.<ref>{{Cite journal |last1=Fountain |first1=J. W. |last2=Giendening |first2=J. M. |last3=Flores |first3=J. F. |date=1994-09-01 |title=Characterization of the p16 gene in the mouse: Evidence for a large gene family |url=https://www.osti.gov/biblio/133832 |journal=American Journal of Human Genetics |language=English |volume=55 |issue=Suppl.3|osti=133832 }}</ref>

== Identification methods ==
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.<ref name="Esteller2007" />

Popular approaches for measuring CpG methylation in cells include:
*[[Biology:Bisulfite sequencing|Bisulfite sequencing]]
*[[Biology:Combined bisulfite restriction analysis|Combined bisulfite restriction analysis]] (COBRA)
*Methylation-specific PCR
*MethyLight
*[[Biology:Pyrosequencing|Pyrosequencing]]
*[[Biology:Restriction landmark genomic scanning|Restriction landmark genomic scanning]]
*Arbitrary primed PCR
*[[Biology:HELP assay|HELP assay]] (HpaII tiny fragment enrichment by ligation-mediated PCR)
*[[Biology:Chromatin immunoprecipitation|Chromatin immunoprecipitation]] ChIP-Chip using antibodies specific for methyl-CpG binding domain proteins
*[[Biology:Methylated DNA immunoprecipitation|Methylated DNA immunoprecipitation]] Methyl-DIP
*Gene-expression profiles via [[Biology:DNA microarray|DNA microarray]] : comparing [[Biology:MRNA|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[1].
Popular approaches for determining histone modification profiles in cancerous versus healthy cells include:<ref name="Esteller2007"/>
*[[Physics:Mass spectrometry|Mass spectrometry]]
*Chromatin Immunoprecipitation Assay

==Diagnosis and prognosis==
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.<ref name="Esteller2007" /> 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 [[Biology:EMP3|Epithelial Membrane Protein 3]] (EMP3) have been linked to more aggressive forms of lung, [[Medicine:Colorectal cancer|colorectal]], and brain cancers.<ref name="Esteller2005" /> 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, [[Biology:O-6-methylguanine-DNA methyltransferase|MGMT]] is an enzyme that reverses the addition of [[Chemistry:Alkyl group|alkyl group]]s to the nucleotide [[Chemistry:Guanine|guanine]].<ref name="Esteller et al 2004" /> Alkylating guanine, however, is the mechanism by which several chemotherapeutic drugs act in order to disrupt DNA and cause [[Biology:Cell death|cell death]].<ref name="Esteller et al 2000" /><ref name="Hegi et al 2005" /><ref name="Esteller et al 2002" /><ref name="Glasspool et al 2006" /> 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 [[Biology:Biomarker|biomarker]]s can also be utilized as tools for molecular prognosis. In primary tumor and mediastinal [[Biology:Lymph node|lymph node]] [[Medicine:Biopsy|biopsy]] samples, hypermethylation of both [[Biology:CDKN2A|CDKN2A]] and CDH13 serves as the marker for increased risk of faster cancer relapse and higher death rate of patients.<ref name="Brock et al 2008" />

==Treatment==
[[File:Decitabine.svg|thumb|right|decitabine]]
Epigenetic control of the proto-onco regions and the tumor suppressor sequences by conformational changes in histones plays a role in the formation and progression of cancer.<ref name="IglesiasLinares2010">{{cite journal | vauthors = Iglesias-Linares A, Yañez-Vico RM, González-Moles MA | title = Potential role of HDAC inhibitors in cancer therapy: insights into oral squamous cell carcinoma | journal = Oral Oncology | volume = 46 | issue = 5 | pages = 323–329 | date = May 2010 | pmid = 20207580 | doi = 10.1016/j.oraloncology.2010.01.009 }}</ref> Pharmaceuticals that reverse epigenetic changes might have a role in a variety of cancers.<ref name="Li2005"/><ref name="IglesiasLinares2010"/><ref name="pmid20664922">{{cite journal | vauthors = Wang LG, Chiao JW | title = Prostate cancer chemopreventive activity of phenethyl isothiocyanate through epigenetic regulation (review) | journal = International Journal of Oncology | volume = 37 | issue = 3 | pages = 533–539 | date = September 2010 | pmid = 20664922 | doi = 10.3892/ijo_00000702 | doi-access = free }}</ref>

Recently, it is evidently known that associations between specific cancer histotypes and epigenetic changes can facilitate the development of novel epi-drugs.<ref>{{cite journal | vauthors = Gherardini L, Sharma A, Capobianco E, Cinti C | title = Targeting Cancer with Epi-Drugs: A Precision Medicine Perspective | journal = Current Pharmaceutical Biotechnology | volume = 17 | issue = 10 | pages = 856–865 | date = 2016-05-27 | pmid = 27229488 | doi = 10.2174/1381612822666160527154757 }}</ref> Drug development has focused mainly on modifying [[Biology:DNA methyltransferase|DNA methyltransferase]], [[Biology:Histone acetyltransferase|histone acetyltransferase]] (HAT) and [[Biology:Histone deacetylase|histone deacetylase]] (HDAC).<ref name="pmid18773966">{{cite journal | vauthors = Spannhoff A, Sippl W, Jung M | title = Cancer treatment of the future: inhibitors of histone methyltransferases | journal = The International Journal of Biochemistry & Cell Biology | volume = 41 | issue = 1 | pages = 4–11 | date = January 2009 | pmid = 18773966 | doi = 10.1016/j.biocel.2008.07.024 }}</ref>

Drugs that specifically target the inverted methylation pattern of cancerous cells include the [[Biology:DNA methyltransferase|DNA methyltransferase]] inhibitors [[Chemistry:Azacitidine|azacitidine]]<ref name="pmid18548103">{{cite journal | vauthors = Garcia-Manero G, Stoltz ML, Ward MR, Kantarjian H, Sharma S | title = A pilot pharmacokinetic study of oral azacitidine | journal = Leukemia | volume = 22 | issue = 9 | pages = 1680–1684 | date = September 2008 | pmid = 18548103 | doi = 10.1038/leu.2008.145 | s2cid = 19854416 | doi-access =  }}</ref><ref name="pmid18841054">{{cite journal | vauthors = Garcia-Manero G | title = Demethylating agents in myeloid malignancies | journal = Current Opinion in Oncology | volume = 20 | issue = 6 | pages = 705–710 | date = November 2008 | pmid = 18841054 | pmc = 3873866 | doi = 10.1097/CCO.0b013e328313699c }}</ref> and [[Chemistry:Decitabine|decitabine]].<ref name="pmid17219444">{{cite journal | vauthors = Aribi A, Borthakur G, Ravandi F, Shan J, Davisson J, Cortes J, Kantarjian H | title = Activity of decitabine, a hypomethylating agent, in chronic myelomonocytic leukemia | journal = Cancer | volume = 109 | issue = 4 | pages = 713–717 | date = February 2007 | pmid = 17219444 | doi = 10.1002/cncr.22457 | doi-access = free }}</ref><ref name="pmid19151791">{{cite journal | vauthors = De Padua Silva L, de Lima M, Kantarjian H, Faderl S, Kebriaei P, Giralt S, Davisson J, Garcia-Manero G, Champlin R, Issa JP, Ravandi F | display-authors = 6 | title = Feasibility of allo-SCT after hypomethylating therapy with decitabine for myelodysplastic syndrome | journal = Bone Marrow Transplantation | volume = 43 | issue = 11 | pages = 839–843 | date = June 2009 | pmid = 19151791 | doi = 10.1038/bmt.2008.400 | s2cid = 42034181 | doi-access =  }}</ref> These hypomethylating agents are used to treat [[Medicine:Myelodysplastic syndrome|myelodysplastic syndrome]],<ref name="pmid19096014">{{cite journal | vauthors = Hambach L, Ling KW, Pool J, Aghai Z, Blokland E, Tanke HJ, Bruijn JA, Halfwerk H, van Boven H, Wieles B, Goulmy E | display-authors = 6 | title = Hypomethylating drugs convert HA-1-negative solid tumors into targets for stem cell-based immunotherapy | journal = Blood | volume = 113 | issue = 12 | pages = 2715–2722 | date = March 2009 | pmid = 19096014 | doi = 10.1182/blood-2008-05-158956 | s2cid = 206871351 | doi-access = free }}</ref> a blood cancer produced by abnormal bone marrow stem cells.<ref name="Jones 2002" /> These agents inhibit all three types of active DNA methyltransferases, and had been thought to be highly toxic, but proved to be effective when used in low dosage, reducing progression of myelodysplastic syndrome to [[Medicine:Leukemia|leukemia]].<ref name="Fenaux et al 2009" />

[[Biology:Histone deacetylase|Histone deacetylase]] (HDAC) inhibitors show efficacy in treatment of T cell lymphoma. two HDAC inhibitors, [[Chemistry:Vorinostat|vorinostat]] and [[Chemistry:Romidepsin|romidepsin]], have been approved by the [[Organization:Food and Drug Administration|Food and Drug Administration]].<ref name="Duvic et al 2007" /><ref name="Olsen et al 2007" /> 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.<ref name="BaylinJones 2011" /> Treatment with HDAC inhibitors has been found to promote gene reactivation after DNA methyl-transferases inhibitors have repressed transcription.<ref name="Cameron et al 1999" /> [[Chemistry:Panobinostat|Panobinostat]] is approved for certain situations in myeloma.<ref>{{cite web | title = New Drug Application: Panobinostat | date = 14 January 2015 | url = http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/205353Orig1s000MedR.pdf | work = Center for Drug Evaluation and Research | publisher = U.S. Food and Drug Administration }}</ref>

Other pharmaceutical targets in research are [[Biology:Histone methyltransferase|histone lysine methyltransferases]] (KMT) and protein arginine methyltransferases (PRMT).<ref name="pmid20219369">{{cite journal | vauthors = Dowden J, Hong W, Parry RV, Pike RA, Ward SG | title = Toward the development of potent and selective bisubstrate inhibitors of protein arginine methyltransferases | journal = Bioorganic & Medicinal Chemistry Letters | volume = 20 | issue = 7 | pages = 2103–2105 | date = April 2010 | pmid = 20219369 | doi = 10.1016/j.bmcl.2010.02.069 }}</ref> Preclinical study has suggested that [[Chemistry:Lunasin|lunasin]] may have potentially beneficial epigenetic effects.<ref name="AJC">{{cite journal |vauthors=Galvez AF, Chen N, Macasieb J, de Lumen BO | title= Chemopreventive Property of a Soybean Peptide (Lunasin) That Binds to Deacetylated Histones and Inhibits Acetylation | journal=Cancer Research | volume=61 | date= October 15, 2001|url= http://cancerres.aacrjournals.org/content/61/20/7473.long}}</ref>

== Epigenetic Therapy ==
Epigenetic therapy of cancer has shown to be a promising and possible treatment of cancerous cells. Epigenetic inactivation is an ideal target for cancerous cells because it targets genes imperative for controlling cell growth, specifically cancer cell growth. It is crucial for these genes to be reactivated in order to suppress tumor growth and sensitize the cells to cancer curing therapies.<ref>{{Cite journal |last1=Brown |first1=Robert |last2=Strathdee |first2=Gordon |date=2002-04-01 |title=Epigenomics and epigenetic therapy of cancer |url=https://www.sciencedirect.com/science/article/pii/S1471491402023146 |journal=Trends in Molecular Medicine |language=en |volume=8 |issue=4 |pages=S43–S48 |doi=10.1016/S1471-4914(02)02314-6 |pmid=11927287 |issn=1471-4914}}</ref> Typical chemotherapy aims to kill and eliminate cancer cells in the body. Cancer initiated by genetic alterations of cells are typically permanent and nearly impossible to reverse, this differs from epigenetic cancer because the cancer causing epigenetic aberrations have the capability of being reversed, and the cells being returned to normal function. The ability for epigenetic mechanisms to be reversed is attributed to the fact that the coding of the genes being silenced through histone and DNA modification is not being altered.<ref>{{Cite journal |last1=Egger |first1=Gerda |last2=Liang |first2=Gangning |last3=Aparicio |first3=Ana |last4=Jones |first4=Peter A. |date=May 2004 |title=Epigenetics in human disease and prospects for epigenetic therapy |url=https://www.nature.com/articles/nature02625 |journal=Nature |language=en |volume=429 |issue=6990 |pages=457–463 |doi=10.1038/nature02625 |pmid=15164071 |bibcode=2004Natur.429..457E |s2cid=4424126 |issn=1476-4687}}</ref>

There are two primary types of epigenetic alterations in cancer cells, these are known as DNA methylation and Histone modification. It is the goal of epigenetic therapies to inhibit these alterations. DNA Methyltransferases (DNMTs) and Histone Deacetylases (HDAC) are the primary catalyzes of the epigenetic modifications of cancer cells.<ref>{{Cite journal |last1=Song |first1=Sang-Hyun |last2=Han |first2=Sae-Won |last3=Bang |first3=Yung-Jue |date=2011-12-01 |title=Epigenetic-Based Therapies in Cancer |url=https://doi.org/10.2165/11596690-000000000-00000 |journal=Drugs |language=en |volume=71 |issue=18 |pages=2391–2403 |doi=10.2165/11596690-000000000-00000 |pmid=22141383 |s2cid=35003553 |issn=1179-1950}}</ref> The goal for epigenetic therapies is to repress this methylation and reverse these modifications in order to create a new epigenome where cancer cells no longer thrive and tumor suppression is the new function. Synthetic drugs are used as tools in epigenetic therapies due to their ability to inhibit enzymes causing histone modifications and DNA methylations. Combination therapy is one method of epigenetic therapy which involves the use of more than one synthetic drug, these drugs include a low dose DNMT inhibitor as well as an HDAC inhibitor. Together, these drugs are able to target the linkage between DNA methylation and Histone modification.<ref>{{Cite journal |last=Saleem |first=Mohammad |date=May 2015 |title=Epigenetic Therapy for Caner |url=https://www.researchgate.net/publication/273648245 |journal=Pak. J. Pharm. Sci |volume=28 |issue=3 |pages=1023–1032}}</ref>

The goal of epigenetic therapies for cancer in relation to DNA methylation is to both decrease the methylation of DNA and in turn decrease the silencing of genes related to tumor suppression.<ref name="aacrjournals.org">{{Cite web |url=https://aacrjournals.org/clincancerres/article/13/6/1634/195851/DNA-Methylation-as-a-Therapeutic-Target-in-Cancer |access-date=2022-10-22 |website=aacrjournals.org}}</ref> The term associated with decreasing the methylation of DNA will be known as hypomethylation. The Food and Drug Administration (FDA) has currently approved one hypomethylating agent which, through the conduction of clinical trials, has shown promising results when utilized to treat patients with Myelodysplastic Syndrome (MDS).<ref>{{Cite journal |last1=Kantarjian |first1=Hagop |last2=Issa |first2=Jean-Pierre J. |last3=Rosenfeld |first3=Craig S. |last4=Bennett |first4=John M. |last5=Albitar |first5=Maher |last6=DiPersio |first6=John |last7=Klimek |first7=Virginia |last8=Slack |first8=James |last9=de Castro |first9=Carlos |last10=Ravandi |first10=Farhad |last11=Helmer |first11=Richard |last12=Shen |first12=Lanlan |last13=Nimer |first13=Stephen D. |last14=Leavitt |first14=Richard |last15=Raza |first15=Azra |date=2006-04-15 |title=Decitabine improves patient outcomes in myelodysplastic syndromes: Results of a phase III randomized study |journal=Cancer |language=en |volume=106 |issue=8 |pages=1794–1803 |doi=10.1002/cncr.21792 |pmid=16532500 |s2cid=9556660 |issn=0008-543X|doi-access=free }}</ref> This hypomethylating agent is known as the doozy analogue of 5-azacytidine and works to promote hypomethylation by targeting all DNA methyltransferases for degradation.<ref name="aacrjournals.org" />

== See also ==
* [[Biology:Pharmacoepigenetics|Pharmacoepigenetics]]
* [[Biology:Regulation of transcription in cancer|Regulation of transcription in cancer]]

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}}


[[Category:Epigenetics]]

{{Sourceattribution|Cancer epigenetics}}