Cancer Genetics and Epigenetics: Two Sides of the Same Coin?
2012; Cell Press; Volume: 22; Issue: 1 Linguagem: Inglês
10.1016/j.ccr.2012.06.008
ISSN1878-3686
AutoresJueng Soo You, Peter A. Jones,
Tópico(s)Cancer-related gene regulation
ResumoEpigenetic and genetic alterations have long been thought of as two separate mechanisms participating in carcinogenesis. A recent outcome of whole exome sequencing of thousands of human cancers has been the unexpected discovery of many inactivating mutations in genes that control the epigenome. These mutations have the potential to disrupt DNA methylation patterns, histone modifications, and nucleosome positioning and hence, gene expression. Genetic alteration of the epigenome therefore contributes to cancer just as epigenetic process can cause point mutations and disable DNA repair functions. This crosstalk between the genome and the epigenome offers new possibilities for therapy. Epigenetic and genetic alterations have long been thought of as two separate mechanisms participating in carcinogenesis. A recent outcome of whole exome sequencing of thousands of human cancers has been the unexpected discovery of many inactivating mutations in genes that control the epigenome. These mutations have the potential to disrupt DNA methylation patterns, histone modifications, and nucleosome positioning and hence, gene expression. Genetic alteration of the epigenome therefore contributes to cancer just as epigenetic process can cause point mutations and disable DNA repair functions. This crosstalk between the genome and the epigenome offers new possibilities for therapy. Cancer has traditionally been viewed as a set of diseases that are driven by the accumulation of genetic mutations that have been considered the major causes of neoplasia (Hanahan and Weinberg, 2011Hanahan D. Weinberg R.A. Hallmarks of cancer: the next generation.Cell. 2011; 144: 646-674Abstract Full Text Full Text PDF PubMed Scopus (4513) Google Scholar). However, this paradigm has now been expanded to incorporate the disruption of epigenetic regulatory mechanisms that are prevalent in cancer (Baylin and Jones, 2011Baylin S.B. Jones P.A. A decade of exploring the cancer epigenome - biological and translational implications.Nat. Rev. Cancer. 2011; 11: 726-734Crossref PubMed Scopus (324) Google Scholar, Sandoval and Esteller, 2012Sandoval J. Esteller M. Cancer epigenomics: beyond genomics.Curr. Opin. Genet. Dev. 2012; 22: 50-55Crossref PubMed Scopus (64) Google Scholar). Both genetic and epigenetic views ultimately involve abnormal gene expression. The expression state of a particular gene is determined by the packaging of its DNA regulatory regions at promoters and/or enhancers and insulators in chromatin and by the presence of TFs and chromatin modifying enzymes. The genetic path to cancer is relatively straightforward: mutation of tumor suppressors and/or oncogenes causes either loss or gain of function and abnormal expression. The epigenetic pathway to cancer is not as simple and is determined by chromatin structure including DNA methylation, histone variants and modifications, nucleosome remodeling as well as small non-coding regulatory RNAs (Sharma et al., 2010Sharma S. Kelly T.K. Jones P.A. Epigenetics in cancer.Carcinogenesis. 2010; 31: 27-36Crossref PubMed Scopus (438) Google Scholar). During tumor initiation and progression, the epigenome goes through multiple alterations, including a genome-wide loss of DNA methylation (hypomethylation), frequent increases in promoter methylation of CpG islands, changes in nucleosome occupancy, and modification profiles. More recently, intriguing evidence has emerged that genetic and epigenetic mechanisms are not separate events in cancer; they intertwine and take advantage of each other during tumorigenesis. Alterations in epigenetic mechanisms can lead to genetic mutations, and genetic mutations in epigenetic regulators lead to an altered epigenome. In this review, we will discuss the collusion between epigenetics and genetics in cancer. Epigenetic mechanisms help establish cellular identities, and failure of the proper preservation of epigenetic marks can result in inappropriate activation or inhibition of various cellular signaling pathways leading to cancer. It is now generally accepted that human cancer cells harbor global epigenetic abnormalities and that epigenetic alterations may be the key to initiating tumorigenesis (Baylin and Jones, 2011Baylin S.B. Jones P.A. A decade of exploring the cancer epigenome - biological and translational implications.Nat. Rev. Cancer. 2011; 11: 726-734Crossref PubMed Scopus (324) Google Scholar, Sandoval and Esteller, 2012Sandoval J. Esteller M. Cancer epigenomics: beyond genomics.Curr. Opin. Genet. Dev. 2012; 22: 50-55Crossref PubMed Scopus (64) Google Scholar, Sharma et al., 2010Sharma S. Kelly T.K. Jones P.A. Epigenetics in cancer.Carcinogenesis. 2010; 31: 27-36Crossref PubMed Scopus (438) Google Scholar). The cancer epigenome is characterized by substantial changes in various epigenetic regulatory layers; herein, we introduce some important examples of epigenetic disruptions that cause mutation of key genes and/or alteration of signaling pathways in cancer development. Promoter hypermethylation of classic tumor suppressor genes is commonly observed in cancers, a phenomenon that has been implicated with driving tumorigenesis (Baylin and Jones, 2011Baylin S.B. Jones P.A. A decade of exploring the cancer epigenome - biological and translational implications.Nat. Rev. Cancer. 2011; 11: 726-734Crossref PubMed Scopus (324) Google Scholar). Genes controlling the cell cycle and DNA repair, such as RB, BRCA1/2, and PTEN, have all been reported to be hypermethylated or mutated/deleted in cancer (Hatziapostolou and Iliopoulos, 2011Hatziapostolou M. Iliopoulos D. Epigenetic aberrations during oncogenesis.Cell. Mol. Life Sci. 2011; 68: 1681-1702Crossref PubMed Scopus (43) Google Scholar). There are also several genes that are seldom mutated but are silenced in cancer; promoter hypermethylation is the predominant mechanism for the loss of their functions (Baylin and Jones, 2011Baylin S.B. Jones P.A. A decade of exploring the cancer epigenome - biological and translational implications.Nat. Rev. Cancer. 2011; 11: 726-734Crossref PubMed Scopus (324) Google Scholar). O6-methylguanine-DNA methyltransferase (MGMT), which encodes a DNA repair gene, Cyclin-dependent kinase inhibitor 2B (CDKN2B), which encodes a cell cycle regulator p15, and RASSF1A, which encodes a protein that binds to the RAS oncogene all belong to this category, and they have been implicated with protective roles against tumorigenesis. Several DNA repair genes are known to be subject to promoter methylation. MGMT removes carcinogen-induced O6-methylguanine adducts from DNA, which result in G to A transition mutations. Cancers with hypermethylated MGMT are susceptible to genetic mutation in critical genes such as p53 or KRAS (Baylin and Jones, 2011Baylin S.B. Jones P.A. A decade of exploring the cancer epigenome - biological and translational implications.Nat. Rev. Cancer. 2011; 11: 726-734Crossref PubMed Scopus (324) Google Scholar, Esteller, 2007Esteller M. Cancer epigenomics: DNA methylomes and histone-modification maps.Nat. Rev. Genet. 2007; 8: 286-298Crossref PubMed Scopus (786) Google Scholar). The mismatch-repair gene MLH1 plays an important role in genomic stability, and the loss of function of this gene by promoter hypermethylation causes microsatellite instability, which is a key factor in several cancers, including colorectal and endometrial cancers (Krivtsov and Armstrong, 2007Krivtsov A.V. Armstrong S.A. MLL translocations, histone modifications and leukaemia stem-cell development.Nat. Rev. Cancer. 2007; 7: 823-833Crossref PubMed Scopus (328) Google Scholar). The MLH1 promoter is already hypermethylated in normal colonic epithelium of some colorectal cancer patients, suggesting this epigenetic change is an early event of tumorigenesis and precedes downstream genetic mutation (Hitchins et al., 2011Hitchins M.P. Rapkins R.W. Kwok C.T. Srivastava S. Wong J.J. Khachigian L.M. Polly P. Goldblatt J. Ward R.L. Dominantly inherited constitutional epigenetic silencing of MLH1 in a cancer-affected family is linked to a single nucleotide variant within the 5′UTR.Cancer Cell. 2011; 20: 200-213Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar). Notably, SNVs of MLH1 5′UTR are correlated with the hypermethylation of its promoter, highlighting a close relationship between genetic and epigenetic disruption in cancer (Hitchins et al., 2011Hitchins M.P. Rapkins R.W. Kwok C.T. Srivastava S. Wong J.J. Khachigian L.M. Polly P. Goldblatt J. Ward R.L. Dominantly inherited constitutional epigenetic silencing of MLH1 in a cancer-affected family is linked to a single nucleotide variant within the 5′UTR.Cancer Cell. 2011; 20: 200-213Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar). Direct evidence for a close epigenetic-genetic cooperation is apparent in the colon cancer cell line HCT116 in which one allele of MLH1 and CDKN2A is genetically mutated, whereas the other allele is silenced by DNA methylation (Baylin and Ohm, 2006Baylin S.B. Ohm J.E. Epigenetic gene silencing in cancer - a mechanism for early oncogenic pathway addiction?.Nat. Rev. Cancer. 2006; 6: 107-116Crossref PubMed Scopus (771) Google Scholar). The lack of functional expression of MLH1 and CDKN2A causes defects in DNA mismatch repair and cell cycle regulation. Another example of epigenetic-genetic cooperation is in the WNT signaling pathway (Schepers and Clevers, 2012Schepers A. Clevers H. Wnt signaling, stem cells, and cancer of the gastrointestinal tract.Cold Spring Harb. Perspect. Biol. 2012; 4: a007989Crossref Scopus (16) Google Scholar). In normal cells, secreted frizzled-related proteins (SFRPs) antagonize WNT signaling. Epigenetic silencing of SFRPs induces abnormal activation of this signaling pathway, further promoting the expression of several genes whose products are responsible for cell proliferation. As a result of survival and proliferative advantages, these cells accumulate genetic mutations in other components of the WNT signaling pathway. There are also several examples where epigenetic silencing allows abnormal proliferation pathways and increases the likelihood for mutation in genetic gate keepers and increases cancer risk (Baylin and Jones, 2011Baylin S.B. Jones P.A. A decade of exploring the cancer epigenome - biological and translational implications.Nat. Rev. Cancer. 2011; 11: 726-734Crossref PubMed Scopus (324) Google Scholar). More recent results from The Cancer Genome Atlas project provide an integrative view of ovarian carcinoma based on integrated genomic analyses (Network, 2011Network C.G.A.R. Cancer Genome Atlas Research NetworkIntegrated genomic analyses of ovarian carcinoma.Nature. 2011; 474: 609-615Crossref PubMed Scopus (859) Google Scholar). The mutation spectrum is unexpectedly simple, showing the predominance of p53 mutations and other low frequency mutations in nine genes including BRCA1, BRCA2, and RB. On the other hand, promoter hypermethylation is observed in 168 genes, and those genes are epigenetically silenced and correlated with reduced expression. It is noteworthy that clustering of variable DNA methylation across tumors can identify subtypes. Indeed, the CpG island methylator phenotype (CIMP) is reported in colorectal cancer and glioblastoma, and this subgroup shows distinctive characters such as genetic and clinical features (Hinoue et al., 2012Hinoue T. Weisenberger D.J. Lange C.P. Shen H. Byun H.M. Van Den Berg D. Malik S. Pan F. Noushmehr H. van Dijk C.M. et al.Genome-scale analysis of aberrant DNA methylation in colorectal cancer.Genome Res. 2012; 22: 271-282Crossref PubMed Scopus (99) Google Scholar, Noushmehr et al., 2010Noushmehr H. Weisenberger D.J. Diefes K. Phillips H.S. Pujara K. Berman B.P. Pan F. Pelloski C.E. Sulman E.P. Bhat K.P. et al.Cancer Genome Atlas Research NetworkIdentification of a CpG island methylator phenotype that defines a distinct subgroup of glioma.Cancer Cell. 2010; 17: 510-522Abstract Full Text Full Text PDF PubMed Scopus (448) Google Scholar). A CIMP-high subgroup is strongly associated with MLH1 DNA hypermethylation and BRAF mutation, while a CIPM-low subgroup is related to KRAS mutation (Hinoue et al., 2012Hinoue T. Weisenberger D.J. Lange C.P. Shen H. Byun H.M. Van Den Berg D. Malik S. Pan F. Noushmehr H. van Dijk C.M. et al.Genome-scale analysis of aberrant DNA methylation in colorectal cancer.Genome Res. 2012; 22: 271-282Crossref PubMed Scopus (99) Google Scholar). The methylation of cytosine residues in the germline has led to an approximately 75% decrease in the frequency of CpG methyl acceptor sites. This is thought to be due to the spontaneous hydrolytic deamination of 5-methylcytosine (5mC) to thymine rather than uracil, which is formed by deamination of cytosine. The resulting T:G mismatch is more difficult to repair, and about a third of all disease causing familial mutations and single nucleotide polymorphisms or variants (SNPs or SNVs) occur at methylated CpG sites. What is often overlooked is that the presence of 5mC in the gene bodies and coding regions of genes such as p53 is responsible for generating inactivating C to T transition mutations, causing hotspots in somatic cells (Rideout et al., 1990Rideout 3rd, W.M. Coetzee G.A. Olumi A.F. Jones P.A. 5-Methylcytosine as an endogenous mutagen in the human LDL receptor and p53 genes.Science. 1990; 249: 1288-1290Crossref PubMed Google Scholar). For example, as many as 50% of p53 point mutations in colon cancer occur at such sites, clearly demonstrating that an epigenetic mark (5mC) directly causes somatic mutations. More interestingly, a somatic DNMT3A hotspot mutation in acute myeloid leukemia (AML) is caused by C to T transitions at a CpG site, possibly due to the methylation of its own exon by the enzyme (epigenetic alteration) and the subsequent deamination of 5mC (genetic mutation) (Ley et al., 2010Ley T.J. Ding L. Walter M.J. McLellan M.D. Lamprecht T. Larson D.E. Kandoth C. Payton J.E. Baty J. Welch J. et al.DNMT3A mutations in acute myeloid leukemia.N. Engl. J. Med. 2010; 363: 2424-2433Crossref PubMed Scopus (426) Google Scholar) (Figure 1). The effect of the point mutation is not yet fully understood since methylation changes are not observed in the tumor. It is possible that this mutation alters DNMT3A function and/or activity and may further disrupt whole epigenetic regulation mechanism (Figure 1). MicroRNAs (miRNAs) are a class of small noncoding RNAs that play key roles in epigenetic regulation by controlling the translation and/or stability of mRNAs. There are over 1,000 human miRNAs and, interestingly, these miRNAs frequently target regions related to cancer development (Ryan et al., 2010Ryan B.M. Robles A.I. Harris C.C. Genetic variation in microRNA networks: the implications for cancer research.Nat. Rev. Cancer. 2010; 10: 389-402Crossref PubMed Scopus (240) Google Scholar). They have been classified as oncogenic, tumor-suppressive, or context-dependent miRNAs (Kasinski and Slack, 2011Kasinski A.L. Slack F.J. Epigenetics and genetics. MicroRNAs en route to the clinic: progress in validating and targeting microRNAs for cancer therapy.Nat. Rev. Cancer. 2011; 11: 849-864Crossref PubMed Scopus (170) Google Scholar). Indeed, oncogenic miRNAs such as miR-155 or miR-21 are frequently overexpressed, and tumor suppressive miRNAs such as miR-146 or miR-15∼16 are deleted in cancers (Kasinski and Slack, 2011Kasinski A.L. Slack F.J. Epigenetics and genetics. MicroRNAs en route to the clinic: progress in validating and targeting microRNAs for cancer therapy.Nat. Rev. Cancer. 2011; 11: 849-864Crossref PubMed Scopus (170) Google Scholar). Mutation in the miRNA can disrupt its recognition of binding targets and further result in oncogene activation and/or tumor suppressor repression. Additionally miRNAs including miR-101 and miR-29 target epigenetic modifiers such as EZH2 (Friedman et al., 2009Friedman J.M. Liang G. Liu C.C. Wolff E.M. Tsai Y.C. Ye W. Zhou X. Jones P.A. The putative tumor suppressor microRNA-101 modulates the cancer epigenome by repressing the polycomb group protein EZH2.Cancer Res. 2009; 69: 2623-2629Crossref PubMed Scopus (170) Google Scholar, Varambally et al., 2008Varambally S. Cao Q. 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SWI/SNF nucleosome remodellers and cancer.Nat. Rev. Cancer. 2011; 11: 481-492Crossref PubMed Scopus (145) Google Scholar).Table 1Epigenetic Modifiers in CancerGeneFunctionTumor TypeAlterationDNA methylationDNMT1DNA methyltransferaseColorectal, non-small cell lung, pancreatic, gastric, breast cancerMutation (Kanai et al., 2003Kanai Y. Ushijima S. Nakanishi Y. Sakamoto M. Hirohashi S. Mutation of the DNA methyltransferase (DNMT) 1 gene in human colorectal cancers.Cancer Lett. 2003; 192: 75-82Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar)Overexpression (Wu et al., 2007Wu Y. Strawn E. Basir Z. Halverson G. Guo S.W. Aberrant expression of deoxyribonucleic acid methyltransferases DNMT1, DNMT3A, and DNMT3B in women with endometriosis.Fertil. Steril. 2007; 87: 24-32Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar)DNMT3ADNA methyltransferaseMDS, AMLMutation (Ley et al., 2010Ley T.J. Ding L. Walter M.J. McLellan M.D. Lamprecht T. Larson D.E. Kandoth C. Payton J.E. Baty J. Welch J. et al.DNMT3A mutations in acute myeloid leukemia.N. Engl. J. Med. 2010; 363: 2424-2433Crossref PubMed Scopus (426) Google Scholar, Yamashita et al., 2010Yamashita Y. Yuan J. Suetake I. Suzuki H. Ishikawa Y. Choi Y.L. Ueno T. Soda M. Hamada T. Haruta H. et al.Array-based genomic resequencing of human leukemia.Oncogene. 2010; 29: 3723-3731Crossref PubMed Scopus (70) Google Scholar, Yan et al., 2011Yan X.J. Xu J. Gu Z.H. Pan C.M. Lu G. Shen Y. Shi J.Y. Zhu Y.M. Tang L. Zhang X.W. et al.Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia.Nat. Genet. 2011; 43: 309-315Crossref PubMed Scopus (180) Google Scholar)DNMT3BDNA methyltransferaseICF syndrome, SNPs in breast and lung adenomaMutation (Wijmenga et al., 2000Wijmenga C. Hansen R.S. Gimelli G. Björck E.J. Davies E.G. Valentine D. Belohradsky B.H. van Dongen J.J. Smeets D.F. van den Heuvel L.P. et al.Genetic variation in ICF syndrome: evidence for genetic heterogeneity.Hum. Mutat. 2000; 16: 509-517Crossref PubMed Scopus (49) Google Scholar)Mutation (Shen et al., 2002Shen H. Wang L. Spitz M.R. Hong W.K. Mao L. Wei Q. A novel polymorphism in human cytosine DNA-methyltransferase-3B promoter is associated with an increased risk of lung cancer.Cancer Res. 2002; 62: 4992-4995PubMed Google Scholar)MBD1/2Methyl binding proteinLung and breast cancerMutation (Sansom et al., 2007Sansom O.J. Maddison K. Clarke A.R. Mechanisms of disease: methyl-binding domain proteins as potential therapeutic targets in cancer.Nat. Clin. Pract. Oncol. 2007; 4: 305-315Crossref PubMed Scopus (47) Google Scholar)TET15′methylcytosine hydroxylaseAMLChromosome translocation (De Carvalho et al., 2010De Carvalho D.D. You J.S. Jones P.A. DNA methylation and cellular reprogramming.Trends Cell Biol. 2010; 20: 609-617Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, Wu and Zhang, 2010Wu S.C. Zhang Y. Active DNA demethylation: many roads lead to Rome.Nat. Rev. Mol. Cell Biol. 2010; 11: 607-620Crossref PubMed Scopus (316) Google Scholar)TET25′methylcytosine hydroxylaseMDS, myeloid malignancies (AML), gliomasMutation/silencing (Tan and Manley, 2009Tan A.Y. Manley J.L. The TET family of proteins: functions and roles in disease.J. Mol. Cell Biol. 2009; 1: 82-92Crossref PubMed Scopus (59) Google Scholar)IDH1/2Isocitrate dehydrogenaseGlioma, AMLMutation (Figueroa et al., 2010Figueroa M.E. Abdel-Wahab O. Lu C. Ward P.S. Patel J. Shih A. Li Y. Bhagwat N. Vasanthakumar A. Fernandez H.F. et al.Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation.Cancer Cell. 2010; 18: 553-567Abstract Full Text Full Text PDF PubMed Scopus (454) Google Scholar, Lu et al., 2012Lu C. Ward P.S. Kapoor G.S. Rohle D. Turcan S. Abdel-Wahab O. Edwards C.R. Khanin R. Figueroa M.E. Melnick A. et al.IDH mutation impairs histone demethylation and results in a block to cell differentiation.Nature. 2012; 483: 474-478Crossref PubMed Scopus (169) Google Scholar, Turcan et al., 2012Turcan S. Rohle D. Goenka A. Walsh L.A. Fang F. Yilmaz E. Campos C. Fabius A.W. Lu C. Ward P.S. et al.IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype.Nature. 2012; 483: 479-483Crossref PubMed Scopus (190) Google Scholar)AID5′cytidine deaminaseCMLAberrant expression (De Carvalho et al., 2010De Carvalho D.D. You J.S. Jones P.A. DNA methylation and cellular reprogramming.Trends Cell Biol. 2010; 20: 609-617Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar)Histone modificationMLL1/2/3Histone methyltransferase H3K4Bladder TCC, ALL and AML, non-Hodgkin lymphoma, B cell lymphoma, prostate (primary)Translocation, mutation, aberrant expression (Gui et al., 2011Gui Y. Guo G. Huang Y. Hu X. Tang A. Gao S. Wu R. Chen C. Li X. Zhou L. et al.Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder.Nat. Genet. 2011; 43: 875-878Crossref PubMed Scopus (126) Google Scholar, Morin et al., 2011Morin R.D. Mendez-Lago M. Mungall A.J. Goya R. Mungall K.L. Corbett R.D. Johnson N.A. Severson T.M. Chiu R. Field M. et al.Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma.Nature. 2011; 476: 298-303Crossref PubMed Scopus (235) Google Scholar)BRD4Bromodomain containing 4Nuclear protein in testis, midline carcinoma, breast, colon, and AMLTranslocation (fusion protein), aberrant expression (Filippakopoulos et al., 2010Filippakopoulos P. Qi J. Picaud S. Shen Y. Smith W.B. Fedorov O. Morse E.M. Keates T. Hickman T.T. Felletar I. et al.Selective inhibition of BET bromodomains.Nature. 2010; 468: 1067-1073Crossref PubMed Scopus (301) Google Scholar, Zuber et al., 2011Zuber J. Shi J. Wang E. Rappaport A.R. Herrmann H. Sison E.A. Magoon D. Qi J. Blatt K. Wunderlich M. et al.RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia.Nature. 2011; 478: 524-528Crossref PubMed Scopus (222) Google Scholar)EZH2Histone methyltransferase H3K27Breast, prostate, bladder, colon, pancreas, liver, gastric, uterine tumors, melanoma, lymphoma, myeloma, and Ewing's sarcomaMutation, aberrant expression (Chase and Cross, 2011Chase A. Cross N.C. Aberrations of EZH2 in cancer.Clin. Cancer Res. 2011; 17: 2613-2618Crossref PubMed Scopus (109) Google Scholar, Tsang and Cheng, 2011Tsang D.P. Cheng A.S. Epigenetic regulation of signaling pathways in cancer: role of the histone methyltransferase EZH2.J. Gastroenterol. Hepatol. 2011; 26: 19-27Crossref PubMed Scopus (38) Google Scholar)ASXLEnhancer of trithorax and polycomb group (EAP) Additional sex combs like 1MDS and AML, Bohring-Opitz syndromeMutation (Gelsi-Boyer et al., 2012Gelsi-Boyer V. Brecqueville M. Devillier R. Murati A. Mozziconacci M.J. Birnbaum D. Mutations in ASXL1 are associated with poor prognosis across the spectrum of malignant myeloid diseases.J. Hematol. Oncol. 2012; 5: 12Crossref PubMed Scopus (17) Google Scholar, Hoischen et al., 2011Hoischen A. van Bon B.W. Rodríguez-Santiago B. Gilissen C. Vissers L.E. de Vries P. Janssen I. van Lier B. Hastings R. Smithson S.F. et al.De novo nonsense mutations in ASXL1 cause Bohring-Opitz syndrome.Nat. Genet. 2011; 43: 729-731Crossref PubMed Scopus (43) Google Scholar)BMI-1PRC1 subunitOvarian, mantle cell lymphomas and Merkel cell carcinomasOverexpression (Jiang et al., 2009Jiang L. Li J. Song L. Bmi-1, stem cells and cancer.Acta Biochim. Biophys. Sin. (Shanghai). 2009; 41: 527-534Crossref PubMed Scopus (31) Google Scholar, Lukacs et al., 2010Lukacs R.U. Memarzadeh S. Wu H. Witte O.N. Bmi-1 is a crucial regulator of prostate stem cell self-renewal and malignant transformation.Cell Stem Cell. 2010; 7: 682-693Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar)G9aHistone methyltransferase H3K9HCC, cervical, uterine, ovarian, and breast cancerAberrant expression (Varier and Timmers, 2011Varier R.A. Timmers H.T. Histone lysine methylation and demethylation pathways in cancer.Biochim. Biophys. Acta. 2011; 1815: 75-89PubMed Google Scholar)PRMT1/5Protein arginine methyltransferaseBreast/gastricAberrant expression (Miremadi et al., 2007Miremadi A. Oestergaard M.Z. Pharoah P.D. Caldas C. Cancer genetics of epigenetic genes.Hum. Mol. Genet. 2007; 16: R28-R49Crossref PubMed Scopus (107) Google Scholar)LSD1Histone demethylase H3K4/H3K9ProstateMutation (Rotili and Mai, 2011Rotili D. Mai A. Targeting histone demethylases: a new avenue for the fight against cancer.Genes Cancer. 2011; 2: 663-679Crossref PubMed Scopus (32) Google Scholar)UTX (KDM6A)Histone demethylase H3K27Bladder, breast, kidney, lung, pancreas, esophagus, colon, uterus, brainMutation (Rotili and Mai, 2011Rotili D. Mai A. Targeting histone demethylases: a new avenue for the fight against cancer.Genes Cancer. 2011; 2: 663-679Crossref PubMed Scopus (32) Google Scholar)JARID1B/CHistone demethylase H3K4/H3K9Testicular and breast, RCCCOverexpression (Rotili and Mai, 2011Rotili D. Ma
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