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Volume 2- Issue 3: 2018 DOI: 10.26717/BJSTR.2018.02.000772 Patrick A Riley. Biomed J Sci & Tech Res ISSN: 2574-1241

Commentary Open Access

Epigenetics and : DNA Abnormalities Associated with and their Possible Source

Patrick A Riley* Totteridge Institute for Advanced Studies, Grange Avenue, London Received: February 07, 2018; Published: February 19, 2018 *Corresponding author: Patrick A Riley, Totteridge Institute for Advanced Studies, The Grange, Grange Avenue, London, Tel: ; Email:

Keywords:

DNA Methylation; Cancer;

Introduction and has been observed in pre-neoplastic lesions such as hyperplasia It is now well-established that the majority of the aberrant

[7-9]. The specificity of the hypomethylated regions appears to be profiles described in human are due changes, including both hypo- and hypermethylation. There is related to the tissue of origin [9-11] and there is evidence that the to epigenetic changes. These patterns reflect DNA methylation evidence to suggest that, in general, hypomethylation is associated Possiblepattern is influencedMechanisms during of tumourDemethylation progression [12,13]. hypermethylation is involved in the silencing of previously with the expression of previously silenced genes whereas DNA transcribed genes and there has been much interest in the inhibition of tumour-suppressor genes as a possible carcinogenic mechanism. This brief overview discusses the possible origins of the observed carcinogenic mechanism lies in the failure of accurate copying of anomalies of DNA methylation and proposes that the initiating the epigenetic pattern during stem cell proliferation. DNA Hypomethylation

The first epigenetic abnormality detected in human cancer cells was DNA hypomethylation [1-3] and many subsequent studies cancer genome in a wide range of that include ovarian, have confirmed this phenomenon as a constant feature of the prostatic, hepatocellular, cervical, colon cancer and also and developmental tumours such as Wilms’ tumors [4]. It can be Figure 1: Schematic outline of the process of copying the epigenetic methylation pattern during DNA replication. concluded that DNA hypomethylation is an ubiquitous feature of human cancers [5]. DNA hypomethylation is most frequently found There would appear to be two basic mechanisms that could in the highly repeated DNA sequences which comprise about half of the human genome, but specific cancer-associated hypomethylation enzymatic demethylation, a process that is known to occur as a has been demonstrated in control sequences [6]. It can be responsible for the hypomethylation of the DNA. One is by in carcinogenesis. Hypomethylation occurs early in tumorigenesis be argued that DNA hypomethylation is the primary abnormality result of the oxidation of 5-methylcytosine to its hydroxylated

Cite this article: : 2693 Patrick A R. Epigenetics and Carcinogenesis: DNA Methylation Abnormalities Associated with Cancer and their Possible Source. Biomed J Sci &Tech Res 2(3)- 2018. BJSTR.MS.ID.000772. DOI 10.26717/BJSTR.2018.02.000772 Patrick A Riley. Biomed J Sci & Tech Res Volume 2- Issue 3: 2018

3. derivative. This involves ‘ten-eleven translocase’ (TET) enzymes 89-92.Feinberg AP, Vogelstein B (1983) Hypomethylation distinguishes genes by unmethylated cytosine. Such a process is likely to constitute a of some human cancers from their normal counterparts. Nature 301: [14] and ultimately leads to with replacement random outcome of metabolic oxidation. 4. Ehrlich M (2009) DNA hypomethylation in cancer cells. Epigenomics 5. 1(2): 239-259. An alternative source of DNA demethylation would be the Weisenberger DJ, Liang G (2015) Contributions of DNA methylation failure of preservation of the DNA methylation pattern during the residues are represented by black circles which are copied onto the aberrancies in shaping the cancer epigenome. Trans Cancer Res 4: 218- process of stem cell proliferation (Figure 1). The 5-methylcytosine 6. 234. Rauch TA, Zhong X, Wu X, Wang M, Kernstine KH, et al. (2008) High- duplicated strands as indicated in the sequence A. This involves resolution mapping of DNA hypermethylation and hypomethylation in the ‘maintenance’ methylase DNA methyl transferase 1 (DNMT1) 7. . Proc Natl Acad Sci USA 105(1): 252-257. this methylation process would result in dissimilar post-division which has an affinity for hemimethylated regions [15]. Failure of Feinberg AP, Gehrke CW, Kuo KC, Ehrlich M (1988) Reduced genomic 5-methylcytosine content in human colonic neoplasia. Cancer Res 48(5): 8. products, as shown in the sequence B. 1159-1161. pattern established in differentiated tissues would result in regions Such a failure in the fidelity of copying of the epigenetic 187-90.Goelz SE, Vogelstein B, Hamilton SR, Feinberg AP (1985) Hypomethylation of DNA from benign and malignant human colon neoplasms. 228(4696): 9. of hypomethylated DNA with the associated re-expression of mechanism occurring at each stem cell division would generate hypomethylation is prevalent even in low-grade breast cancers. Cancer previously silenced genes [16]. Moreover, such a hypomethylation Jackson K, Yu MC, Arakawa K, Fiala E, Youn B, et al. (2004) DNA an expanding set of epigenetically anomalous genomes and thus account for the increasing diversity of characteristics observed in 10. Biol Ther 3(12): 1225-1231. Widschwendter M, Jiang G, Woods C, Müller HM, Fiegl H, et al. (2004) DNA hypomethylation and biology. Cancer Res 64(13): the progression phase of carcinogenesis [17]. The preferred model 11. 4472-4480. to explain the hypomethylation of DNA associated with cancer relativelyMarkl ID, Chengstable inJ, Liangvivo and G, Shibata in vitro D, Laird PW, et al. (2001) Global and cells as outlined above requires the initiation of carcinogenesis to gene-specific epigenetic patterns in human bladder cancer genomes are be dependent on an event (e.g. a )causing a derangement over time. Cancer Res 61(15): 5875- process that ensures the perpetuation of the differentiated state 12. 5884. of the epigenetic copying mechanism and/or an authentication as a prognostic marker in patients with breast carcinoma. Clin Pakneshan P, Tetu B, Rabbani SA (2004) Demethylation of urokinase is consistent with observation of the relationship with stem cell during stem cell proliferation, such as [18]. This approach 13. Cancer Res 10(9): 3035-3041. activation of urokinase plasminogen activator is involved in progression Pulukuri SM, Estes N, Patel J, Rao JS (2007) Demethylation-linked proliferation shown by Tomasetti & Vogelstein [19] and age-related DNAcancer Hypermethylationincidence data [20]. 14. of cancer. Cancer Res 67(3): 930-939. Pfeifer GP, Xiong W, Hahn MA, Jin SG (2014) The role of 5-hydroxymethyl and particularly affecting promoters of tumour-suppressor genes 15. cytosine in human cancer. Cell Tissue Res 356(3): 631-641. Hypermethylation of homeobox genes and other sequences, Jones PA (2012) Functions of DNA methylation: islands, start sites, gene instances there is a close association between hypomethylation 16. bodies and beyond. Nature Rev. Genet 13(7): 484-492. is a prominent feature of the cancer genome [21,22]. In most and hypermethylation, although affecting different regions of Riley PA (2014) Failure of fidelity of vertical transmission of epigenetic 17. patterning as the basis of cancer. Res 24(5): 424-427. of the selective gene activity in differentiated cells. Cancer Research hypermethylation is a secondary compensatory hypermethylation Riley PA (2015) Cancer is the outcome of defective epigenetic copying the genome [5,23]. It can be argued that the observed DNA 18. Frontiers 1(3): 280-287. and may be the consequence of a process such as the demethylation Riley PA (2017) The epigenetic theory of carcinogenesis: p53 as the of silenced genes such as those coding for DNA methyl transferase 19. guardian of the epigenome. J. Oncol & Cancer Res 1:1-6. enzymes. Given that DNA methylation is dysregulated in all tumour tissues can be explained by the number of stem cell divisions. Science offer optimistic prospects for the development of screening and Tomasetti C, Vogelstein B (2015) Variation in cancer risk among types, the recent advances in methylation screening techniques monitoring methods and the possibility of constructive interference 20. 347(6217): 78-81. with the fundamental processes underlying cancer biology. Riley PA (2017) Epigenetic theory of carcinogenesis: investigation of the Acknowledgement 21. model of age-specific incidence. PRAS 1: 14- 19. Graff JR, Herman JG, Lapidus RG, Chopra H, Xu R, et al. (1995) E-cahedrin discussions. expression is silenced by DNA hypermethylationin human breast and I thank Mark Burkitt, Ferdy Lejeune, and John Vince for helpful 22. prostate carcinomas. Cancer Res 55(22): 5195-5199. References Costello JF, Frühwald MC, Smiraglia DJ, Rush LJ, Robertson GP, et al. 1. (2000) Aberrant CpG-island methylation has non-random and tumor- 23. type-specific patterns. Nature Genet 24(2): 132-138. Gama Sosa MA, Slagel VA, Trewyn RW, Oxenhandler R, Kuo KC, et al. Ehrlich M, Woods CB, Yu MC, Dubeau L, Yang F, et al. (2006) (1983) The 5-methylcytosine content of DNA from human tumors. Quantitative analysis of association between DNA hypermethylation, 2. Nucleic Acids Res 11(19): 6883-6894. hypomethylation, and DNMT RNA levels in ovarian tumors. Feinberg AP, Vogelstein B (1983) Hypomethylation of ras in 25(18): 2636-2645. primary human cancers. Biochem. Biophys. Res Commun 111(1): 47-54. Biomedical Journal of Scientific & Technical Research (BJSTR) 2694 Patrick A Riley. Biomed J Sci & Tech Res Volume 2- Issue 3: 2018

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Biomedical Journal of Scientific & Technical Research (BJSTR) 2695