Joanne Holahan Nurse and Pink Hope Ambassador continues to educate us on epigenetics and in this post covers DNA methylation, genetics and cancer.
The best known and most extensively studied epigenetic marker is DNA methylation (7, 11, 12). DNA methylation is a chemical process in the body which modifies a strand of DNA after replication where a methyl (carbon) group is added to a strand of DNA (5, 7). Methylation is characterized by epigenetic DNA modifications that play an important role in maintaining gene integrity, replication and development (13). This leads to gene “silencing” or the prevention of a gene replicating and “noncoding” where DNA components do not code protein sequences during replication (13, 14).
Many changes in DNA methylation levels occur in the promoter region of genes, which is the area that initiates replication of the gene (13). These changes can involve hypo (reduced) as well as hyper (increased) methylation that lead to cell differentiation and growth disorders (10, 13). Therefore it can become the switch that initiates different pathological processes including cancer (7, 11, 13, 14).
More than 20% of cancers have been causally linked to human pathogens (viruses, fungi, bacterial). Research indicates that epigenetic changes can occur as a result of the inflammation accompanying an infection. There is an increase in methylation as an acute infection becomes chronic which can progress to premalignant lesions and invasive cancer (11, 12).
Hypermethylation in the promoter regions of tumor-suppressor genes is a major event in the origin of many cancers, including BRAC1 (13, 15, 18). It can affect genes involved in the cell cycle, DNA repair, metabolism of carcinogens, cell to cell interaction, apoptosis (programmed cell death) and angiogenesis (creation of new blood vessels), all of which are involved in the development of cancer (11,13,16 ).
DNA hypomethylation in tumor cells is primarily caused by the loss of methylation from repetitive DNA sequence resulting in genomic instability and a disturbed imprinting pattern (7, 11, 13, 18). In cancer hypomethylation is often associated with oncogenes and in specific promoter regions can activate abnormal expression of oncogenes (7, 13). Hypomethylation has been reported in a wide range of cancers including breast and ovarian (7, 11, 13, 18).
Epigenetic silencing of tumor suppressor genes may occur more frequently than by genetic ones (5, 13). In each case, silencing of the DNA repair gene blocks the repair of genetic mistakes, opening the way to neoplastic changes of the cell (2, 5, 7, 13, 15, 18). Studies show that all kinds of environmental factors from pesticides and pollutants to diet, exercise, smoking and alcohol, can alter methylation patterns (1, 2, 7, 11, 15). Once methylation patterns have changed, there can be lasting effects. Some changes may last for decades, as a small change in development could increase genetic instability in the future (1 ,2, 5, 11, 15) and may even be passed on to our children (2, 9, 15).
DNA methylation increasingly emerges as a useful marker for the risk of cancer development including breast, ovarian, liver and colon cancers. (3, 7, 11, 13, 15, 18)
(1) The Age, “Sins of the fathers and mothers”. Lifestyle. Thea O’Conner, Monday, January 20 2014
(2) The Age, “You are what you mother ate”. Diet &Fitness. Thursday March 15, 2012
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(4) Epigenetics as a Therapeutic Target in Breast Cancer. Journal of Mammary Gland Biology and Neoplasia, 2012; 17 (3-4): 191-204
(5) Williams SCP. Epigenetics. Proceedings of the National Academy of Science. 2013, 110;9.
(6) Ptshane M. Faddish Stuff: Epigenetics and the inheritance of Acquired Characteristics. FASEB Journal. 2013;27:1-2
(7) Esteller M. Epigenetis in Cancer. N Eng J Med. 2008;358:1148-59
(8) Ptshane M. Epigenetics: Core misconcept Proceedings of the National Academy of Science. 2013, 110;18:7101-7103
(9 What is Epigenetic. Australian epigenetic alliance. wwwepialliance.org.au/contents/
(10) Epigenetic Research – Garvan institute of Medical Research. www.garvan.org.au/research/cancer/epigenetics
(11) Stein RA. Epigenetics – The Link Between Infectious Diseases and Cancer. JAMA 2011; 305(14):1484-1485
(12) Haitian L et al. Inflammation, a key event in cancer development. Mol CancerRes 2006; 4(4):221-33
(13) Kanwal, R Gupta S. Epigenetic modifications in cancer. Clinical Genetics.
(14) Popiela AL et al. The meaning of the methylation of genomic DNA in the regulation of gene expression levels. Euro J of Genetics
(15) Burdge, GC, et al
(16) Kanwal R, Gupta S. Epigenetic an Cancer. J Appl Physiol, 2010:109: 598-605
(17) Magnani L et al. ChIping away at breast cancer. Lancet Oncology, 2012: 13:12; 1185-7
(18) Wang Y et al. Epigenetic inactivation of BRCA1 through promoter Hypermethylation in ovarian cancer progression. J Ob&G Research, 2013: 39:2; 549-554