Editing Cancer (section)

=== Epigenetics ===
{{Main|Cancer epigenetics}}
[[File:Diagram Damage to Cancer Wiki 300dpi.svg|thumb|upright=1.35|The central role of DNA damage and epigenetic defects in DNA repair genes in carcinogenesis]]

The classical view of cancer is a set of diseases driven by progressive [[Genetics|genetic]] [[abnormalities]] that include mutations in tumor-suppressor genes and [[oncogene]]s, and in [[chromosome|chromosomal]] abnormalities. A role for [[Epigenetics|epigenetic alterations]] was identified in the early 21st century.<ref>{{cite journal |vauthors=Baylin SB, Ohm JE |s2cid=2514545 |title=Epigenetic gene silencing in cancer – a mechanism for early oncogenic pathway addiction? |journal=Nature Reviews. Cancer |volume=6 |issue=2 |pages=107–16 |date=February 2006 |pmid=16491070 |doi=10.1038/nrc1799}}</ref>

[[Epigenetics|Epigenetic]] alterations are functionally relevant modifications to the genome that do not change the nucleotide sequence. Examples of such modifications are changes in [[DNA methylation]] (hypermethylation and hypomethylation), [[histone modification]]<ref>{{cite journal |vauthors=Kanwal R, Gupta S |title=Epigenetic modifications in cancer |journal=Clinical Genetics |volume=81 |issue=4 |pages=303–11 |date=April 2012 |pmid=22082348 |pmc=3590802 |doi=10.1111/j.1399-0004.2011.01809.x}}</ref> and changes in chromosomal architecture (caused by inappropriate expression of proteins such as [[HMGA2]] or [[HMGA1]]).<ref>{{cite journal |vauthors=Baldassarre G, Battista S, Belletti B, Thakur S, Pentimalli F, Trapasso F, Fedele M, Pierantoni G, Croce CM, Fusco A |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=2225–38 |date=April 2003 |pmid=12640109 |pmc=150734 |doi=10.1128/MCB.23.7.2225-2238.2003}}/</ref> Each of these alterations regulates gene expression without altering the underlying [[DNA sequence]]. These changes may remain through [[cell division]]s, endure for multiple generations, and can be considered as equivalent to mutations.

Epigenetic alterations occur frequently in cancers. As an example, one study listed protein coding genes that were frequently altered in their [[methylation]] in association with colon cancer. These included 147 hypermethylated and 27 hypomethylated genes. Of the hypermethylated genes, 10 were hypermethylated in 100% of colon cancers and many others were hypermethylated in more than 50% of colon cancers.<ref name="Sch">{{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>

While epigenetic alterations are found in cancers, the epigenetic alterations in DNA repair genes, causing reduced expression of DNA repair proteins, may be of particular importance. Such alterations may occur early in the progression to cancer and are a possible cause of the [[Genome instability|genetic]] instability characteristic of cancers.<ref>{{cite journal |vauthors=Jacinto FV, Esteller M |title=Mutator pathways unleashed by epigenetic silencing in human cancer |journal=Mutagenesis |volume=22 |issue=4 |pages=247–53 |date=July 2007 |pmid=17412712 |doi=10.1093/mutage/gem009|doi-access=free }}</ref><ref>{{cite journal |vauthors=Lahtz C, Pfeifer GP |title=Epigenetic changes of DNA repair genes in cancer |journal=Journal of Molecular Cell Biology |volume=3 |issue=1 |pages=51–8 |date=February 2011 |pmid=21278452 |pmc=3030973 |doi=10.1093/jmcb/mjq053}}</ref><ref>{{cite journal |vauthors=Bernstein C, Nfonsam V, Prasad AR, Bernstein H |title=Epigenetic field defects in progression to cancer |journal=World Journal of Gastrointestinal Oncology |volume=5 |issue=3 |pages=43–49 |date=March 2013 |pmid=23671730 |pmc=3648662 |doi=10.4251/wjgo.v5.i3.43 |doi-access=free }}</ref>

Reduced expression of DNA repair genes disrupts DNA repair. This is shown in the figure at the 4th level from the top. (In the figure, red wording indicates the central role of DNA damage and defects in DNA repair in the progression to cancer.) When DNA repair is deficient DNA damage remains in cells at a higher than usual level (5th level) and causes increased frequencies of mutation and/or epimutation (6th level). Mutation rates increase substantially in cells defective in [[DNA mismatch repair]]<ref>{{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=3122–27 |date=April 1997 |pmid=9096356 |pmc=20332 |doi=10.1073/pnas.94.7.3122|bibcode=1997PNAS...94.3122N |doi-access=free }}</ref><ref>{{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=2402–08 |date=December 2006 |pmid=16728433 |pmc=2612936 |doi=10.1093/carcin/bgl079}}</ref> or in [[homologous recombination]]al repair (HRR).<ref>{{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=255–60 |date=March 2002 |pmid=11850397 |pmc=1084010 |doi=10.1093/embo-reports/kvf037}}</ref> Chromosomal rearrangements and aneuploidy also increase in HRR defective cells.<ref>{{cite journal |vauthors=German J |title=Bloom's syndrome. I. Genetical and clinical observations in the first twenty-seven patients |journal=American Journal of Human Genetics |volume=21 |issue=2 |pages=196–227 |date=March 1969 |pmid=5770175 |pmc=1706430}}</ref>

Higher levels of DNA damage cause increased mutation (right side of figure) and increased epimutation. During repair of DNA double strand breaks, or repair of other DNA damage, incompletely cleared repair sites can cause epigenetic gene silencing.<ref>{{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 | veditors = Lee JT |doi-access=free }}</ref><ref>{{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 |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>

Deficient expression of DNA repair proteins due to an inherited mutation can increase cancer risks. Individuals with an inherited impairment in any of 34 DNA repair genes (see article [[DNA repair-deficiency disorder]]) have increased cancer risk, with some defects ensuring a 100% lifetime chance of cancer (e.g. p53 mutations).<ref>{{cite journal |vauthors=Malkin D |title=Li-fraumeni syndrome |journal=Genes & Cancer |volume=2 |issue=4 |pages=475–84 |date=April 2011 |pmid=21779515 |pmc=3135649 |doi=10.1177/1947601911413466}}</ref> Germline DNA repair mutations are noted on the figure's left side. However, such [[germline]] mutations (which cause highly penetrant cancer syndromes) are the cause of only about 1 percent of cancers.<ref>{{cite journal |vauthors=Fearon ER |title=Human cancer syndromes: clues to the origin and nature of cancer |journal=Science |volume=278 |issue=5340 |pages=1043–50 |date=November 1997 |pmid=9353177 |doi=10.1126/science.278.5340.1043|bibcode=1997Sci...278.1043F }}</ref>

In sporadic cancers, deficiencies in DNA repair are occasionally caused by a mutation in a DNA repair gene but are much more frequently caused by epigenetic alterations that reduce or silence expression of DNA repair genes. This is indicated in the figure at the 3rd level. Many studies of heavy metal-induced carcinogenesis show that such heavy metals cause a reduction in expression of DNA repair enzymes, some through epigenetic mechanisms. DNA repair inhibition is proposed to be a predominant mechanism in heavy metal-induced carcinogenicity. In addition, frequent epigenetic alterations of the DNA sequences code for small RNAs called [[microRNA]]s (or miRNAs). miRNAs do not code for proteins, but can "target" protein-coding genes and reduce their expression.

Cancers usually arise from an assemblage of mutations and epimutations that confer a selective advantage leading to clonal expansion (see [[Neoplasm#Field defects in progression to cancer|Field defects in progression to cancer]]). Mutations, however, may not be as frequent in cancers as epigenetic alterations. An average cancer of the breast or colon can have about 60 to 70 protein-altering mutations, of which about three or four may be "driver" mutations and the remaining ones may be "passenger" mutations.<ref>{{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=1546–58 |date=March 2013 |pmid=23539594 |pmc=3749880 |doi=10.1126/science.1235122|bibcode=2013Sci...339.1546V }}</ref>