Editing Neoplasm (section)

===DNA damage===
[[File:Diagram Damage to Cancer Wiki 300dpi.svg|thumb|The central role of DNA damage and epigenetic defects in [[DNA repair]] genes in malignant neoplasms]]
[[DNA damage (naturally occurring)|DNA damage]] is considered to be the primary underlying cause of malignant neoplasms known as cancers.<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=Mol. Cancer Res. |volume=6 |issue=4 |pages=517–24 |year=2008 |pmid=18403632 |doi=10.1158/1541-7786.MCR-08-0020 |doi-access=free }}</ref> Its central role in progression to cancer is illustrated in the figure in this section, in the box near the top. (The central features of DNA damage, [[Epigenetics|epigenetic]] alterations and deficient DNA repair in progression to cancer are shown in red.) DNA damage is very common. [[DNA damage (naturally occurring)|Naturally occurring DNA damages]] (mostly due to [[cellular metabolism]] and the properties of DNA in water at body temperatures) occur at a rate of more than 10,000 new damages, on average, per human cell, per day.<ref name=Ames1993>{{cite journal |vauthors=Ames BN, Shigenaga MK, Hagen TM |title=Oxidants, antioxidants, and the degenerative diseases of aging |journal=Proc Natl Acad Sci U S A |volume=90 |issue=17 |pages=7915–22 |date=September 1993 |pmid=8367443 |pmc=47258 |doi=10.1073/pnas.90.17.7915 |doi-access=free |bibcode=1993PNAS...90.7915A }}</ref> Additional DNA damages can arise from exposure to [[Exogeny|exogenous]] agents. [[Tobacco smoke]] causes increased exogenous DNA damage, and these DNA damages are the likely cause of [[lung cancer]] due to smoking.<ref name="pmid21802474">{{cite journal |vauthors=Cunningham FH, Fiebelkorn S, Johnson M, Meredith C | title = A novel application of the Margin of Exposure approach: segregation of tobacco smoke toxicants | journal = Food Chem. Toxicol. | volume = 49 | issue = 11 | pages = 2921–33 |date=November 2011 | pmid = 21802474 | doi = 10.1016/j.fct.2011.07.019 }}</ref> [[Ultraviolet|UV light]] from solar radiation causes DNA damage that is important in [[melanoma]].<ref name="pmid22123420">{{cite journal |vauthors=Kanavy HE, Gerstenblith MR | title = Ultraviolet radiation and melanoma | journal = Semin Cutan Med Surg | volume = 30 | issue = 4 | pages = 222–8 |date=December 2011 | pmid = 22123420 | doi = 10.1016/j.sder.2011.08.003  | doi-broken-date = 1 November 2024 }}</ref> ''[[Helicobacter pylori]]'' infection produces high levels of [[reactive oxygen species]] that damage DNA and contributes to gastric cancer.<ref name="pmid21605492">{{cite journal |vauthors=Handa O, Naito Y, Yoshikawa T | title = Redox biology and gastric carcinogenesis: the role of Helicobacter pylori | journal = Redox Rep. | volume = 16 | issue = 1 | pages = 1–7 | year = 2011 | pmid = 21605492 | doi = 10.1179/174329211X12968219310756 | pmc = 6837368 | doi-access = free }}</ref> [[Bile acid]]s, at high levels in the colons of humans eating a high fat diet, also cause DNA damage and contribute to [[Colorectal cancer|colon cancer]].<ref name="pmid21267546">{{cite journal |vauthors=Bernstein C, Holubec H, Bhattacharyya AK, Nguyen H, Payne CM, Zaitlin B, Bernstein H | title = Carcinogenicity of deoxycholate, a secondary bile acid | journal = Arch. Toxicol. | volume = 85 | issue = 8 | pages = 863–71 |date=August 2011 | pmid = 21267546 | pmc = 3149672 | doi = 10.1007/s00204-011-0648-7 | bibcode = 2011ArTox..85..863B }}</ref> Katsurano et al. indicated that [[macrophage]]s and [[neutrophil]]s in an inflamed colonic epithelium are the source of reactive oxygen species causing the DNA damages that initiate colonic tumorigenesis (creation of tumors in the colon).<ref name="pmid21685942">{{cite journal |vauthors=Katsurano M, Niwa T, Yasui Y, Shigematsu Y, Yamashita S, Takeshima H, Lee MS, Kim YJ, Tanaka T, Ushijima T | title = Early-stage formation of an epigenetic field defect in a mouse colitis model, and non-essential roles of T- and B-cells in DNA methylation induction | journal = Oncogene | volume = 31 | issue = 3 | pages = 342–51 |date=January 2012 | pmid = 21685942 | doi = 10.1038/onc.2011.241 | doi-access = free }}</ref>{{Unreliable source?|date=August 2019|reason=one study in mice}} Some sources of DNA damage are indicated in the boxes at the top of the figure in this section.{{Clarify|date=October 2023}}

Individuals with a [[germline mutation]] causing deficiency in any of 34 [[DNA repair]] genes (see article [[DNA repair-deficiency disorder]]) are at increased risk of [[cancer]]. Some germline mutations in DNA repair genes cause up to 100% lifetime chance of cancer (e.g., [[p53]] mutations).<ref name="pmid21779515">{{cite journal | author = 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> These germline mutations are indicated in a box at the left of the figure with an arrow indicating their contribution to DNA repair deficiency.

About 70% of malignant (cancerous) neoplasms have no [[Heredity|hereditary]] component and are called "sporadic cancers".<ref name="pmid10891514">{{cite journal |vauthors=Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, Pukkala E, Skytthe A, Hemminki K | title = Environmental and heritable factors in the causation of cancer—analyses of cohorts of twins from Sweden, Denmark, and Finland | journal = N. Engl. J. Med. | volume = 343 | issue = 2 | pages = 78–85 |date=July 2000 | pmid = 10891514 | doi = 10.1056/NEJM200007133430201 | doi-access =free  }}</ref> Only a minority of sporadic cancers have a deficiency in DNA repair due to mutation in a DNA repair gene. However, a majority of sporadic cancers have deficiency in DNA repair due to [[Epigenetics|epigenetic]] alterations that reduce or silence DNA repair gene expression. For example, of 113 sequential colorectal cancers, only four had a [[missense mutation]] in the DNA repair gene [[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 name="pmid15888787">{{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> Five reports present evidence that between 40% and 90% of colorectal cancers have reduced MGMT expression due to methylation of the MGMT promoter region.<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 | title = MGMT promoter methylation and field defect in sporadic colorectal cancer | journal = J. Natl. Cancer Inst. | volume = 97 | issue = 18 | pages = 1330–8 |date=September 2005 | pmid = 16174854 | doi = 10.1093/jnci/dji275 | doi-access = free }}</ref><ref name="pmid20653064">{{cite journal |vauthors=Psofaki V, Kalogera C, Tzambouras N, Stephanou D, Tsianos E, Seferiadis K, Kolios G | title = Promoter methylation status of hMLH1, MGMT, and CDKN2A/p16 in colorectal adenomas | journal = World J. Gastroenterol. | volume = 16 | issue = 28 | pages = 3553–60 |date=July 2010 | pmid = 20653064 | pmc = 2909555 | doi = 10.3748/wjg.v16.i28.3553 | doi-access = free }}</ref><ref name="Lee KH 2011">{{cite journal |vauthors=Lee KH, Lee JS, Nam JH, Choi C, Lee MC, Park CS, Juhng SW, Lee JH | title = Promoter methylation status of hMLH1, hMSH2, and MGMT genes in colorectal cancer associated with adenoma-carcinoma sequence | journal = Langenbecks Arch Surg | volume = 396 | issue = 7 | pages = 1017–26 |date=October 2011 | pmid = 21706233 | doi = 10.1007/s00423-011-0812-9 | s2cid = 8069716 }}</ref><ref name="pmid23422094">{{cite journal |vauthors=Amatu A, Sartore-Bianchi A, Moutinho C, Belotti A, Bencardino K, Chirico G, Cassingena A, Rusconi F, Esposito A, Nichelatti M, Esteller M, Siena S | title = Promoter CpG island hypermethylation of the DNA repair enzyme MGMT predicts clinical response to dacarbazine in a phase II study for metastatic colorectal cancer | journal = Clin. Cancer Res. | volume = 19 | issue = 8 | pages = 2265–72 |date=April 2013 | pmid = 23422094 | doi = 10.1158/1078-0432.CCR-12-3518 | doi-access = free }}</ref><ref name="pmid23271133">{{cite journal |vauthors=Mokarram P, Zamani M, Kavousipour S, Naghibalhossaini F, Irajie C, Moradi Sarabi M, Hosseini SV |display-authors = 6| title = Different patterns of DNA methylation of the two distinct O6-methylguanine-DNA methyltransferase (O6-MGMT) promoter regions in colorectal cancer | journal = Mol. Biol. Rep. | volume = 40 | issue = 5 | pages = 3851–7 |date=May 2013 | pmid = 23271133 | doi = 10.1007/s11033-012-2465-3 |s2cid = 18733871}}</ref>

Similarly, out of 119 cases of mismatch repair-deficient colorectal cancers that lacked DNA repair gene PMS2 expression, PMS2 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="pmid15887099">{{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 = 1160–71 |date=May 2005 | pmid = 15887099 | doi = 10.1053/j.gastro.2005.01.056 | doi-access = free }}</ref> 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="pmid20351277">{{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 = Proc. Natl. Acad. Sci. U.S.A. | volume = 107 | issue = 15 | pages = 6982–7 |date=April 2010 | pmid = 20351277 | pmc = 2872463 | doi = 10.1073/pnas.1002472107 |bibcode = 2010PNAS..107.6982V|doi-access = free}}</ref>

In further examples, epigenetic defects were found at frequencies of between 13%-100% for the DNA repair genes [[BRCA1]], [[Werner syndrome ATP-dependent helicase|WRN]], [[FANCB]], [[FANCF]], MGMT, [[MLH1]], [[MSH2]], [[MSH4]], [[ERCC1]], [[ERCC4|XPF]], [[NEIL1]] and [[Ataxia telangiectasia mutated|ATM]]. These epigenetic defects occurred in various cancers, including breast, ovarian, colorectal, and head and neck cancers. Two or three deficiencies in expression of ERCC1, XPF or PMS2 occur simultaneously in the majority of the 49 colon cancers evaluated by Facista et al.<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 Integr | volume = 3 | issue = 1 | pages = 3 | year = 2012 | pmid = 22494821 | pmc = 3351028 | doi = 10.1186/2041-9414-3-3 |doi-access = free}}</ref> Epigenetic alterations causing reduced expression of DNA repair genes is shown in a central box at the third level from the top of the figure in this section, and the consequent DNA repair deficiency is shown at the fourth level.

When expression of DNA repair genes is reduced, DNA damages accumulate in cells at a higher than normal level, and these excess damages cause increased frequencies of [[mutation]] or epimutation. Mutation rates strongly increase in cells defective in [[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 = Proc. Natl. Acad. Sci. U.S.A. | volume = 94 | issue = 7 | pages = 3122–7 |date=April 1997 | pmid = 9096356 | pmc = 20332 | doi = 10.1073/pnas.94.7.3122 | bibcode = 1997PNAS...94.3122N | doi-access = free }}</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 = 2402–8 |date=December 2006 | pmid = 16728433 | pmc = 2612936 | doi = 10.1093/carcin/bgl079 }}</ref> or in [[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 Rep. | volume = 3 | issue = 3 | pages = 255–60 |date=March 2002 | pmid = 11850397 | pmc = 1084010 | doi = 10.1093/embo-reports/kvf037 }}</ref>

During [[Double-strand break repair model|repair of DNA double strand breaks]], or repair of other DNA damages, incompletely cleared sites of repair can cause [[Epigenetics|epigenetic]] [[gene silencing]].<ref name="pmid18704159">{{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 Genet. | volume = 4 | issue = 8 | pages = e1000155 | year = 2008 | pmid = 18704159 | pmc = 2491723 | doi = 10.1371/journal.pgen.1000155 | editor1-last = Lee | editor1-first = Jeannie T | doi-access = free }}</ref><ref name="pmid17616978">{{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 Genet. | volume = 3 | issue = 7 | pages = e110 |date=July 2007 | pmid = 17616978 | pmc = 1913100 | doi = 10.1371/journal.pgen.0030110 | doi-access = free }}</ref> DNA repair deficiencies (level 4 in the figure) cause increased DNA damages (level 5 in the figure) which result in increased [[somatic mutation]]s and epigenetic alterations (level 6 in the figure).

Field defects, normal-appearing tissue with multiple alterations (and discussed in the section below), are common precursors to development of the disordered and improperly proliferating clone of tissue in a malignant neoplasm. Such field defects (second level from bottom of figure) may have multiple mutations and epigenetic alterations.

Once a cancer is formed, it usually has [[genome instability]]. This instability is likely due to reduced DNA repair or excessive DNA damage. Because of such instability, the cancer continues to evolve and to produce sub clones. For example, a renal cancer, sampled in 9 areas, had 40 ubiquitous mutations, demonstrating [[tumour heterogeneity|tumor heterogeneity]] (i.e. present in all areas of the cancer), 59 mutations shared by some (but not all areas), and 29 "private" mutations only present in one of the areas of the cancer.<ref name="pmid22397650">{{cite journal |vauthors=Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P, Varela I, Phillimore B, Begum S, McDonald NQ, Butler A, Jones D, Raine K, Latimer C, Santos CR, Nohadani M, Eklund AC, Spencer-Dene B, Clark G, Pickering L, Stamp G, Gore M, Szallasi Z, Downward J, Futreal PA, Swanton C |display-authors = 6| title = Intratumor heterogeneity and branched evolution revealed by multiregion sequencing | journal = N. Engl. J. Med. | volume = 366 | issue = 10 | pages = 883–92 |date=March 2012 | pmid = 22397650 | doi = 10.1056/NEJMoa1113205 | pmc=4878653}}</ref>