Editing Neoplasm (section)

==Malignant neoplasms==

===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>

===Field defects===

[[File:Image of resected colon segment with cancer & 4 nearby polyps plus schematic of field defects with sub-clones.jpg|thumb|Longitudinally opened freshly resected colon segment showing a cancer and four polyps, plus a schematic diagram indicating a likely field defect (a region of tissue that precedes and predisposes to the development of cancer) in this colon segment. The diagram indicates sub-clones and sub-sub-clones that were precursors to the tumors.]]

Various other terms have been used to describe this [[phenomenon]], including "field effect", "field cancerization", and "field [[carcinogenesis]]". The term "field cancerization" was first used in 1953 to describe an area or "field" of epithelium that has been preconditioned by (at that time) largely unknown processes so as to predispose it towards development of cancer.<ref name="pmid13094644">{{cite journal |vauthors=Slaughter DP, Southwick HW, Smejkal W | title = Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin | journal = Cancer | volume = 6 | issue = 5 | pages = 963–8 |date=September 1953 | pmid = 13094644 | doi = 10.1002/1097-0142(195309)6:5<963::AID-CNCR2820060515>3.0.CO;2-Q | s2cid = 6736946 | doi-access = free }}</ref> Since then, the terms "field cancerization" and "field defect" have been used to describe pre-malignant tissue in which new cancers are likely to arise.{{cn|date=January 2022}}

Field defects are important in progression to cancer.<ref name="pmid18164807">{{cite journal |vauthors=Bernstein C, Bernstein H, Payne CM, Dvorak K, Garewal H | title = Field defects in progression to gastrointestinal tract cancers | journal = Cancer Lett. | volume = 260 | issue = 1–2 | pages = 1–10 |date=February 2008 | pmid = 18164807 | pmc = 2744582 | doi = 10.1016/j.canlet.2007.11.027 }}</ref><ref name="pmid20689513">{{cite journal |vauthors=Nguyen H, Loustaunau C, Facista A, Ramsey L, Hassounah N, Taylor H, Krouse R, Payne CM, Tsikitis VL, Goldschmid S, Banerjee B, Perini RF, Bernstein C | title = Deficient Pms2, ERCC1, Ku86, CcOI in field defects during progression to colon cancer | journal = J Vis Exp | issue = 41 | pages = 1931| year = 2010 | pmid = 20689513 | pmc = 3149991 | doi = 10.3791/1931 }}</ref> However, in most cancer research, as pointed out by Rubin<ref name="pmid21254148">{{cite journal | author = Rubin H | title = Fields and field cancerization: the preneoplastic origins of cancer: asymptomatic hyperplastic fields are precursors of neoplasia, and their progression to tumors can be tracked by saturation density in culture | journal = BioEssays | volume = 33 | issue = 3 | pages = 224–31 |date=March 2011 | pmid = 21254148 | doi = 10.1002/bies.201000067 | s2cid = 44981539 }}</ref> "The vast majority of studies in cancer research has been done on well-defined tumors in vivo, or on discrete neoplastic foci in vitro. Yet there is evidence that more than 80% of the somatic mutations found in mutator phenotype human colorectal tumors occur before the onset of terminal clonal expansion.<ref name="pmid10655514">{{cite journal |vauthors=Tsao JL, Yatabe Y, Salovaara R, Järvinen HJ, Mecklin JP, Aaltonen LA, Tavaré S, Shibata D | title = Genetic reconstruction of individual colorectal tumor histories | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 97 | issue = 3 | pages = 1236–41 |date=February 2000 | pmid = 10655514 | pmc = 15581 | doi = 10.1073/pnas.97.3.1236 | bibcode = 2000PNAS...97.1236T | doi-access = free }}</ref> Similarly, Vogelstein et al.<ref name=Vogelstein>{{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> point out that more than half of somatic mutations identified in tumors occurred in a pre-neoplastic phase (in a field defect), during growth of apparently normal cells. Likewise, epigenetic alterations present in tumors may have occurred in pre-neoplastic field defects.{{cn|date=January 2022}}

An expanded view of field effect has been termed "etiologic field effect", which encompasses not only molecular and pathologic changes in pre-neoplastic cells but also influences of exogenous environmental factors and molecular changes in the local [[microenvironment (biology)|microenvironment]] on neoplastic evolution from tumor initiation to patient death.<ref>{{cite journal |vauthors=Lochhead P, Chan AT, Nishihara R, Fuchs CS, Beck AH, Giovannucci E, Ogino S | year = 2014 | title = Etiologic field effect: reappraisal of the field effect concept in cancer predisposition and progression | journal = Mod Pathol | volume = 28| issue = 1| pages = 14–29| doi = 10.1038/modpathol.2014.81 | pmid=24925058 | pmc=4265316}}</ref>

In the colon, a field defect probably arises by natural selection of a mutant or epigenetically altered cell among the stem cells at the base of one of the [[Intestinal gland|intestinal crypts]] on the inside surface of the colon. A mutant or epigenetically altered stem cell may replace the other nearby stem cells by natural selection. Thus, a patch of abnormal tissue may arise. The figure in this section includes a photo of a freshly resected and lengthwise-opened segment of the colon showing a colon cancer and four polyps. Below the photo, there is a schematic diagram of how a large patch of mutant or epigenetically altered cells may have formed, shown by the large area in yellow in the diagram. Within this first large patch in the diagram (a large clone of cells), a second such mutation or epigenetic alteration may occur so that a given stem cell acquires an advantage compared to other stem cells within the patch, and this altered stem cell may expand clonally forming a secondary patch, or sub-clone, within the original patch. This is indicated in the diagram by four smaller patches of different colors within the large yellow original area. Within these new patches (sub-clones), the process may be repeated multiple times, indicated by the still smaller patches within the four secondary patches (with still different colors in the diagram) which clonally expand, until stem cells arise that generate either small polyps or else a malignant neoplasm (cancer).{{cn|date=January 2022}}

In the photo, an apparent field defect in this segment of a colon has generated four polyps (labeled with the size of the polyps, 6mm, 5mm, and two of 3mm, and a cancer about 3&nbsp;cm across in its longest dimension). These neoplasms are also indicated, in the diagram below the photo, by 4 small tan circles (polyps) and a larger red area (cancer). The cancer in the photo occurred in the cecal area of the colon, where the colon joins the small intestine (labeled) and where the appendix occurs (labeled). The fat in the photo is external to the outer wall of the colon.  In the segment of colon shown here, the colon was cut open lengthwise to expose the inner surface of the colon and to display the cancer and polyps occurring within the inner epithelial lining of the colon.{{cn|date=January 2022}}

If the general process by which sporadic colon cancers arise is the formation of a pre-neoplastic clone that spreads by natural selection, followed by formation of internal sub-clones within the initial clone, and sub-sub-clones inside those, then colon cancers generally should be associated with, and be preceded by, fields of increasing abnormality reflecting the succession of premalignant events. The most extensive region of abnormality (the outermost yellow irregular area in the diagram) would reflect the earliest event in formation of a malignant neoplasm.{{cn|date=January 2022}}

In experimental evaluation of specific DNA repair deficiencies in cancers, many specific DNA repair deficiencies were also shown to occur in the field defects surrounding those cancers. The Table, below, gives examples for which the DNA repair deficiency in a cancer was shown to be caused by an epigenetic alteration, and the somewhat lower frequencies with which the same epigenetically caused DNA repair deficiency was found in the surrounding field defect.

{| class="wikitable sortable"
|+ Frequency of epigenetic changes in DNA repair genes in sporadic cancers and in adjacent field defects
! Cancer !!Gene !!Frequency in cancer !!Frequency in field defect!!{{Refh}}
|-
!Colorectal
|MGMT || 46%||34%||<ref name="pmid16174854" />
|-
!Colorectal
|MGMT || 47%||11%||<ref name="Lee KH 2011"/>
|-
!Colorectal
|MGMT || 70%||60%||<ref name="Svrcek et al 2010">{{cite journal |vauthors=Svrcek M, Buhard O, Colas C, Coulet F, Dumont S, Massaoudi I, Lamri A, Hamelin R, Cosnes J, Oliveira C, Seruca R, Gaub MP, Legrain M, Collura A, Lascols O, Tiret E, Fléjou JF, Duval A|display-authors = 6 | title = Methylation tolerance due to an O6-methylguanine DNA methyltransferase (MGMT) field defect in the colonic mucosa: an initiating step in the development of mismatch repair-deficient colorectal cancers | journal = Gut | volume = 59 | issue = 11 | pages = 1516–26 |date=November 2010 | pmid = 20947886 | doi = 10.1136/gut.2009.194787 |s2cid = 206950452 }}</ref>
|-
!Colorectal
|MSH2 || 13%||5%||<ref name="Lee KH 2011"/>
|-
!Colorectal
|ERCC1 || 100%||40%||<ref name=Facista />
|-
!Colorectal
|PMS2 || 88%||50%||<ref name=Facista />
|-
!Colorectal
|XPF || 55%||40%||<ref name=Facista />
|-
!Head and Neck
|MGMT || 54%||38%||<ref name="Jaroslaw et al 2011">{{cite journal |vauthors=Paluszczak J, Misiak P, Wierzbicka M, Woźniak A, Baer-Dubowska W | title = Frequent hypermethylation of DAPK, RARbeta, MGMT, RASSF1A and FHIT in laryngeal squamous cell carcinomas and adjacent normal mucosa | journal = Oral Oncol. | volume = 47 | issue = 2 | pages = 104–7 |date=February 2011 | pmid = 21147548 | doi = 10.1016/j.oraloncology.2010.11.006 }}</ref>
|-
!Head and Neck
|MLH1 || 33%||25%||<ref name="Chunlai et al 2009">{{cite journal |vauthors=Zuo C, Zhang H, Spencer HJ, Vural E, Suen JY, Schichman SA, Smoller BR, Kokoska MS, Fan CY | title = Increased microsatellite instability and epigenetic inactivation of the hMLH1 gene in head and neck squamous cell carcinoma | journal = Otolaryngol Head Neck Surg | volume = 141 | issue = 4 | pages = 484–90 |date=October 2009 | pmid = 19786217 | doi = 10.1016/j.otohns.2009.07.007 | s2cid = 8357370 }}</ref>
|-
!Head and Neck
|MLH1 || 31%||20%||<ref name="Tawfik et al 2011">{{cite journal |vauthors=Tawfik HM, El-Maqsoud NM, Hak BH, El-Sherbiny YM | title = Head and neck squamous cell carcinoma: mismatch repair immunohistochemistry and promoter hypermethylation of hMLH1 gene | journal = Am J Otolaryngol | volume = 32 | issue = 6 | pages = 528–36 | year = 2011 | pmid = 21353335 | doi = 10.1016/j.amjoto.2010.11.005 }}</ref>
|-
!Stomach
|MGMT || 88%||78%||<ref name="Zou et al 2009">{{cite journal |vauthors=Zou XP, Zhang B, Zhang XQ, Chen M, Cao J, Liu WJ | title = Promoter hypermethylation of multiple genes in early gastric adenocarcinoma and precancerous lesions | journal = Hum. Pathol. | volume = 40 | issue = 11 | pages = 1534–42 |date=November 2009 | pmid = 19695681 | doi = 10.1016/j.humpath.2009.01.029 }}</ref>
|-
!Stomach
|MLH1 || 73%||20%||<ref name="pmid23098428">{{cite journal |vauthors=Wani M, Afroze D, Makhdoomi M, Hamid I, Wani B, Bhat G, Wani R, Wani K | title = Promoter methylation status of DNA repair gene (hMLH1) in gastric carcinoma patients of the Kashmir valley | journal = Asian Pac. J. Cancer Prev. | volume = 13 | issue = 8 | pages = 4177–81 | year = 2012 | pmid = 23098428 | doi = 10.7314/APJCP.2012.13.8.4177 | doi-access = free }}</ref>
|-
!Esophagus
|MLH1 || 77%-100%||23%-79%||<ref name="Agarwal et al 2012">{{cite journal |vauthors=Agarwal A, Polineni R, Hussein Z, Vigoda I, Bhagat TD, Bhattacharyya S, Maitra A, Verma A | title = Role of epigenetic alterations in the pathogenesis of Barrett's esophagus and esophageal adenocarcinoma | journal = Int J Clin Exp Pathol | volume = 5 | issue = 5 | pages = 382–96 | year = 2012 | pmid = 22808291 | pmc = 3396065 }}</ref>
|}
Some of the small polyps in the field defect shown in the photo of the opened colon segment may be relatively benign neoplasms. Of polyps less than 10mm in size, found during colonoscopy and followed with repeat colonoscopies for 3 years, 25% were unchanged in size, 35% regressed or shrank in size while 40% grew in size.<ref name="pmid8949653">{{cite journal |vauthors=Hofstad B, Vatn MH, Andersen SN, Huitfeldt HS, Rognum T, Larsen S, Osnes M | title = Growth of colorectal polyps: redetection and evaluation of unresected polyps for a period of three years | journal = Gut | volume = 39 | issue = 3 | pages = 449–56 |date=September 1996 | pmid = 8949653 | pmc = 1383355 | doi = 10.1136/gut.39.3.449 }}</ref>

===Genome instability===
Cancers are known to exhibit [[genome instability]] or a mutator phenotype.<ref name="pmid22954224">{{cite journal |vauthors=Schmitt MW, Prindle MJ, Loeb LA | title = Implications of genetic heterogeneity in cancer | journal = Ann. N. Y. Acad. Sci. | volume = 1267 | issue = 1| pages = 110–6 |date=September 2012 | pmid = 22954224 | pmc = 3674777 | doi = 10.1111/j.1749-6632.2012.06590.x | bibcode = 2012NYASA1267..110S }}</ref> The protein-coding DNA within the nucleus is about 1.5% of the total genomic DNA.<ref name="pmid11237011">{{cite journal | vauthors = Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, Devon K, Dewar K, Doyle M, FitzHugh W | title = Initial sequencing and analysis of the human genome | journal = Nature | volume = 409 | issue = 6822 | pages = 860–921 | date = February 2001 | pmid = 11237011 | doi = 10.1038/35057062 | bibcode = 2001Natur.409..860L | display-authors = etal | url = https://deepblue.lib.umich.edu/bitstream/2027.42/62798/1/409860a0.pdf | doi-access = free | access-date = 2019-09-02 | archive-date = 2020-07-29 | archive-url = https://web.archive.org/web/20200729030748/https://deepblue.lib.umich.edu/bitstream/handle/2027.42/62798/409860a0.pdf;jsessionid=C72311E1AB91A832789410D56B35F9F1?sequence=1 | url-status = live }}</ref> Within this protein-coding DNA (called the [[exome]]), an average cancer of the breast or colon can have about 60 to 70 protein altering mutations, of which about 3 or 4 may be "driver" mutations, and the remaining ones may be "passenger" mutations.<ref name=Vogelstein /> However, the average number of DNA sequence mutations in the entire genome (including [[Noncoding DNA|non-protein-coding regions]]) within a breast cancer tissue sample is about 20,000.<ref name="pmid22492626">{{cite journal |vauthors=Yost SE, Smith EN, Schwab RB, Bao L, Jung H, Wang X, Voest E, Pierce JP, Messer K, Parker BA, Harismendy O, Frazer KA | title = Identification of high-confidence somatic mutations in whole genome sequence of formalin-fixed breast cancer specimens | journal = Nucleic Acids Res. | volume = 40 | issue = 14 | pages = e107 |date=August 2012 | pmid = 22492626 | pmc = 3413110 | doi = 10.1093/nar/gks299 }}</ref> In an average melanoma tissue sample (where melanomas have a higher [[exome]] mutation frequency<ref name=Vogelstein />) the total number of DNA sequence mutations is about 80,000.<ref name="pmid22622578">{{cite journal |vauthors=Berger MF, Hodis E, Heffernan TP, Deribe YL, Lawrence MS, Protopopov A, Ivanova E, Watson IR, Nickerson E, Ghosh P, Zhang H, Zeid R, Ren X, Cibulskis K, Sivachenko AY, Wagle N, Sucker A, Sougnez C, Onofrio R, Ambrogio L, Auclair D, Fennell T, Carter SL, Drier Y, Stojanov P, Singer MA, Voet D, Jing R, Saksena G, Barretina J, Ramos AH, Pugh TJ, Stransky N, Parkin M, Winckler W, Mahan S, Ardlie K, Baldwin J, Wargo J, Schadendorf D, Meyerson M, Gabriel SB, Golub TR, Wagner SN, Lander ES, Getz G, Chin L, Garraway LA|display-authors = 6 | title = Melanoma genome sequencing reveals frequent PREX2 mutations | journal = Nature | volume = 485 | issue = 7399 | pages = 502–6 |date=May 2012 | pmid = 22622578 | pmc = 3367798 | doi = 10.1038/nature11071 |bibcode = 2012Natur.485..502B }}</ref> This compares to the very low mutation frequency of about 70 new mutations in the entire genome between generations (parent to child) in humans.<ref name="pmid20220176">{{cite journal | vauthors = Roach JC, Glusman G, Smit AF, Huff CD, Hubley R, Shannon PT, Rowen L, Pant KP, Goodman N, Bamshad M, Shendure J, Drmanac R, Jorde LB, Hood L, Galas DJ|display-authors = 6| title = Analysis of genetic inheritance in a family quartet by whole-genome sequencing | journal = Science | volume = 328 | issue = 5978 | pages = 636–9 | date = April 2010 | pmid = 20220176 | pmc = 3037280 | doi = 10.1126/science.1186802 |bibcode = 2010Sci...328..636R}}</ref><ref name="pmid23001126">{{cite journal | vauthors = Campbell CD, Chong JX, Malig M, Ko A, Dumont BL, Han L, Vives L, O'Roak BJ, Sudmant PH, Shendure J, Abney M, Ober C, Eichler EE |display-authors = 6| title = Estimating the human mutation rate using autozygosity in a founder population | journal = Nat. Genet. | volume = 44 | issue = 11 | pages = 1277–81 | date = November 2012 | pmid = 23001126 | pmc = 3483378 | doi = 10.1038/ng.2418 }}</ref>

The high frequencies of mutations in the total nucleotide sequences within cancers suggest that often an early alteration in the field defects giving rise to a cancer (e.g. yellow area in the diagram in this section) is a deficiency in DNA repair. The large field defects surrounding colon cancers (extending to at about 10&nbsp;cm on each side of a cancer) were shown by Facista et al.<ref name=Facista /> to frequently have epigenetic defects in 2 or 3 DNA repair proteins ([[ERCC1]], XPF or [[PMS2]]) in the entire area of the field defect. Deficiencies in DNA repair cause increased mutation rates.<ref name=Narayanan /><ref name=Hegan /><ref name=Tutt /> A deficiency in DNA repair, itself, can allow DNA damages to accumulate, and error-prone [[DNA repair|translesion synthesis]] past some of those damages may give rise to mutations. In addition, faulty repair of these accumulated DNA damages may give rise to epimutations. These new mutations or epimutations may provide a proliferative advantage, generating a field defect. Although the mutations/epimutations in DNA repair genes do not, themselves, confer a selective advantage, they may be carried along as passengers in cells when the cells acquire additional mutations/epimutations that do provide a proliferative advantage.{{cn|date=May 2023}}