Editing Neoplasm (section)

===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>