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[[File:Image of resected colon segment with cancer & 4 nearby polyps plus schematic of field defects with sub-clones.jpg|thumb|300px| 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.]]
⚫
'''Field cancerization''' (also termed '''field carcinogenesis''', '''cancer field effect''' or '''premalignant field defect''') is a biological process in which large areas of [[Cell (biology)|cell]]s at a [[Tissue (biology)|tissue]] surface or within an [[organ (biology)|organ]] are affected by a [[carcinogenesis|carcinogenic insult]]. The process arises from exposure to an injurious environment, often over a lengthy period.<ref name="McGraw-Hill2001"/> The initial step in field cancerization is associated with various molecular lesions such as acquired [[genetic mutation]]s and [[epigenetic]] changes, occurring over a widespread, multi-focal "field".<ref name="Rubin2011"/><ref name="Kadara2012"/><ref name="Braathen2012"/><ref name="Nonn2009"/><ref name="Vatve2007"/><ref name="Heaphy2009"/><ref name="Torezan2013"/> These initial molecular changes may subsequently progress to [[cytology|cytologically]] recognizable [[premalignant]] foci of [[dysplasia]], and eventually to [[carcinoma in situ]] (CIS) or [[cancer]].<ref name="McGraw-Hill2001"/><ref name="Nonn2009"/>
'''Field cancerization''' (also termed '''field carcinogenesis''', '''cancer field effect''' or '''premalignant field defect''') is a biological process in which large areas of [[Cell (biology)|cell]]s at a [[Tissue (biology)|tissue]] surface or within an [[organ (biology)|organ]] are affected by a [[carcinogenesis#Contribution_of_Field_Defects_to_carcinogenesis|carcinogenic alteration(s)]]. The process arises from exposure to an injurious environment, often over a lengthy period.<ref name="McGraw-Hill2001"/>


==How field cacerization arises==
⚫
The initial step in field cancerization is associated with various molecular lesions such as acquired [[genetic mutation]]s and [[epigenetic]] changes, occurring over a widespread, multi-focal "field".<ref name="Rubin2011"/><ref name="Kadara2012"/><ref name="Braathen2012"/><ref name="Nonn2009"/><ref name="Vatve2007"/><ref name="Heaphy2009"/><ref name="Torezan2013"/> These initial molecular changes may subsequently progress to [[cytology|cytologically]] recognizable [[premalignant]] foci of [[dysplasia]], and eventually to [[carcinoma in situ]] (CIS) or [[cancer]].<ref name="McGraw-Hill2001"/><ref name="Nonn2009"/> The image of a longitudinally opened colon resection on this page shows an area of a colon resection that likely has a field cancerization or field defect. It has one cancer and four premalignant polyps.
Field cancerization can occur in any tissue.<ref name="McGraw-Hill2001"/> Prominent examples of field cancerization include premalignant field defects in [[head and neck cancer]],<ref name="Wu1999"/> [[lung cancer]],<ref name="Rubin2011"/><ref name="Kadara2012"/> [[colorectal cancer]],<ref name="Vogelstein2013"/> [[Barrett's esophagus]],<ref name="Zeki2011"/><ref name="Gong2009"/><ref name="Debruyne2006"/> skin,<ref name="Braathen2012"/><ref name="Vatve2007"/><ref name="Torezan2013"/> breast ducts<ref name="Heaphy2009"/><ref name="Rivenbark2012"/> and bladder.<ref name="McGraw-Hill2001"/><ref name="Cheng2010"/> Field cancerization has implications for cancer surveillance and treatment.<ref name="Kadara2012"/><ref name="Braathen2012"/><ref name="Torezan2013"/><ref name="Zeki2011"/><ref name="Rivenbark2012"/><ref name="Dakubo2010"/> Despite adequate resection and being [[histology|histologically]] normal, the remaining locoregional tissue has an increased [[risk]] for developing multiple independent [[cancer]]s, either [[synchronous]]ly or [[wikt:metachronous|metachronously]].<ref name="McGraw-Hill2001"/><ref name="Wu1999"/><ref name="Kufe2003"/>
Field cancerization can occur in any tissue.<ref name="McGraw-Hill2001"/> Prominent examples of field cancerization include premalignant field defects in [[head and neck cancer]],<ref name="Wu1999"/> [[lung cancer]],<ref name="Rubin2011"/><ref name="Kadara2012"/> [[colorectal cancer]],<ref name="Vogelstein2013"/> [[Barrett's esophagus]],<ref name="Zeki2011"/><ref name="Gong2009"/><ref name="Debruyne2006"/> skin,<ref name="Braathen2012"/><ref name="Vatve2007"/><ref name="Torezan2013"/> breast ducts<ref name="Heaphy2009"/><ref name="Rivenbark2012"/> and bladder.<ref name="McGraw-Hill2001"/><ref name="Cheng2010"/> Field cancerization has implications for cancer surveillance and treatment.<ref name="Kadara2012"/><ref name="Braathen2012"/><ref name="Torezan2013"/><ref name="Zeki2011"/><ref name="Rivenbark2012"/><ref name="Dakubo2010"/> Despite adequate resection and being [[histology|histologically]] normal, the remaining locoregional tissue has an increased [[risk]] for developing multiple independent [[cancer]]s, either [[synchronous]]ly or [[wikt:metachronous|metachronously]].<ref name="McGraw-Hill2001"/><ref name="Wu1999"/><ref name="Kufe2003"/>

==Common early carcinogenic alterations==
A common carcinogenic alteration, found in many cancers and in their adjacent field defects from which the cancers likely arose, is reduced expression of one or more DNA repair enzymes. Since reduced DNA repair expression is often present in a field cancerization or a field defect, it is likely to have been an early step in progression to the cancer.

{| class="wikitable sortable"
|+ Frequency of finding epigenetic reductions in protein expression of DNA repair genes in sporadic cancers and in adjacent field defects
! Cancer !!Gene !!Frequency in Cancer !!Frequency in Field Defect!!Ref.
|-
!Colorectal
|MGMT || 46%||34%||<ref name="pmid16174854">{{cite journal |author=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 |year=2005 |month=September |pmid=16174854 |doi=10.1093/jnci/dji275 |url=http://jnci.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=16174854}}</ref>
|-
!Colorectal
|MGMT || 47%||11%||<ref name="pmid21706233">{{cite journal |author=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 |year=2011 |month=October |pmid=21706233 |doi=10.1007/s00423-011-0812-9 |url=http://dx.doi.org/10.1007/s00423-011-0812-9}}</ref>
|-
!Colorectal
|MGMT || 70%||60%||<ref name="Svrcek et al 2010">{{cite journal | author = 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 | 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 }}</ref>
|-
!Colorectal
|MSH2 || 13%||5%|| <ref name="pmid21706233">{{cite journal |author=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 |year=2011 |month=October |pmid=21706233 |doi=10.1007/s00423-011-0812-9 |url=http://dx.doi.org/10.1007/s00423-011-0812-9}}</ref>
|-
!Colorectal
|ERCC1 || 100%||40%||<ref name=Facista>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. (2012). Deficient expression of DNA repair enzymes in early progression to sporadic colon cancer. ''Genome Integr'' 3(1) 3. doi: 10.1186/2041-9414-3-3. PMID 22494821 http://www.ncbi.nlm.nih.gov/pubmed/22494821</ref>
|-
!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 | author = 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 | author = 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 }}</ref>
|-
!Head and Neck
|MLH1 || 31%||20%||<ref name="Tawfik et al 2011">{{cite journal | author = 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 | author = 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 | author = 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 }}</ref>
|-
!Esophagus
|MLH1 || 77%-100%||23%-79%||<ref name="Agarwal et al 2012">{{cite journal | author = 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 | doi = }}</ref>
|}

==Pattern of alterations in a field defect==
[[File:Expression of DNA repair proteins ERCC1, PMS2 & KU86 in field defect.jpg|thumb|300px| A colon cancer resection, 22 cm long, had 6 tissue samples evaluated for expression of 3 DNA repair proteins, KU86, ERCC1 and PMS2. All 3 proteins are expressed at near 100% in colon tissue from a person without any colonic neoplasia, but adjacent to a colon cancer, in this instance, there is a field of more than 20 cm in which ERCC1 and PMS2 have reduced expression.]]
The diagram shows results obtained by Facista et al.<ref name=Facista /> when evaluating a particular colon resection for deficiencies in 3 different DNA repair enzymes, KU86 (active in the non-homologous end joining pathway), ERCC1 (active in the nucleotide excision DNA repair pathway) and PMS2 (active in the mismatch DNA repair pathway). While KU86 had occasional small deficiencies in expression, both ERCC1 and PMS2 had fairly large deficiencies in expression in each of the 6 locations sampled. Both ERCC1 and PMS2, in this tissue, were thought to be deficient due to epigenetic alterations.


== References ==
== References ==

Revision as of 18:16, 1 May 2014

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.

Field cancerization (also termed field carcinogenesis, cancer field effect or premalignant field defect) is a biological process in which large areas of cells at a tissue surface or within an organ are affected by a carcinogenic alteration(s). The process arises from exposure to an injurious environment, often over a lengthy period.[1]

How field cacerization arises

The initial step in field cancerization is associated with various molecular lesions such as acquired genetic mutations and epigenetic changes, occurring over a widespread, multi-focal "field".[2][3][4][5][6][7][8] These initial molecular changes may subsequently progress to cytologically recognizable premalignant foci of dysplasia, and eventually to carcinoma in situ (CIS) or cancer.[1][5] The image of a longitudinally opened colon resection on this page shows an area of a colon resection that likely has a field cancerization or field defect. It has one cancer and four premalignant polyps.

Field cancerization can occur in any tissue.[1] Prominent examples of field cancerization include premalignant field defects in head and neck cancer,[9] lung cancer,[2][3] colorectal cancer,[10] Barrett's esophagus,[11][12][13] skin,[4][6][8] breast ducts[7][14] and bladder.[1][15] Field cancerization has implications for cancer surveillance and treatment.[3][4][8][11][14][16] Despite adequate resection and being histologically normal, the remaining locoregional tissue has an increased risk for developing multiple independent cancers, either synchronously or metachronously.[1][9][17]

Common early carcinogenic alterations

A common carcinogenic alteration, found in many cancers and in their adjacent field defects from which the cancers likely arose, is reduced expression of one or more DNA repair enzymes. Since reduced DNA repair expression is often present in a field cancerization or a field defect, it is likely to have been an early step in progression to the cancer.

Frequency of finding epigenetic reductions in protein expression of DNA repair genes in sporadic cancers and in adjacent field defects
Cancer Gene Frequency in Cancer Frequency in Field Defect Ref.
Colorectal MGMT 46% 34% [18]
Colorectal MGMT 47% 11% [19]
Colorectal MGMT 70% 60% [20]
Colorectal MSH2 13% 5% [19]
Colorectal ERCC1 100% 40% [21]
Colorectal PMS2 88% 50% [21]
Colorectal XPF 55% 40% [21]
Head and Neck MGMT 54% 38% [22]
Head and Neck MLH1 33% 25% [23]
Head and Neck MLH1 31% 20% [24]
Stomach MGMT 88% 78% [25]
Stomach MLH1 73% 20% [26]
Esophagus MLH1 77%-100% 23%-79% [27]

Pattern of alterations in a field defect

A colon cancer resection, 22 cm long, had 6 tissue samples evaluated for expression of 3 DNA repair proteins, KU86, ERCC1 and PMS2. All 3 proteins are expressed at near 100% in colon tissue from a person without any colonic neoplasia, but adjacent to a colon cancer, in this instance, there is a field of more than 20 cm in which ERCC1 and PMS2 have reduced expression.

The diagram shows results obtained by Facista et al.[21] when evaluating a particular colon resection for deficiencies in 3 different DNA repair enzymes, KU86 (active in the non-homologous end joining pathway), ERCC1 (active in the nucleotide excision DNA repair pathway) and PMS2 (active in the mismatch DNA repair pathway). While KU86 had occasional small deficiencies in expression, both ERCC1 and PMS2 had fairly large deficiencies in expression in each of the 6 locations sampled. Both ERCC1 and PMS2, in this tissue, were thought to be deficient due to epigenetic alterations.

References

  1. ^ a b c d e Field cancerization Medical Dictionary - The Free Dictionary McGraw-Hill Concise Dictionary of Modern Medicine. 2002 by The McGraw-Hill Companies, Inc. [1]
  2. ^ a b Rubin H (March 2011). "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". Bioessays. 33 (3): 224–31. doi:10.1002/bies.201000067. PMID 21254148.
  3. ^ a b c Kadara H Wistuba II Field cancerization in non-small cell lung cancer: implications in disease pathogenesis. Proc Am Thorac Soc. 2012 May;9(2):38-42. doi: 10.1513/pats.201201-004MS PMID 22550239
  4. ^ a b c Braathen LR Morton CA Basset-Seguin N Bissonnette R Gerritsen MJ Gilaberte Y Calzavara-Pinton P Sidoroff A Wulf HC Szeimies RM. Photodynamic therapy for skin field cancerization: an international consensus. International Society for Photodynamic Therapy in Dermatology. J Eur Acad Dermatol Venereol. 2012 Sep;26(9):1063-6. doi: 10.1111/j.1468-3083.2011.04432.x. Epub 2012 Jan 5. PMID 22220503
  5. ^ a b Nonn L Ananthanarayanan V Gann PH Evidence for field cancerization of the prostate. Prostate. 2009 Sep 15;69(13):1470-9. doi: 10.1002/pros.20983 PMID 19462462
  6. ^ a b Vatve M Ortonne JP Birch-Machin MA Gupta G. Management of field change in actinic keratosis. Br J Dermatol. 2007 Dec;157 Suppl 2:21-4. PMID 18067627
  7. ^ a b Heaphy CM Griffith JK Bisoffi M Mammary field cancerization: molecular evidence and clinical importance. Breast Cancer Res Treat. 2009 Nov;118(2):229-39. doi: 10.1007/s10549-009-0504-0. Epub 2009 Aug 15. PMID 19685287
  8. ^ a b c Torezan LA, Festa-Neto C. Cutaneous field cancerization: clinical, histopathological and therapeutic aspects. An Bras Dermatol. 2013 Oct;88(5):775-86. doi: 10.1590/abd1806-4841.20132300 PMID 24173184
  9. ^ a b Wu X, Hu Y, Lippman SM. Upper Aerodigestive Tract Cancers. page 325 in Neugut AI, Meadows AT, Robinson E. Multiple Primary Cancers. Lippincott Williams & Wilkins, 1999.
  10. ^ Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Kinzler KW (March 2013). "Cancer genome landscapes". Science. 339 (6127): 1546–58. doi:10.1126/science.1235122. PMC 3749880. PMID 23539594.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ^ a b Zeki SS McDonald SA Graham TA Field cancerization in Barrett's esophagus. Discov Med. 2011 Nov;12(66):371-9. PMID 22127108
  12. ^ Gong L, Debruyne PR, Witek M, Nielsen K, Snook A, Lin JE, Bombonati A, Palazzo J, Schulz S, Waldman SA (2009). "Bile acids initiate lineage-addicted gastroesophageal tumorigenesis by suppressing the EGF receptor-AKT axis". Clin Transl Sci. 2 (4): 286–93. doi:10.1111/j.1752-8062.2009.00131.x. PMID 20443907.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ^ Debruyne PR, Witek M, Gong L, Birbe R, Chervoneva I, Jin T, Domon-Cell C, Palazzo JP, Freund JN, Li P, Pitari GM, Schulz S, Waldman SA (April 2006). "Bile acids induce ectopic expression of intestinal guanylyl cyclase C through nuclear factor-kappaB and Cdx2 in human esophageal cells". Gastroenterology. 130 (4): 1191–206. doi:10.1053/j.gastro.2005.12.032. PMID 16618413.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  14. ^ a b Rivenbark AG Coleman WB Field cancerization in mammary carcinogenesis -Implications for prevention and treatment of breast cancer. Exp Mol Pathol. 2012 Dec;93(3):391-8. doi: 10.1016/j.yexmp.2012.10.018. Epub 2012 Nov 6. PMID-23142414
  15. ^ Cheng L Davidson DD Maclennan GT Williamson SR Zhang S Koch MO Montironi R Lopez-Beltran A. The origins of urothelial carcinoma. Expert Rev Anticancer Ther. 2010 Jun;10(6):865-80. doi: 10.1586/era.10.73 PMID 20553211
  16. ^ Dakubo GD. Field Cancerization: Basic Science and Clinical Applications. Nova Science Publishers, 2010.ISBN 9781617610066
  17. ^ Kufe, DW; Holland, JF; Frei, E; Cancer medicine. 6th ed. pages 1391 and 2625. BC Decker, 2003. NLM ID 101189332 [2]
  18. ^ 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 (2005). "MGMT promoter methylation and field defect in sporadic colorectal cancer". J. Natl. Cancer Inst. 97 (18): 1330–8. doi:10.1093/jnci/dji275. PMID 16174854. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  19. ^ a b Lee KH, Lee JS, Nam JH, Choi C, Lee MC, Park CS, Juhng SW, Lee JH (2011). "Promoter methylation status of hMLH1, hMSH2, and MGMT genes in colorectal cancer associated with adenoma-carcinoma sequence". Langenbecks Arch Surg. 396 (7): 1017–26. doi:10.1007/s00423-011-0812-9. PMID 21706233. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  20. ^ 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 (November 2010). "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". Gut. 59 (11): 1516–26. doi:10.1136/gut.2009.194787. PMID 20947886.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  21. ^ a b c d 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. (2012). Deficient expression of DNA repair enzymes in early progression to sporadic colon cancer. Genome Integr 3(1) 3. doi: 10.1186/2041-9414-3-3. PMID 22494821 http://www.ncbi.nlm.nih.gov/pubmed/22494821
  22. ^ Paluszczak J, Misiak P, Wierzbicka M, Woźniak A, Baer-Dubowska W (February 2011). "Frequent hypermethylation of DAPK, RARbeta, MGMT, RASSF1A and FHIT in laryngeal squamous cell carcinomas and adjacent normal mucosa". Oral Oncol. 47 (2): 104–7. doi:10.1016/j.oraloncology.2010.11.006. PMID 21147548.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  23. ^ Zuo C, Zhang H, Spencer HJ, Vural E, Suen JY, Schichman SA, Smoller BR, Kokoska MS, Fan CY (October 2009). "Increased microsatellite instability and epigenetic inactivation of the hMLH1 gene in head and neck squamous cell carcinoma". Otolaryngol Head Neck Surg. 141 (4): 484–90. doi:10.1016/j.otohns.2009.07.007. PMID 19786217.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  24. ^ Tawfik HM, El-Maqsoud NM, Hak BH, El-Sherbiny YM (2011). "Head and neck squamous cell carcinoma: mismatch repair immunohistochemistry and promoter hypermethylation of hMLH1 gene". Am J Otolaryngol. 32 (6): 528–36. doi:10.1016/j.amjoto.2010.11.005. PMID 21353335.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  25. ^ Zou XP, Zhang B, Zhang XQ, Chen M, Cao J, Liu WJ (November 2009). "Promoter hypermethylation of multiple genes in early gastric adenocarcinoma and precancerous lesions". Hum. Pathol. 40 (11): 1534–42. doi:10.1016/j.humpath.2009.01.029. PMID 19695681.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  26. ^ Wani M, Afroze D, Makhdoomi M, Hamid I, Wani B, Bhat G, Wani R, Wani K (2012). "Promoter methylation status of DNA repair gene (hMLH1) in gastric carcinoma patients of the Kashmir valley". Asian Pac. J. Cancer Prev. 13 (8): 4177–81. doi:10.7314/APJCP.2012.13.8.4177. PMID 23098428.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  27. ^ Agarwal A, Polineni R, Hussein Z, Vigoda I, Bhagat TD, Bhattacharyya S, Maitra A, Verma A (2012). "Role of epigenetic alterations in the pathogenesis of Barrett's esophagus and esophageal adenocarcinoma". Int J Clin Exp Pathol. 5 (5): 382–96. PMC 3396065. PMID 22808291.{{cite journal}}: CS1 maint: multiple names: authors list (link)

External links

Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 13094644, please use {{cite journal}} with |pmid=13094644 instead.
Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 16079316, please use {{cite journal}} with |pmid=16079316 instead.
Leemans, CR (January 2011). "Field cancerization and local relapse". Nature Reviews Cancer 2011;11:9-22. {{cite web}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

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