Stomach cancer pathophysiology: Difference between revisions

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==== Oncogenes ====
==== Oncogenes ====
* ''[[Ras oncogene|K-ras]]'' [[mutations]] is found in [[Invasive (medical)|invasive]] [[Cancer|cancers]] and intestinal [[metaplasia]].<ref name="pmid11760076">{{cite journal| author=Yasui W, Oue N, Kuniyasu H, Ito R, Tahara E, Yokozaki H| title=Molecular diagnosis of gastric cancer: present and future. | journal=Gastric Cancer | year= 2001 | volume= 4 | issue= 3 | pages= 113-21 | pmid=11760076 | doi=10.1007/s101200100001 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11760076  }}</ref>
* ''[[Ras oncogene|K-ras]]'' [[mutations]] is found in [[Invasive (medical)|invasive]] [[Cancer|cancers]] and intestinal [[metaplasia]].<ref name="pmid11760076">{{cite journal| author=Yasui W, Oue N, Kuniyasu H, Ito R, Tahara E, Yokozaki H| title=Molecular diagnosis of gastric cancer: present and future. | journal=Gastric Cancer | year= 2001 | volume= 4 | issue= 3 | pages= 113-21 | pmid=11760076 | doi=10.1007/s101200100001 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11760076  }}</ref>
* [[Hepatocyte growth factor]] [[Receptor (biochemistry)|receptor]] c''-met'' [[oncogene]], encoding the h is supported by the finding that gene expression is found in intestinal-type gastric cancers. Effector protein CagA made by H.pylori modulates c-met receptor signal transduction pathways.<ref name="pmid16718776">{{cite journal| author=Smith MG, Hold GL, Tahara E, El-Omar EM| title=Cellular and molecular aspects of gastric cancer. | journal=World J Gastroenterol | year= 2006 | volume= 12 | issue= 19 | pages= 2979-90 | pmid=16718776 | doi= | pmc=4124370 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16718776  }}</ref>
* [[Hepatocyte growth factor]] [[Receptor (biochemistry)|receptor]] c''-met'' [[oncogene]], encoding the h is supported by the finding that gene expression is found in intestinal-type gastric cancers. Effector protein CagA made by [[H.pylori gastric adenocarcinoma pathophysiology|H.pylori]] modulates c-met receptor [[signal transduction]] pathways.<ref name="pmid16718776">{{cite journal| author=Smith MG, Hold GL, Tahara E, El-Omar EM| title=Cellular and molecular aspects of gastric cancer. | journal=World J Gastroenterol | year= 2006 | volume= 12 | issue= 19 | pages= 2979-90 | pmid=16718776 | doi= | pmc=4124370 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16718776  }}</ref>


==== Tumor suppressor genes ====
==== Tumor suppressor genes ====
* Almost 50% of gastric cancers have alterations in genes ''TP53,'' ''TP73'', ''APC'', TFF, ''DCC'', LOH, and ''FHIT.''<ref name="pmid17058198">{{cite journal| author=Ushiku T, Chong JM, Uozaki H, Hino R, Chang MS, Sudo M et al.| title=p73 gene promoter methylation in Epstein-Barr virus-associated gastric carcinoma. | journal=Int J Cancer | year= 2007 | volume= 120 | issue= 1 | pages= 60-6 | pmid=17058198 | doi=10.1002/ijc.22275 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17058198  }}</ref>  
* Almost 50% of gastric cancers have alterations in genes ''[[TP53 (gene)|TP53]],'' ''[[TP73L|TP73]]'', ''[[APC]]'', TFF, ''[[DCC1|DCC]]'', LOH, and ''[[FHIT]].''<ref name="pmid17058198">{{cite journal| author=Ushiku T, Chong JM, Uozaki H, Hino R, Chang MS, Sudo M et al.| title=p73 gene promoter methylation in Epstein-Barr virus-associated gastric carcinoma. | journal=Int J Cancer | year= 2007 | volume= 120 | issue= 1 | pages= 60-6 | pmid=17058198 | doi=10.1002/ijc.22275 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17058198  }}</ref>  
* Inactivation of p53 in gastric epithelial cells may reduce their ability to undergo apoptosis.<ref name="pmid12870784">{{cite journal| author=Ashktorab H, Ahmed A, Littleton G, Wang XW, Allen CR, Tackey R et al.| title=p53 and p14 increase sensitivity of gastric cells to H. pylori-induced apoptosis. | journal=Dig Dis Sci | year= 2003 | volume= 48 | issue= 7 | pages= 1284-91 | pmid=12870784 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12870784  }}</ref>  
* Inactivation of [[P53 (protein)|p53]] in gastric [[epithelial cells]] reduce their ability to undergo [[apoptosis]].<ref name="pmid12870784">{{cite journal| author=Ashktorab H, Ahmed A, Littleton G, Wang XW, Allen CR, Tackey R et al.| title=p53 and p14 increase sensitivity of gastric cells to H. pylori-induced apoptosis. | journal=Dig Dis Sci | year= 2003 | volume= 48 | issue= 7 | pages= 1284-91 | pmid=12870784 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12870784  }}</ref>  


* Abnormalities are found in intestinal-type , intestinal metaplasia and dysplasia, and H. pylori-associated chronic gastritis.<ref name="pmid17461446">{{cite journal| author=Kodama M, Murakami K, Okimoto T, Sato R, Watanabe K, Fujioka T| title=Expression of mutant type-p53 products in H pylori-associated chronic gastritis. | journal=World J Gastroenterol | year= 2007 | volume= 13 | issue= 10 | pages= 1541-6 | pmid=17461446 | doi= | pmc=4146896 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17461446  }}</ref>
* Abnormalities are found in intestinal-type , intestinal [[metaplasia]] and [[dysplasia]], and H. pylori-associated [[Chronic (medical)|chronic]] [[gastritis]].<ref name="pmid17461446">{{cite journal| author=Kodama M, Murakami K, Okimoto T, Sato R, Watanabe K, Fujioka T| title=Expression of mutant type-p53 products in H pylori-associated chronic gastritis. | journal=World J Gastroenterol | year= 2007 | volume= 13 | issue= 10 | pages= 1541-6 | pmid=17461446 | doi= | pmc=4146896 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17461446  }}</ref>
* Mutations in the ''APC'' gene are found in intestinal-type gastric cancers [70]. APC mutations alternate the Wnt/cateninsignaling pathway.<ref name="pmid8242071">{{cite journal| author=Nakatsuru S, Yanagisawa A, Furukawa Y, Ichii S, Kato Y, Nakamura Y et al.| title=Somatic mutations of the APC gene in precancerous lesion of the stomach. | journal=Hum Mol Genet | year= 1993 | volume= 2 | issue= 9 | pages= 1463-5 | pmid=8242071 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8242071  }}</ref>  
* [[Mutation|Mutations]] in the ''[[APC]]'' gene are found in intestinal-type gastric cancers. [[APC]] [[Mutation|mutations]] alternate the [[Wnt signaling pathway|Wnt/catenin]] signaling pathway.<ref name="pmid8242071">{{cite journal| author=Nakatsuru S, Yanagisawa A, Furukawa Y, Ichii S, Kato Y, Nakamura Y et al.| title=Somatic mutations of the APC gene in precancerous lesion of the stomach. | journal=Hum Mol Genet | year= 1993 | volume= 2 | issue= 9 | pages= 1463-5 | pmid=8242071 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8242071  }}</ref>  
* The trefoil factor family (TFF) is normally expressed in the gastroduodenal mucosa. Loss of TFF1 expression has been observed in gastric carcinomas.<ref name="pmid12210076">{{cite journal| author=Leung WK, Yu J, Chan FK, To KF, Chan MW, Ebert MP et al.| title=Expression of trefoil peptides (TFF1, TFF2, and TFF3) in gastric carcinomas, intestinal metaplasia, and non-neoplastic gastric tissues. | journal=J Pathol | year= 2002 | volume= 197 | issue= 5 | pages= 582-8 | pmid=12210076 | doi=10.1002/path.1147 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12210076  }}</ref>
* The [[Trefoil factor 1|trefoil factor family]] (TFF) is normally expressed in the gastroduodenal [[Mucous membrane|mucosa]]. Loss of TFF1 expression has been observed in gastric carcinomas.<ref name="pmid12210076">{{cite journal| author=Leung WK, Yu J, Chan FK, To KF, Chan MW, Ebert MP et al.| title=Expression of trefoil peptides (TFF1, TFF2, and TFF3) in gastric carcinomas, intestinal metaplasia, and non-neoplastic gastric tissues. | journal=J Pathol | year= 2002 | volume= 197 | issue= 5 | pages= 582-8 | pmid=12210076 | doi=10.1002/path.1147 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12210076  }}</ref>


==== Cell cycle regulatory molecules ====
==== Cell cycle regulatory molecules ====
* Cyclin E overexpression is found in gastric carcinomas.<ref name="pmid15746045">{{cite journal| author=Bani-Hani KE, Almasri NM, Khader YS, Sheyab FM, Karam HN| title=Combined evaluation of expressions of cyclin E and p53 proteins as prognostic factors for patients with gastric cancer. | journal=Clin Cancer Res | year= 2005 | volume= 11 | issue= 4 | pages= 1447-53 | pmid=15746045 | doi=10.1158/1078-0432.CCR-04-1730 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15746045  }}</ref>   
* [[Cyclin E]] overexpression is found in gastric carcinomas.<ref name="pmid15746045">{{cite journal| author=Bani-Hani KE, Almasri NM, Khader YS, Sheyab FM, Karam HN| title=Combined evaluation of expressions of cyclin E and p53 proteins as prognostic factors for patients with gastric cancer. | journal=Clin Cancer Res | year= 2005 | volume= 11 | issue= 4 | pages= 1447-53 | pmid=15746045 | doi=10.1158/1078-0432.CCR-04-1730 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15746045  }}</ref>   
* Cyclin E and Cyclin dependent kinase inhibitor 1B are cell-cycle regulators.<ref name="pmid10666388">{{cite journal| author=Takano Y, Kato Y, van Diest PJ, Masuda M, Mitomi H, Okayasu I| title=Cyclin D2 overexpression and lack of p27 correlate positively and cyclin E inversely with a poor prognosis in gastric cancer cases. | journal=Am J Pathol | year= 2000 | volume= 156 | issue= 2 | pages= 585-94 | pmid=10666388 | doi=10.1016/S0002-9440(10)64763-3 | pmc=1850035 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10666388  }}</ref>  
* [[Cyclin E]] and [[Cyclin-dependent kinase inhibitor protein|Cyclin-dependent kinase inhibitor]] 1B are [[cell cycle]] regulators.<ref name="pmid10666388">{{cite journal| author=Takano Y, Kato Y, van Diest PJ, Masuda M, Mitomi H, Okayasu I| title=Cyclin D2 overexpression and lack of p27 correlate positively and cyclin E inversely with a poor prognosis in gastric cancer cases. | journal=Am J Pathol | year= 2000 | volume= 156 | issue= 2 | pages= 585-94 | pmid=10666388 | doi=10.1016/S0002-9440(10)64763-3 | pmc=1850035 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10666388  }}</ref>  


==== '''Epigenetic events''' ====
==== '''Epigenetic events''' ====
* DNA methylation of gene promoters can silence the expression of ''CDH1.''<ref name="pmid172492692">{{cite journal| author=Yasui W, Sentani K, Motoshita J, Nakayama H| title=Molecular pathobiology of gastric cancer. | journal=Scand J Surg | year= 2006 | volume= 95 | issue= 4 | pages= 225-31 | pmid=17249269 | doi=10.1177/145749690609500403 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17249269  }}</ref>  
* [[DNA]] [[methylation]] of [[gene]] promoters can silence the expression of ''[[CDH11|CDH1]].''<ref name="pmid172492692">{{cite journal| author=Yasui W, Sentani K, Motoshita J, Nakayama H| title=Molecular pathobiology of gastric cancer. | journal=Scand J Surg | year= 2006 | volume= 95 | issue= 4 | pages= 225-31 | pmid=17249269 | doi=10.1177/145749690609500403 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17249269  }}</ref>  
* Hypermethylation of the ''Reprimo'' gene has been found in the plasma of patients with gastric cancer and can be used as biomarkers in the detection of early gastric cancer.<ref name="pmid18829507">{{cite journal| author=Bernal C, Aguayo F, Villarroel C, Vargas M, Díaz I, Ossandon FJ et al.| title=Reprimo as a potential biomarker for early detection in gastric cancer. | journal=Clin Cancer Res | year= 2008 | volume= 14 | issue= 19 | pages= 6264-9 | pmid=18829507 | doi=10.1158/1078-0432.CCR-07-4522 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18829507  }}</ref>  
* Hypermethylation of the [[Reprimo|''Reprimo'' gene]] has been found in the [[plasma]] of patients with gastric cancer and can be used as [[biomarkers]] in the detection of early gastric cancer.<ref name="pmid18829507">{{cite journal| author=Bernal C, Aguayo F, Villarroel C, Vargas M, Díaz I, Ossandon FJ et al.| title=Reprimo as a potential biomarker for early detection in gastric cancer. | journal=Clin Cancer Res | year= 2008 | volume= 14 | issue= 19 | pages= 6264-9 | pmid=18829507 | doi=10.1158/1078-0432.CCR-07-4522 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18829507  }}</ref>  
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'''Beta-catenin/Wnt signaling'''
'''Beta-catenin/Wnt signaling'''
* Beta-catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer.<ref name="pmid12067995">{{cite journal| author=Clements WM, Wang J, Sarnaik A, Kim OJ, MacDonald J, Fenoglio-Preiser C et al.| title=beta-Catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer. | journal=Cancer Res | year= 2002 | volume= 62 | issue= 12 | pages= 3503-6 | pmid=12067995 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12067995  }}</ref>  
* [[Beta-catenin]] [[mutation]] is a frequent cause of [[Wnt signaling pathway|Wnt]] pathway activation in gastric cancer.<ref name="pmid12067995">{{cite journal| author=Clements WM, Wang J, Sarnaik A, Kim OJ, MacDonald J, Fenoglio-Preiser C et al.| title=beta-Catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer. | journal=Cancer Res | year= 2002 | volume= 62 | issue= 12 | pages= 3503-6 | pmid=12067995 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12067995  }}</ref>  
* Beta-catenin is a part of Wnt signaling pathway which regulates coordination of individual events such as intercellular adhesion junctions, migration, proliferation, and differentiation.  
* [[Beta-catenin]] is a part of Wnt signaling pathway which regulates coordination of events such as intercellular adhesion junctions, migration, proliferation, and differentiation.  
* Beta-catenin is normally bound to protein complexes in the cell membrane that are involved in normal intercellular adhesions.   
* Beta-catenin is normally bound to protein complexes in the cell membrane that are involved in normal intercellular adhesions.   


* APC gene protein prevents the accumulation of beta-catenin. APC mutations lead to loss of regulation of beta-catenin which leads to proliferation, angiogenesis, tumor invasion, and metastasis of cells.<ref name="pmid16651426">{{cite journal| author=Lowy AM, Clements WM, Bishop J, Kong L, Bonney T, Sisco K et al.| title=beta-Catenin/Wnt signaling regulates expression of the membrane type 3 matrix metalloproteinase in gastric cancer. | journal=Cancer Res | year= 2006 | volume= 66 | issue= 9 | pages= 4734-41 | pmid=16651426 | doi=10.1158/0008-5472.CAN-05-4268 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16651426  }}</ref>
* [[APC]] [[gene]] [[protein]] prevents the accumulation of [[beta-catenin]]. [[APC]] [[mutations]] lead to loss of regulation of [[beta-catenin]] which leads to proliferation, [[angiogenesis]], tumor invasion, and [[metastasis]] of cells.<ref name="pmid16651426">{{cite journal| author=Lowy AM, Clements WM, Bishop J, Kong L, Bonney T, Sisco K et al.| title=beta-Catenin/Wnt signaling regulates expression of the membrane type 3 matrix metalloproteinase in gastric cancer. | journal=Cancer Res | year= 2006 | volume= 66 | issue= 9 | pages= 4734-41 | pmid=16651426 | doi=10.1158/0008-5472.CAN-05-4268 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16651426  }}</ref>
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=== '''Diffuse-type gastric cancer''' ===
=== '''Diffuse-type gastric cancer''' ===
* Diffuse gastric carcinomas do not have a precancerous lesion.
* Diffuse gastric carcinomas do not have a [[precancerous]] lesion.
* They are highly metastatic with a poorer prognosis than intestinal cancers. When the entire stomach wall is infiltrated, it results in a rigid thickened stomach wall called linitis plastic.<ref name="pmid14630673">{{cite journal| author=Graziano F, Humar B, Guilford P| title=The role of the E-cadherin gene (CDH1) in diffuse gastric cancer susceptibility: from the laboratory to clinical practice. | journal=Ann Oncol | year= 2003 | volume= 14 | issue= 12 | pages= 1705-13 | pmid=14630673 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14630673  }}</ref>
* They are highly [[Metastasis|metastatic]] with a poorer [[prognosis]] than [[Intestine|intestinal]] cancers. When the entire [[stomach]] wall is infiltrated, it results in a rigid thickened stomach wall called [[Linitis plastica|linitis plastic]].<ref name="pmid14630673">{{cite journal| author=Graziano F, Humar B, Guilford P| title=The role of the E-cadherin gene (CDH1) in diffuse gastric cancer susceptibility: from the laboratory to clinical practice. | journal=Ann Oncol | year= 2003 | volume= 14 | issue= 12 | pages= 1705-13 | pmid=14630673 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14630673  }}</ref>
* Intracellular mucin is accumulating pushing the nucleus giving the histological figure of signet ring carcinoma.  
* Intracellular [[mucin]] is accumulating pushing the [[Cell nucleus|nucleus]] giving the histological figure of [[Signet ring cell|signet ring carcinoma]].  
* The E-cadherin gene (CDH1) encodes a transmembrane cellular adhesion protein. Its cytoplasmic tail interacts with catenins making the adhesion.
* The [[E-cadherin]] [[gene]] (CDH1) encodes a [[Transmembrane protein|transmembrane cellular adhesion protein]]. Its [[Cytoplasm|cytoplasmic]] tail interacts with [[Catenin|catenins]] making the adhesion.
* Somatic mutations in the ''CDH1'' gene by hypermethylation, mutation, and loss of heterozygosity are identified in 40 to 83 percent of sporadic diffuse-type gastric cancers.<ref name="pmid16555931">{{cite journal| author=Ramos-de la Medina A, More H, Medina-Franco H, Humar B, Gamboa A, Ortiz LJ et al.| title=Single nucleotide polymorphisms (SNPs) at CDH1 promoter region in familial gastric cancer. | journal=Rev Esp Enferm Dig | year= 2006 | volume= 98 | issue= 1 | pages= 36-41 | pmid=16555931 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16555931  }}</ref>  
* [[Somatic]] [[mutations]] in the ''[[CDH11|CDH1]]'' gene by hypermethylation, [[mutation]], and [[loss of heterozygosity]] are identified in 40 to 83 percent of sporadic diffuse-type gastric cancers.<ref name="pmid16555931">{{cite journal| author=Ramos-de la Medina A, More H, Medina-Franco H, Humar B, Gamboa A, Ortiz LJ et al.| title=Single nucleotide polymorphisms (SNPs) at CDH1 promoter region in familial gastric cancer. | journal=Rev Esp Enferm Dig | year= 2006 | volume= 98 | issue= 1 | pages= 36-41 | pmid=16555931 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16555931  }}</ref>  
* Prostate stem cell antigen gene is also involved in regulating gastric epithelial cell proliferation.<ref name="pmid18488030">{{cite journal| author=Study Group of Millennium Genome Project for Cancer. Sakamoto H, Yoshimura K, Saeki N, Katai H, Shimoda T et al.| title=Genetic variation in PSCA is associated with susceptibility to diffuse-type gastric cancer. | journal=Nat Genet | year= 2008 | volume= 40 | issue= 6 | pages= 730-40 | pmid=18488030 | doi=10.1038/ng.152 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18488030  }}</ref>
* Prostate stem cell antigen gene is also involved in regulating gastric [[Epithelium|epithelial cell]] proliferation.<ref name="pmid18488030">{{cite journal| author=Study Group of Millennium Genome Project for Cancer. Sakamoto H, Yoshimura K, Saeki N, Katai H, Shimoda T et al.| title=Genetic variation in PSCA is associated with susceptibility to diffuse-type gastric cancer. | journal=Nat Genet | year= 2008 | volume= 40 | issue= 6 | pages= 730-40 | pmid=18488030 | doi=10.1038/ng.152 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18488030  }}</ref>


=== Apoptosis pathway ===
=== Apoptosis pathway ===


==== '''Neutrophil activation''' ====
==== '''Neutrophil activation''' ====
* ''H. pylori'' infection results in the migration of neutrophils to the site of infection and adhesion to the surface epithelium.
* ''[[Helicobacter pylori|H. pylori]]'' infection results in the migration of [[neutrophils]] to the site of infection and adhesion to the surface [[epithelium]].
* The neutrophils produce nitric oxide synthase which damage DNA.  
* The [[Neutrophil|neutrophils]] produce [[nitric oxide synthase]] which damage [[DNA]].  
* CD11a/CD18- and CD11b/CD18-neutrophils interact with intercellular adhesion molecule-1 (ICAM-1).<ref name="pmid11556297">{{cite journal| author=Uemura N, Okamoto S, Yamamoto S, Matsumura N, Yamaguchi S, Yamakido M et al.| title=Helicobacter pylori infection and the development of gastric cancer. | journal=N Engl J Med | year= 2001 | volume= 345 | issue= 11 | pages= 784-9 | pmid=11556297 | doi=10.1056/NEJMoa001999 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11556297  }}</ref>
* [[CD11a]]/[[CD18]]- and [[CD11b]]/CD18[[Neutrophil|-neutrophils]] interact with [[intercellular adhesion molecule-1]] (ICAM-1).<ref name="pmid11556297">{{cite journal| author=Uemura N, Okamoto S, Yamamoto S, Matsumura N, Yamaguchi S, Yamakido M et al.| title=Helicobacter pylori infection and the development of gastric cancer. | journal=N Engl J Med | year= 2001 | volume= 345 | issue= 11 | pages= 784-9 | pmid=11556297 | doi=10.1056/NEJMoa001999 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11556297  }}</ref>
* Epithelial cells respond by signaling pathways leading to apoptosis, proliferation, differentiation, and autophagy.
* [[Epithelial cells]] respond by signaling pathways leading to [[apoptosis]], proliferation, differentiation, and autophagy.


==== '''Apoptotic pathways''' ====
==== '''Apoptotic pathways''' ====
* Apoptosis occurs as a protective mechanism to prevent replication of mutated DNA which leads to atrophy of epithelium so called atrophic gastritis which returns to normal following eradication therapy.<ref name="pmid11197247">{{cite journal| author=Xia HH, Talley NJ| title=Apoptosis in gastric epithelium induced by Helicobacter pylori infection: implications in gastric carcinogenesis. | journal=Am J Gastroenterol | year= 2001 | volume= 96 | issue= 1 | pages= 16-26 | pmid=11197247 | doi=10.1111/j.1572-0241.2001.03447.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11197247  }}</ref>  
* [[Apoptosis]] occurs as a protective mechanism to prevent replication of mutated DNA which leads to atrophy of epithelium so called atrophic gastritis which returns to normal following eradication therapy.<ref name="pmid11197247">{{cite journal| author=Xia HH, Talley NJ| title=Apoptosis in gastric epithelium induced by Helicobacter pylori infection: implications in gastric carcinogenesis. | journal=Am J Gastroenterol | year= 2001 | volume= 96 | issue= 1 | pages= 16-26 | pmid=11197247 | doi=10.1111/j.1572-0241.2001.03447.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11197247  }}</ref>  
* ''H. pylori'' enhances expression of the Fas receptor on gastric epithelial cells and may mediate apoptosis through signaling mechanisms related to the Fas death receptor.
* ''[[Helicobacter pylori|H. pylori]]'' enhances expression of the Fas receptor on gastric epithelial cells and may mediate apoptosis through signaling mechanisms related to the Fas death receptor.
* Another trial supported that the source of tumorigenesis is from bone marrow-derived cells that differentiate into gastric epithelial cells in the presence of ''H. pylori.''<ref name="pmid15567866">{{cite journal| author=Houghton J, Stoicov C, Nomura S, Rogers AB, Carlson J, Li H et al.| title=Gastric cancer originating from bone marrow-derived cells. | journal=Science | year= 2004 | volume= 306 | issue= 5701 | pages= 1568-71 | pmid=15567866 | doi=10.1126/science.1099513 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15567866  }}</ref>
* Another trial supported that the source of tumorigenesis is from [[bone marrow]]-derived cells that differentiate into gastric [[epithelial cells]] in the presence of ''[[Helicobacter pylori|H. pylori]].''<ref name="pmid15567866">{{cite journal| author=Houghton J, Stoicov C, Nomura S, Rogers AB, Carlson J, Li H et al.| title=Gastric cancer originating from bone marrow-derived cells. | journal=Science | year= 2004 | volume= 306 | issue= 5701 | pages= 1568-71 | pmid=15567866 | doi=10.1126/science.1099513 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15567866  }}</ref>
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Line 173: Line 173:
|'''Epithelial tumors'''
|'''Epithelial tumors'''
|
|
* '''Adenoma'''
* '''[[Adenoma]]'''
* '''Carcinoma'''
* '''[[Carcinoma]]'''
* Adenocarcinoma
* [[Adenocarcinoma]]
* Intestinal type
* Intestinal type
* Diffuse type
* Diffuse type
* Papillary adenocarcinoma
* [[Papillary]] adenocarcinoma
* Tubular adenocarcinoma
* [[Tubular]] adenocarcinoma
* Mucinous adenocarcinoma
* [[Mucinous]] adenocarcinoma
* Signet-ring cell carcinoma
* [[Signet ring cell|Signet-ring cell]] carcinoma
* Adenosquamous carcinoma
* [[Adenosquamous carcinoma]]
* Squamous cell carcinoma
* [[Squamous cell carcinoma]]
* Small cell carcinoma
* [[Small cell carcinoma]]
* Undifferentiated carcinoma
* Undifferentiated carcinoma


Line 190: Line 190:
|-
|-
|'''Non-epithelial tumors'''
|'''Non-epithelial tumors'''
|Leiomyoma
|[[Leiomyoma]]
Schwannoma
[[Schwannoma]]


Granular cell tumour
[[Granular cell tumor]]


Glomus tumour
[[Glomus tumor]]


Leiomyosarcoma
[[Leiomyosarcoma]]


GI stromal tumour
GI stromal tumor


Benign
Benign
Line 207: Line 207:
Malignant
Malignant


Kaposi sarcoma
[[Kaposi's sarcoma|Kaposi sarcoma]]
|-
|-
|'''Malignant lymphomas'''
|'''Malignant lymphomas'''
|Marginal zone B-cell lymphoma of MALT-type
|Marginal zone B-cell lymphoma of MALT-type
Mantle cell lymphoma
[[Mantle cell lymphoma]]


Diffuse large B-cell lymphoma
[[Diffuse large B cell lymphoma|Diffuse large B-cell lymphoma]]
|}
|}


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|
|
===== Benign epithelial tumor =====
===== Benign epithelial tumor =====
Adenoma  
[[Adenoma]]


===== Malignant epithelial tumor =====
===== Malignant epithelial tumor =====

Revision as of 21:47, 20 November 2017


Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Parminder Dhingra, M.D. [2]

Stomach cancer Microchapters

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Overview

The pathophysiology of stomach cancer depends on histologic subtypes.

Physiology of stomach

  • The stomach consists of two functional areas; oxyntic and pyloric glands. The oxyntic area contains parietal cells that produce gastric acid.
  • The antrum contains pyloric glands that secrete gastrin and somatostatin.

Pathophysiology

Molecular effect of H.pylori:

  • The exact pathway for oncogenesis is not known but many trials supported the adenoma-carcinoma sequence.

Oncogenes

Tumor suppressor genes

Cell cycle regulatory molecules

Epigenetic events

{{#ev:youtube|_aAhcNjmvhc}}

Beta-catenin/Wnt signaling

  • Beta-catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer.[15]
  • Beta-catenin is a part of Wnt signaling pathway which regulates coordination of events such as intercellular adhesion junctions, migration, proliferation, and differentiation.
  • Beta-catenin is normally bound to protein complexes in the cell membrane that are involved in normal intercellular adhesions.

{{#ev:youtube|oweNT288BXo}}

Diffuse-type gastric cancer

Apoptosis pathway

Neutrophil activation 

Apoptotic pathways

  • Apoptosis occurs as a protective mechanism to prevent replication of mutated DNA which leads to atrophy of epithelium so called atrophic gastritis which returns to normal following eradication therapy.[21]
  • H. pylori enhances expression of the Fas receptor on gastric epithelial cells and may mediate apoptosis through signaling mechanisms related to the Fas death receptor.
  • Another trial supported that the source of tumorigenesis is from bone marrow-derived cells that differentiate into gastric epithelial cells in the presence of H. pylori.[22]

{{#ev:youtube|SyvOPXeg4ig}}

 
 
 
 
 
 
 
 
Helicobacter pylori infection
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inflammatory response
secretes IL-8 ,IL-1b
 
 
 
 
Production of
alkaline ammonia
 
 
 
 
Production of urease
bacterial phospholipase A
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Infux of neutophils and macrophages
release of lysosomal enzymes
leukotrienes (LT)and
reactive oxygen
 
 
 
 
inhibition of D-cells
leads to inappropriate release of somatostatin
and hypergastrinemia
 
 
 
 
Production of urease
,phospholipase
A and C
release toxic metabolities
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mucosal injury
 
 
 
 
 


Associated disorders

Familial predisposition

  • Although most gastric cancers are sporadic, 10 percent of cases are familial.

Hereditary diffuse gastric cancer

  • Clinical criteria for HDGC as described by the International Gastric Cancer Linkage Consortium (IGCLC).[23]
  • Germline truncating mutations in the CDH1 gene, which encodes the cell adhesion protein E-cadherin, have been identified HDGC is inherited as an autosomal dominant trait with high penetrance.[24]
  • The cumulative risk for gastric cancer by age 80 for CDH1 mutation carriers is up to 70 percent in men and up to 56 percent in women.[25]
  • Promoter hypermethylation, mutation, and loss of heterozygosity. The end result is loss of expression of the cell adhesion molecule E-cadherin.
  • The risk of gastric cancer in asymptomatic carriers of a pathogenetic CDH1 mutation who belong to families with highly penetrant hereditary diffuse gastric cancer is sufficiently high to warrant prophylactic gastrectomy.
  • Women in these affected families are also at high risk of developing breast cancer, predominantly lobular. The cumulative risk of breast cancer to age 80 for CDH1 mutation carriers is approximately 42 percent, and like the gastric cancers, the increased relative risk starts early.

Gastric Adenocarcinoma and Proximal Polyposis of the Stomach (GAPPS)

  • GAPPS was characterized by the autosomal dominant transmission of fundic gland polyposis that is restricted to the proximal stomach, with no evidence of duodenal or colorectal polyposis or other hereditary gastrointestinal (GI) cancer syndrome.[26]

Familial intestinal gastric cancer

  • FIGC should be considered a potential diagnosis when histopathological reports denote intestinal-type gastric cancers that segregate within families without gastric polyposis.[27]

Other hereditary cancer syndromes:[27]

  • Lynch syndrome (hereditary nonpolyposis colorectal cancer)
  • Familial adenomatous polyposis (FAP)
  • Li-Fraumeni syndrome
  • Peutz Jeghers syndrome
  • juvenile polyposis
  • Hereditary breast and ovarian cancer syndrome
  • Cowden's syndrome

Gross pathology

Type Description
Type 0  (superficial) Typical of T1 tumors.
Type 1 (mass) Polypoid tumors sharply demarcated from the

surrounding mucosa.

Type 2 (ulcerative) Ulcerated tumors with raised margins

surrounded by a thickened gastric wall with

clear margins.

Type 3 (infiltrative ulcerative)

Ulcerated tumors with raised margins,

surrounded by a thickened gastric wall

without clear margins

Type 4 (diffuse infiltrative)

Tumors without marked ulceration or raised

margins, the gastric wall is thickened and

indurated and the margin is unclear.

Type 5 (unclassifiable)

Tumors that cannot be classified into any of the

above types.

Video shows growth pathology of gastric cancer

{{#ev:youtube|ih-npVIJA6U}}

Image shows gastric adenocarcinoma linitis plastica, source: Case courtesy of Dr Andrew Ryan, Radiopaedia.org, rID: 16159


Histopathology

  • Gastric adenocarcinoma is a malignant epithelial tumor, originating from glandular epithelium of the gastric mucosa. It invades the gastric wall, infiltrating the muscularis mucosae, the submucosa and hence the muscular propria. Histologically, there are two major types of gastric cancer (Lauren classification): intestinal type and diffuse type.
    • Intestinal type adenocarcinoma: Tumor cells describe irregular tubular structures, harboring pluristratification, multiple lumens, and reduced stroma ("back to back" aspect). Often, it associates intestinal metaplasia in neighboring mucosa. Depending on glandular architecture, cellular pleomorphism and mucosecretion, adenocarcinoma may present 3 degrees of differentiation: well, moderate and poorly differentiated.
    • Diffuse type adenocarcinoma (mucinous, colloid): tumor cells are discohesive and secrete mucus which is delivered in the interstitium producing large pools of mucus/colloid (optically "empty" spaces). It is poorly differentiated. If the mucus remains inside the tumor cell, it pushes the nucleus at the periphery - "signet-ring cell".

World Health Organization histological classification of gastric tumors:

Types Histological features
Epithelial tumors
  • Carcinoid (well differentiated endocrine neoplasm)
Non-epithelial tumors Leiomyoma

Schwannoma

Granular cell tumor

Glomus tumor

Leiomyosarcoma

GI stromal tumor

Benign

Uncertain malignant potential

Malignant

Kaposi sarcoma

Malignant lymphomas Marginal zone B-cell lymphoma of MALT-type

Mantle cell lymphoma

Diffuse large B-cell lymphoma

Japanese histological classification of gastric tumors:

Types Histological features
Epithelial tumors
Benign epithelial tumor

Adenoma

Malignant epithelial tumor

Common type

Papillary adenocarcinoma

Tubular adenocarcinoma

Well-differentiated

Moderately differentiated

Poorly differentiated adenocarcinoma

Solid type

Non-solid type

Signet-ring cell carcinoma

Mucinous adenocarcinoma 

Special types Carcinoid tumor

Endocrine carcinoma

Carcinoma with lymphoid stroma

Hepatoid adenocarcinoma

Adenosquamous carcinoma

Squamous cell carcinoma

Undifferentiated carcinoma

Miscellaneous carcinoma Non-epithelial tumor

Gastrointestinal stromal tumor (GIST)

Smooth muscle tumor

Neurogenic tumor

Miscellaneous non-epithelial tumors

Lymphoma

B-cell lymphoma

MALT (mucosa-associated lymphoid tissue) lymphoma

Follicular lymphoma

Mantle cell lymphoma

Diffuse large B-cell lymphoma

Other B-cell lymphomas

T-cell lymphoma

Other lymphomas

Metastatic tumor

Tumor-like lesion

Hyperplastic polyp

Fundic gland polyp

Heterotopic submucosal gland

Heterotopic pancreas

Inflammatory fibroid polyp

Gastrointestinal polyposis

Familial polyposis coli, Peutz–Jeghers syndrome

Adrenocortical carcinoma,source: Public Domain, https://commons.wikimedia.org/w/index.php?curid=182915
signet ring appearance gastric cancer, source: CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=502927


Video shows microscopic pathology of gastric cancer {{#ev:youtube|lRvq1fEW8sY}} {{#ev:youtube|lWeECaiEfSs}}


References

  1. ↑ Eslick GD, Lim LL, Byles JE, Xia HH, Talley NJ (1999). "Association of Helicobacter pylori infection with gastric carcinoma: a meta-analysis". Am J Gastroenterol. 94 (9): 2373–9. doi:10.1111/j.1572-0241.1999.01360.x. PMID 10483994.
  2. ↑ Mera R, Fontham ET, Bravo LE, Bravo JC, Piazuelo MB, Camargo MC; et al. (2005). "Long term follow up of patients treated for Helicobacter pylori infection". Gut. 54 (11): 1536–40. doi:10.1136/gut.2005.072009. PMC 1462952. PMID 15985559.
  3. ↑ Mannick EE, Bravo LE, Zarama G, Realpe JL, Zhang XJ, Ruiz B; et al. (1996). "Inducible nitric oxide synthase, nitrotyrosine, and apoptosis in Helicobacter pylori gastritis: effect of antibiotics and antioxidants". Cancer Res. 56 (14): 3238–43. PMID 8764115.
  4. ↑ Yasui W, Oue N, Kuniyasu H, Ito R, Tahara E, Yokozaki H (2001). "Molecular diagnosis of gastric cancer: present and future". Gastric Cancer. 4 (3): 113–21. doi:10.1007/s101200100001. PMID 11760076.
  5. ↑ Smith MG, Hold GL, Tahara E, El-Omar EM (2006). "Cellular and molecular aspects of gastric cancer". World J Gastroenterol. 12 (19): 2979–90. PMC 4124370. PMID 16718776.
  6. ↑ Ushiku T, Chong JM, Uozaki H, Hino R, Chang MS, Sudo M; et al. (2007). "p73 gene promoter methylation in Epstein-Barr virus-associated gastric carcinoma". Int J Cancer. 120 (1): 60–6. doi:10.1002/ijc.22275. PMID 17058198.
  7. ↑ Ashktorab H, Ahmed A, Littleton G, Wang XW, Allen CR, Tackey R; et al. (2003). "p53 and p14 increase sensitivity of gastric cells to H. pylori-induced apoptosis". Dig Dis Sci. 48 (7): 1284–91. PMID 12870784.
  8. ↑ Kodama M, Murakami K, Okimoto T, Sato R, Watanabe K, Fujioka T (2007). "Expression of mutant type-p53 products in H pylori-associated chronic gastritis". World J Gastroenterol. 13 (10): 1541–6. PMC 4146896. PMID 17461446.
  9. ↑ Nakatsuru S, Yanagisawa A, Furukawa Y, Ichii S, Kato Y, Nakamura Y; et al. (1993). "Somatic mutations of the APC gene in precancerous lesion of the stomach". Hum Mol Genet. 2 (9): 1463–5. PMID 8242071.
  10. ↑ Leung WK, Yu J, Chan FK, To KF, Chan MW, Ebert MP; et al. (2002). "Expression of trefoil peptides (TFF1, TFF2, and TFF3) in gastric carcinomas, intestinal metaplasia, and non-neoplastic gastric tissues". J Pathol. 197 (5): 582–8. doi:10.1002/path.1147. PMID 12210076.
  11. ↑ Bani-Hani KE, Almasri NM, Khader YS, Sheyab FM, Karam HN (2005). "Combined evaluation of expressions of cyclin E and p53 proteins as prognostic factors for patients with gastric cancer". Clin Cancer Res. 11 (4): 1447–53. doi:10.1158/1078-0432.CCR-04-1730. PMID 15746045.
  12. ↑ Takano Y, Kato Y, van Diest PJ, Masuda M, Mitomi H, Okayasu I (2000). "Cyclin D2 overexpression and lack of p27 correlate positively and cyclin E inversely with a poor prognosis in gastric cancer cases". Am J Pathol. 156 (2): 585–94. doi:10.1016/S0002-9440(10)64763-3. PMC 1850035. PMID 10666388.
  13. ↑ Yasui W, Sentani K, Motoshita J, Nakayama H (2006). "Molecular pathobiology of gastric cancer". Scand J Surg. 95 (4): 225–31. doi:10.1177/145749690609500403. PMID 17249269.
  14. ↑ Bernal C, Aguayo F, Villarroel C, Vargas M, Díaz I, Ossandon FJ; et al. (2008). "Reprimo as a potential biomarker for early detection in gastric cancer". Clin Cancer Res. 14 (19): 6264–9. doi:10.1158/1078-0432.CCR-07-4522. PMID 18829507.
  15. ↑ Clements WM, Wang J, Sarnaik A, Kim OJ, MacDonald J, Fenoglio-Preiser C; et al. (2002). "beta-Catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer". Cancer Res. 62 (12): 3503–6. PMID 12067995.
  16. ↑ Lowy AM, Clements WM, Bishop J, Kong L, Bonney T, Sisco K; et al. (2006). "beta-Catenin/Wnt signaling regulates expression of the membrane type 3 matrix metalloproteinase in gastric cancer". Cancer Res. 66 (9): 4734–41. doi:10.1158/0008-5472.CAN-05-4268. PMID 16651426.
  17. ↑ Graziano F, Humar B, Guilford P (2003). "The role of the E-cadherin gene (CDH1) in diffuse gastric cancer susceptibility: from the laboratory to clinical practice". Ann Oncol. 14 (12): 1705–13. PMID 14630673.
  18. ↑ Ramos-de la Medina A, More H, Medina-Franco H, Humar B, Gamboa A, Ortiz LJ; et al. (2006). "Single nucleotide polymorphisms (SNPs) at CDH1 promoter region in familial gastric cancer". Rev Esp Enferm Dig. 98 (1): 36–41. PMID 16555931.
  19. ↑ Study Group of Millennium Genome Project for Cancer. Sakamoto H, Yoshimura K, Saeki N, Katai H, Shimoda T; et al. (2008). "Genetic variation in PSCA is associated with susceptibility to diffuse-type gastric cancer". Nat Genet. 40 (6): 730–40. doi:10.1038/ng.152. PMID 18488030.
  20. ↑ Uemura N, Okamoto S, Yamamoto S, Matsumura N, Yamaguchi S, Yamakido M; et al. (2001). "Helicobacter pylori infection and the development of gastric cancer". N Engl J Med. 345 (11): 784–9. doi:10.1056/NEJMoa001999. PMID 11556297.
  21. ↑ Xia HH, Talley NJ (2001). "Apoptosis in gastric epithelium induced by Helicobacter pylori infection: implications in gastric carcinogenesis". Am J Gastroenterol. 96 (1): 16–26. doi:10.1111/j.1572-0241.2001.03447.x. PMID 11197247.
  22. ↑ Houghton J, Stoicov C, Nomura S, Rogers AB, Carlson J, Li H; et al. (2004). "Gastric cancer originating from bone marrow-derived cells". Science. 306 (5701): 1568–71. doi:10.1126/science.1099513. PMID 15567866.
  23. ↑ Hansford S, Kaurah P, Li-Chang H, Woo M, Senz J, Pinheiro H; et al. (2015). "Hereditary Diffuse Gastric Cancer Syndrome: CDH1 Mutations and Beyond". JAMA Oncol. 1 (1): 23–32. doi:10.1001/jamaoncol.2014.168. PMID 26182300.
  24. ↑ van der Post RS, Vogelaar IP, Carneiro F, Guilford P, Huntsman D, Hoogerbrugge N; et al. (2015). "Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers". J Med Genet. 52 (6): 361–74. doi:10.1136/jmedgenet-2015-103094. PMC 4453626. PMID 25979631.
  25. ↑ van der Post RS, Vogelaar IP, Manders P, van der Kolk LE, Cats A, van Hest LP; et al. (2015). "Accuracy of Hereditary Diffuse Gastric Cancer Testing Criteria and Outcomes in Patients With a Germline Mutation in CDH1". Gastroenterology. 149 (4): 897–906.e19. doi:10.1053/j.gastro.2015.06.003. PMID 26072394.
  26. ↑ Brosens LA, Giardiello FM, Offerhaus GJ, Montgomery EA (2016). "Syndromic Gastric Polyps: At the Crossroads of Genetic and Environmental Cancer Predisposition". Adv Exp Med Biol. 908: 347–69. doi:10.1007/978-3-319-41388-4_17. PMID 27573780.
  27. ↑ 27.0 27.1 Choi YJ, Kim N (2016). "Gastric cancer and family history". Korean J Intern Med. 31 (6): 1042–1053. doi:10.3904/kjim.2016.147. PMC 5094936. PMID 27809451.

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