{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T17:25:22Z","timestamp":1784913922387,"version":"3.55.0"},"reference-count":65,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2008,6,9]],"date-time":"2008-06-09T00:00:00Z","timestamp":1212969600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecular Carcinogenesis"],"published-print":{"date-parts":[[2009,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Gallbladder carcinoma (GBC) is a highly malignant neoplasm and represents the leading cause of cancer death in Chilean women. In order to determine the potential role of promoter methylation in gallbladder carcinogenesis, we investigated the frequency of this epigenetic mechanism by methylation\u2010specific polymerase chain reaction (MSP) in 35 chronic cholecystitis (CC, separated according to the presence or absence of metaplasia), 19 early cancers (mucosa or muscularis propia invasion) and 48 advanced carcinomas with invasion of the gallbladder subserosa (25 cases) and serosa (23 cases). We examined 14 genes and observed an increase of multigenic methylation during tumoral progression which was not significantly associated with the patient's age. Four genes (<jats:italic>DAPK1<\/jats:italic>, <jats:italic>DLC1<\/jats:italic>, <jats:italic>TIMP3<\/jats:italic>, and <jats:italic>RAR\u03b22<\/jats:italic>) displayed a progressive increase in their methylation status from CC without metaplasia to advanced carcinoma invading the serosa layer (<jats:italic>P<\/jats:italic>\u2009\u2264\u20090.05). The survival analysis indicated that a methylated condition of <jats:italic>DLC1<\/jats:italic> gene is significantly associated with poor prognosis (<jats:italic>P<\/jats:italic>\u2009=\u20090.04), whereas a methylated state of <jats:italic>MGMT<\/jats:italic> gene correlated with better patient survival (<jats:italic>P<\/jats:italic>\u2009=\u20090.006). Our findings indicate that aberrant hypermethylation of promoter regions is an early, progressive and cumulative event in gallbladder carcinogenesis. Furthermore, the methylation levels seems to accumulate in the progression of CC without metaplasia to CC with metaplasia, a fact that could provide new evidence to consider this morphological adaptation of GB mucosa as a premalignant lesion. Finally, the methylation status of some individual genes could be useful biomarkers with potential clinical application in diagnosis or prognosis of GBC if they are validated in a greater number of clinical samples. \u00a9 2008 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/mc.20457","type":"journal-article","created":{"date-parts":[[2008,6,9]],"date-time":"2008-06-09T16:47:32Z","timestamp":1213030052000},"page":"79-89","source":"Crossref","is-referenced-by-count":46,"title":["Promoter methylation profile in preneoplastic and neoplastic gallbladder lesions"],"prefix":"10.1002","volume":"48","author":[{"given":"Patricia","family":"Garc\u00eda","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Manterola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Carlos","family":"Araya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Villaseca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Guzm\u00e1n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Sanhueza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Thomas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e9ctor","family":"Alvarez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Carlos","family":"Roa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2008,6,9]]},"reference":[{"key":"e_1_2_7_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(03)01021-0"},{"key":"e_1_2_7_3_2","doi-asserted-by":"publisher","DOI":"10.3322\/canjclin.51.6.349"},{"key":"e_1_2_7_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6690101"},{"key":"e_1_2_7_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1429"},{"key":"e_1_2_7_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0142(19821115)50:10<2226::AID-CNCR2820501043>3.0.CO;2-3"},{"key":"e_1_2_7_7_2","first-page":"673","article-title":"Clinicopathological features of gallbladder polyps and adenomas","volume":"132","author":"Roa I","year":"2004","journal-title":"Rev Med Chil"},{"key":"e_1_2_7_8_2","first-page":"946","article-title":"Risk factor for extrahepatic bile duct cancer in patients pancreaticobiliary ductal union","volume":"51","author":"Jung YS","year":"2004","journal-title":"Hepatogastroenterology"},{"key":"e_1_2_7_9_2","first-page":"1369","article-title":"Inactivation of CDKN2A gene (p16) in gallbladder carcinoma","volume":"132","author":"Roa JC","year":"2004","journal-title":"Rev Med Chil"},{"key":"e_1_2_7_10_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-1137-3"},{"key":"e_1_2_7_11_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1440-1827.1999.00821.x"},{"key":"e_1_2_7_12_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1572-0241.1999.01155.x"},{"key":"e_1_2_7_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/1096-9098(200012)75:4<246::AID-JSO4>3.0.CO;2-V"},{"key":"e_1_2_7_14_2","first-page":"955","article-title":"K\u2010ras gene mutation in gallbladder carcinoma","volume":"132","author":"Roa JC","year":"2004","journal-title":"Rev Med Chil"},{"key":"e_1_2_7_15_2","doi-asserted-by":"publisher","DOI":"10.1245\/ASO.2003.02.014"},{"key":"e_1_2_7_16_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00535-005-1752-3"},{"key":"e_1_2_7_17_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-04-0579"},{"key":"e_1_2_7_18_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.45.120403.095832"},{"key":"e_1_2_7_19_2","first-page":"3225","article-title":"A gene hypermethylation profile of human cancer","volume":"61","author":"Esteller M","year":"2001","journal-title":"Cancer Res"},{"key":"e_1_2_7_20_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/10.26.3001"},{"key":"e_1_2_7_21_2","first-page":"1114","article-title":"A systematic profile of DNA methylation in human cancer cell lines","volume":"63","author":"Paz MF","year":"2003","journal-title":"Cancer Res"},{"key":"e_1_2_7_22_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.cco.0000147383.04709.10"},{"key":"e_1_2_7_23_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.18.9821"},{"key":"e_1_2_7_24_2","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v11.i9.1333"},{"key":"e_1_2_7_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)64262-9"},{"key":"e_1_2_7_26_2","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v10.i23.3441"},{"key":"e_1_2_7_27_2","first-page":"1157","article-title":"Expressions of cyclooxygenase\u20102 and prostaglandin E\u2010receptors in carcinoma of the gallbladder: Crucial role of arachidonate metabolism in tumor growth and progression","volume":"8","author":"Asano T","year":"2002","journal-title":"Clin Cancer Res"},{"key":"e_1_2_7_28_2","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.10222"},{"key":"e_1_2_7_29_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-0701-3"},{"key":"e_1_2_7_30_2","first-page":"2511","article-title":"Allele\u2010specific mutations involved in the pathogenesis of endemic gallbladder carcinoma in Chile","volume":"55","author":"Wistuba II","year":"1995","journal-title":"Cancer Res"},{"key":"e_1_2_7_31_2","doi-asserted-by":"publisher","DOI":"10.1007\/s004230100220"},{"key":"e_1_2_7_32_2","doi-asserted-by":"publisher","DOI":"10.1002\/jso.20527"},{"key":"e_1_2_7_33_2","first-page":"11","article-title":"Detection of acid mucins in gastric metaplasia of the gallbladder","volume":"37","author":"Buitrago Salassa C","year":"2007","journal-title":"Acta Gastroenterol Latinoam"},{"key":"e_1_2_7_34_2","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0142(19930915)72:6<1878::AID-CNCR2820720615>3.0.CO;2-2"},{"key":"e_1_2_7_35_2","doi-asserted-by":"crossref","first-page":"386","DOI":"10.5858\/2005-129-386-PPOGDA","article-title":"Putative precursors of gallbladder dysplasia: A review of 400 routinely resected specimens","volume":"129","author":"Mukhopadhyay S","year":"2005","journal-title":"Arch Pathol Lab Med"},{"key":"e_1_2_7_36_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00535-004-1497-4"},{"key":"e_1_2_7_37_2","doi-asserted-by":"publisher","DOI":"10.1615\/CritRevOncog.v12.i1-2.20"},{"key":"e_1_2_7_38_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2036.2001.01046.x"},{"key":"e_1_2_7_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mrfmmm.2006.05.029"},{"key":"e_1_2_7_40_2","doi-asserted-by":"publisher","DOI":"10.1006\/scbi.1999.0135"},{"key":"e_1_2_7_41_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1205600"},{"key":"e_1_2_7_42_2","first-page":"1031","article-title":"Frequent death\u2010associated protein\u2010kinase promoter brain metastases of solid tumors","volume":"10","author":"Gonzalez\u2010Gomez P","year":"2003","journal-title":"Oncol Rep"},{"key":"e_1_2_7_43_2","doi-asserted-by":"publisher","DOI":"10.1023\/A:1015364104672"},{"key":"e_1_2_7_44_2","first-page":"937","article-title":"Promoter hypermethylation of Death\u2010associated protein\u2010kinase gene associated with advance stage gastric cancer","volume":"13","author":"Chan AW","year":"2005","journal-title":"Oncol Rep"},{"key":"e_1_2_7_45_2","doi-asserted-by":"publisher","DOI":"10.1593\/neo.06802"},{"key":"e_1_2_7_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2005.08.034"},{"key":"e_1_2_7_47_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1349-7006.2003.tb01447.x"},{"key":"e_1_2_7_48_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1349-7006.2004.tb03254.x"},{"key":"e_1_2_7_49_2","first-page":"7646","article-title":"Genetic and epigenetic alterations of DLC\u20101 gene in hepatocellular carcinoma","volume":"63","author":"Wong CM","year":"2003","journal-title":"Cancer Res"},{"key":"e_1_2_7_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-4608(02)00674-X"},{"key":"e_1_2_7_51_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1206573"},{"key":"e_1_2_7_52_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1207291"},{"key":"e_1_2_7_53_2","doi-asserted-by":"publisher","DOI":"10.1136\/jcp.2005.031377"},{"key":"e_1_2_7_54_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI13709"},{"key":"e_1_2_7_55_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2407-2-29"},{"key":"e_1_2_7_56_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6602636"},{"key":"e_1_2_7_57_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.mpa.0000153325.62192.8a"},{"key":"e_1_2_7_58_2","first-page":"798","article-title":"Methylation\u2010associated silencing of the tissue inhibitor of metalloproteinase\u20103 gene suggest a suppressor role in kidney, brain, and other human cancers","volume":"59","author":"Bachman KE","year":"1999","journal-title":"Cancer Res"},{"key":"e_1_2_7_59_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10434-001-0807-9"},{"key":"e_1_2_7_60_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6600743"},{"key":"e_1_2_7_61_2","doi-asserted-by":"publisher","DOI":"10.1245\/ASO.2005.07.020"},{"key":"e_1_2_7_62_2","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.3800287"},{"key":"e_1_2_7_63_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0016-5085(03)00278-6"},{"key":"e_1_2_7_64_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/94.1.26"},{"key":"e_1_2_7_65_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-03-0384"},{"key":"e_1_2_7_66_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2007.03.013"}],"container-title":["Molecular Carcinogenesis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fmc.20457","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mc.20457","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,9]],"date-time":"2023-10-09T19:05:09Z","timestamp":1696878309000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/mc.20457"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,6,9]]},"references-count":65,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2009,1]]}},"alternative-id":["10.1002\/mc.20457"],"URL":"https:\/\/doi.org\/10.1002\/mc.20457","archive":["Portico"],"relation":{},"ISSN":["0899-1987","1098-2744"],"issn-type":[{"value":"0899-1987","type":"print"},{"value":"1098-2744","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,6,9]]}}}