{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T10:09:00Z","timestamp":1790503740690,"version":"4.1.0"},"reference-count":27,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2013,1,18]],"date-time":"2013-01-18T00:00:00Z","timestamp":1358467200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancer"],"published-print":{"date-parts":[[2013,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>BACKGROUND:<\/jats:title><jats:p>Similar to the pancreatic intraepithelial neoplasia (PanIN)\u2010pancreatic carcinoma sequence model, intrahepatic cholangiocarcinoma (ICC) also reportedly follows a stepwise carcinogenesis process through the a precursor lesion: biliary intraepithelial neoplasia (BilIN). For this study, the authors investigated the status of v\u2010Ki\u2010<jats:italic>ras<\/jats:italic>2 Kirsten rat sarcoma viral oncogene homolog (<jats:italic>KRAS<\/jats:italic>) and <jats:italic>GNAS<\/jats:italic> complex locus (<jats:italic>GNAS<\/jats:italic>) mutations and tumor protein 53 (p53) overexpression in the stepwise process of cholangiocarcinogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS:<\/jats:title><jats:p>Thirty patients with hepatolithiasis were surveyed, and their lesions were categorized as follows: non\u2010neoplastic large bile duct (LBD) (n = 12), peribiliary gland (PBG) (n = 9), BilIN\u20101 (low\u2010grade dysplasia; n = 12), BilIN\u20102 (high\u2010grade dysplasia; n = 16), and BilIN\u20103 (noninvasive or in situ carcinoma; n = 10). <jats:italic>KRAS<\/jats:italic> mutation at codons 12 and 13 and <jats:italic>GNAS<\/jats:italic> mutations at codons 601 and 602 were analyzed using genomic DNA extracted from isolated lesions by laser capture microdissection. Immunohistochemical expression of p53 also was evaluated in BilIN lesions, ICCs, and extrahepatic cholangiocarcinomas (ExCCs).<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS:<\/jats:title><jats:p>A prevalence of <jats:italic>KRAS<\/jats:italic> mutations was identified in patients with ICC (31.5%), BilIN\u20103 (30%), and BilIN\u20102 (43.8%) compared with BilIN\u20101 (25%). Furthermore, <jats:italic>KRAS<\/jats:italic> mutations were detected in LBD lesions (41.7%) and PBG lesions (44.4%), and these mutations were observed with greater frequency in patients who had BilIN with <jats:italic>KRAS<\/jats:italic> mutations. <jats:italic>GNAS<\/jats:italic> mutations were not identified in any of the ICCs or other lesions examined. The overexpression of p53 was not identified in BilIN lesions and was less frequent in ICCs (18.2%) compared with ExCCs (38.1%) and gallbladder carcinomas (61.5%).<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS:<\/jats:title><jats:p><jats:italic>KRAS<\/jats:italic> mutations, which were present in approximately 33% of BilIN lesions, occurred as an early molecular event during the progression of BilIN to ICC, whereas p53 overexpression was identified as a late molecular event. Furthermore, the current results indicted that BilIN also may arise from LBD and PBG lesions in patients who have hepatolithiasis with <jats:italic>KRAS<\/jats:italic> mutations. Cancer 2013. \u00a9 2013 American Cancer Society.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cncr.27955","type":"journal-article","created":{"date-parts":[[2013,1,18]],"date-time":"2013-01-18T10:08:28Z","timestamp":1358503708000},"page":"1669-1674","source":"Crossref","is-referenced-by-count":117,"title":["<i>KRAS<\/i> and <i>GNAS<\/i> mutations and p53 overexpression in biliary intraepithelial neoplasia and intrahepatic cholangiocarcinomas"],"prefix":"10.1002","volume":"119","author":[{"given":"Maylee","family":"Hsu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motoko","family":"Sasaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saya","family":"Igarashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasunori","family":"Sato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuni","family":"Nakanuma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2013,1,18]]},"reference":[{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.22310"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2003.11.030"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1158\/1055-9965.EPI-05-0811"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(02)00297-0"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1746.1994.tb01221.x"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2005.09.025"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF01600212"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.510240516"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.24471"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.1097\/PAS.0b013e3181bc96f9"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.3800788"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00710556"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1827.2010.02543.x"},{"key":"e_1_2_6_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.722"},{"key":"e_1_2_6_16_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0701158104"},{"key":"e_1_2_6_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature02009"},{"key":"e_1_2_6_18_2","first-page":"1534","article-title":"Pancreatic adenocarcinomas frequently show p53 gene mutations","volume":"142","author":"Scarpa A","year":"1993","journal-title":"Am J Pathol."},{"key":"e_1_2_6_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(88)90571-5"},{"key":"e_1_2_6_20_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2011.12.042"},{"key":"e_1_2_6_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep00161"},{"key":"e_1_2_6_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2273"},{"key":"e_1_2_6_23_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2009.12.005"},{"key":"e_1_2_6_24_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0676.1987.tb00308.x"},{"key":"e_1_2_6_25_2","doi-asserted-by":"publisher","DOI":"10.1136\/gut.47.5.721"},{"key":"e_1_2_6_26_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00534-002-0729-3"},{"key":"e_1_2_6_27_2","doi-asserted-by":"publisher","DOI":"10.1002\/path.3017"},{"key":"e_1_2_6_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.humpath.2004.08.014"}],"container-title":["Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fcncr.27955","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acsjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cncr.27955","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T17:41:44Z","timestamp":1760290904000},"score":1,"resource":{"primary":{"URL":"https:\/\/acsjournals.onlinelibrary.wiley.com\/doi\/10.1002\/cncr.27955"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,1,18]]},"references-count":27,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2013,5]]}},"alternative-id":["10.1002\/cncr.27955"],"URL":"https:\/\/doi.org\/10.1002\/cncr.27955","archive":["Portico"],"relation":{},"ISSN":["0008-543X","1097-0142"],"issn-type":[{"value":"0008-543X","type":"print"},{"value":"1097-0142","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,1,18]]}}}