{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T20:11:59Z","timestamp":1790971919882,"version":"4.1.0"},"reference-count":49,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2020,9,12]],"date-time":"2020-09-12T00:00:00Z","timestamp":1599868800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2020,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The molecular and clinical characteristics of non\u2010ampullary duodenal adenomas and intramucosal adenocarcinomas are not fully understood because they are rare. To clarify these characteristics, we performed genetic and epigenetic analysis of cancer\u2010related genes in these lesions. One hundred and seven non\u2010ampullary duodenal adenomas and intramucosal adenocarcinomas, including 100 small intestinal\u2010type tumors (90 adenomas and 10 intramucosal adenocarcinomas) and 7 gastric\u2010type tumors (2 pyloric gland adenomas and 5 intramucosal adenocarcinomas), were investigated. Using bisulfite pyrosequencing, we assessed the methylation status of CpG island methylator phenotype (CIMP) markers and <jats:italic>MLH1<\/jats:italic>. Then using next\u2010generation sequencing, we performed targeted exome sequence analysis within 75 cancer\u2010related genes in 102 lesions. There were significant differences in the clinicopathological and molecular variables between small intestinal\u2010 and gastric\u2010type tumors, which suggests the presence of at least two separate carcinogenic pathways in non\u2010ampullary duodenal adenocarcinomas. The prevalence of CIMP\u2010positive lesions was higher in intramucosal adenocarcinomas than in adenomas. Thus, concurrent hypermethylation of multiple CpG islands is likely associated with development of non\u2010ampullary duodenal intramucosal adenocarcinomas. Mutation analysis showed that <jats:italic>APC<\/jats:italic> was the most frequently mutated gene in these lesions (56\/102; 55%), followed by <jats:italic>KRAS<\/jats:italic> (13\/102; 13%), <jats:italic>LRP1B<\/jats:italic> (10\/102; 10%), <jats:italic>GNAS<\/jats:italic> (8\/102; 8%), <jats:italic>ERBB3<\/jats:italic> (7\/102; 7%), and <jats:italic>RNF43<\/jats:italic> (6\/102; 6%). Additionally, the high prevalence of diffuse or focal nuclear <jats:bold>\u03b2<\/jats:bold>\u2010catenin accumulation (87\/102; 85%) as well as mutations of WNT pathway components (60\/102; 59%) indicates the importance of WNT signaling to the initiation of duodenal adenomas. The higher than previously reported frequency of <jats:italic>APC<\/jats:italic> gene mutations in small bowel adenocarcinomas as well as the difference in the <jats:italic>APC<\/jats:italic> mutation distributions between small intestinal\u2010type adenomas and intramucosal adenocarcinomas may indicate that the adenoma\u2013carcinoma sequence has only limited involvement in duodenal carcinogenesis. \u00a9 2020 The Authors. <jats:italic>The Journal of Pathology<\/jats:italic> published by John Wiley &amp; Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.5529","type":"journal-article","created":{"date-parts":[[2020,8,8]],"date-time":"2020-08-08T05:28:09Z","timestamp":1596864489000},"page":"330-342","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Integrated genetic and epigenetic analysis of cancer\u2010related genes in non\u2010ampullary duodenal adenomas and intramucosal adenocarcinomas"],"prefix":"10.1002","volume":"252","author":[{"given":"Ryosuke","family":"Ota","sequence":"first","affiliation":[{"name":"Division of Translational and Clinical Oncology, Cancer Research Institute Kanazawa University  Kanazawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8202-7789","authenticated-orcid":false,"given":"Takeshi","family":"Sawada","sequence":"additional","affiliation":[{"name":"Division of Translational and Clinical Oncology, Cancer Research Institute Kanazawa University  Kanazawa Japan"},{"name":"Department of Gastroenterology and Metabolism Nagoya City University Graduate School of Medical Sciences  Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sho","family":"Tsuyama","sequence":"additional","affiliation":[{"name":"Department of Human Pathology Juntendo University Graduate School of Medicine  Tokyo 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