{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T11:54:01Z","timestamp":1792929241743,"version":"4.5.0"},"reference-count":43,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2018,11,14]],"date-time":"2018-11-14T00:00:00Z","timestamp":1542153600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["P30 CA008748"],"award-info":[{"award-number":["P30 CA008748"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acsjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer"],"published-print":{"date-parts":[[2019,2,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Although rare in the United States, gallbladder cancer (GBCA) is a common cause of cancer death in some parts of the world. To investigate regional differences in pathogenesis and outcomes for GBCA, tumor mutations were analyzed from a sampling of specimens.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Primary tumors from patients with GBCA who were treated in Chile, Japan, and the United States between 1999 and 2016 underwent targeted sequencing of known cancer\u2010associated genes. Fisher exact and Kruskal\u2010Wallis tests assessed differences in clinicopathologic and genetic factors. Kaplan\u2010Meier methods evaluated differences in overall survival from the time of surgery between mutations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A total of 81 patients were included. Japanese patients (11 patients) were older (median age, 72 years [range, 54\u201081 years]) compared with patients from Chile (21 patients; median age, 59 years [range, 32\u201073 years]) and the United States (49 patients; median age, 66 years [range, 46\u201087 years]) (\n                      <jats:italic>P\u00a0<\/jats:italic>\n                      =\u00a0.002) and had more well\u2010differentiated tumors (46% vs 0% for Chile\/United States;\n                      <jats:italic>P\u00a0<\/jats:italic>\n                      &lt;\n                      <jats:italic>\u00a0<\/jats:italic>\n                      .001) and fewer gallstone\u2010associated cancers (36% vs 67% for Chile and 69% for the United States;\n                      <jats:italic>P\u00a0<\/jats:italic>\n                      =\u00a0.13). Japanese patients had a median mutation burden of 6 (range, 1\u201023) compared with Chile (median mutation burden, 7 [range, 3\u201020]) and the United States (median mutation burden, 4 [range, 0\u201027]) (\n                      <jats:italic>P\u00a0<\/jats:italic>\n                      =\u00a0.006). Tumors from Japanese patients lacked AT\u2010rich interaction domain 1A (\n                      <jats:italic>ARID1A<\/jats:italic>\n                      ) and phosphatidylinositol\u20104,5\u2010bisphosphate 3\u2010kinase catalytic subunit alpha (\n                      <jats:italic>PIK3CA<\/jats:italic>\n                      ) mutations, whereas Chilean tumors lacked Erb\u2010B2 receptor tyrosine kinase 3 (\n                      <jats:italic>ERBB3<\/jats:italic>\n                      ) and AT\u2010rich interaction domain 2 (\n                      <jats:italic>ARID2<\/jats:italic>\n                      ) mutations. SMAD family member 4 (\n                      <jats:italic>SMAD4<\/jats:italic>\n                      ) was found to be mutated similarly across centers (38% in Chile, 36% in Japan, and 27% in the United States;\n                      <jats:italic>P\u00a0<\/jats:italic>\n                      =\u00a0.68) and was univariately associated with worse overall survival (median, 10 months vs 25 months;\n                      <jats:italic>P\u00a0<\/jats:italic>\n                      =\u00a0.039). At least one potentially actionable gene was found to be altered in 80% of tumors.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Differences in clinicopathologic variables suggest the possibility of distinct GBCA pathogenesis in Japanese patients, which may be supported by differences in mutation pattern. Among all centers,\n                      <jats:italic>SMAD4<\/jats:italic>\n                      mutations were detected in approximately one\u2010third of patients and may represent a converging factor associated with worse survival. The majority of patients carried mutations in actionable gene targets, which may inform the design of future trials.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cncr.31850","type":"journal-article","created":{"date-parts":[[2018,11,14]],"date-time":"2018-11-14T09:16:00Z","timestamp":1542186960000},"page":"575-585","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Regional differences in gallbladder cancer pathogenesis: Insights from a multi\u2010institutional comparison of tumor mutations"],"prefix":"10.1002","volume":"125","author":[{"given":"Raja R.","family":"Narayan","sequence":"first","affiliation":[{"name":"Hepatopancreatobiliary Service, Department of Surgery Memorial Sloan Kettering Cancer Center New York New York"},{"name":"Department of Surgery Stanford University School of Medicine Stanford California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John M.","family":"Creasy","sequence":"additional","affiliation":[{"name":"Hepatopancreatobiliary Service, Department of Surgery Memorial Sloan Kettering Cancer Center New York New York"},{"name":"Department of Surgery New York Presbyterian Hospital Weill Cornell Medical Center New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debra A.","family":"Goldman","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics Memorial Sloan Kettering Cancer Center New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mithat","family":"G\u00f6nen","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics Memorial Sloan Kettering Cancer Center New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cyriac","family":"Kandoth","sequence":"additional","affiliation":[{"name":"Marie\u2010Josee and Henry R. 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