{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T16:47:11Z","timestamp":1789577231018,"version":"build-2803163510"},"reference-count":47,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"12","license":[{"start":{"date-parts":[[2022,10,20]],"date-time":"2022-10-20T00:00:00Z","timestamp":1666224000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Chinese\u00a0Academy of Medical Sciences Innovation Fund for Medical Sciences","award":["2021\u2010I2M\u20101\u2010002"],"award-info":[{"award-number":["2021\u2010I2M\u20101\u2010002"]}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Commun"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">Neuroendocrine carcinomas of the gastrointestinal tract (GI\u2010NECs) remain a disease of grim prognosis with limited therapeutic options. Their molecular characteristics are still undefined. This study aimed to explore the underlying genetic basis and heterogeneity of GI\u2010NECs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p xml:lang=\"en\">Comprehensive genomic analysis using whole\u2010exome sequencing was performed on 143 formalin\u2010fixed, paraffin\u2010embedded samples of surgically resected GI\u2010NEC with a thorough histological evaluation. Mutational signatures, somatic mutations, and copy number aberrations were analyzed and compared across anatomic locations and histological subtypes. Survival analysis was conducted to identify the independent factors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      In total, 143 GI\u2010NECs were examined: the stomach, 87 cases (60.8%); the esophagus, 29 cases (20.3%); the colorectum, 20 cases (14.0%); and the small intestine, 7 cases (4.9%). Eighty\u2010three (58.0%) and 60 (42.0%) cases were subclassified into small cell and large cell subtypes, respectively. GI\u2010NECs showed distinct genetic alterations from their lung counterparts and non\u2010neuroendocrine carcinomas in the same locations. Obvious heterogeneity of mutational signatures, somatic mutations, and copy number variations was revealed across anatomic locations rather than histological subtypes. Except for tumor protein p53 (\n                      <jats:italic toggle=\"yes\">TP53<\/jats:italic>\n                      ) and retinoblastoma 1 (\n                      <jats:italic toggle=\"yes\">RB1<\/jats:italic>\n                      ), the most frequently mutated genes in the stomach, esophagus, colorectum, and small intestine were low\u2010density lipoprotein receptor\u2010related protein 1B (\n                      <jats:italic toggle=\"yes\">LRP1B<\/jats:italic>\n                      ), notch receptor 1 (\n                      <jats:italic toggle=\"yes\">NOTCH1<\/jats:italic>\n                      ), adenomatosis polyposis coli (\n                      <jats:italic toggle=\"yes\">APC<\/jats:italic>\n                      ), catenin beta 1 (\n                      <jats:italic toggle=\"yes\">CTNNB1<\/jats:italic>\n                      ), respectively. Mutations in the WNT\u2010\u03b2\u2010catenin, NOTCH and erythroblastic leukemia viral oncogene B (ERBB) pathways were prevalently identified in gastric, esophageal, and colorectal NECs, respectively. Importantly, 104 (72.7%) GI\u2010NECs harbored putative clinically relevant alterations, and non\u2010gastric location and\n                      <jats:italic toggle=\"yes\">RB1<\/jats:italic>\n                      bi\u2010allelic inactivation with copy number alterations were identified as two independent poor prognostic factors. Furthermore, we found that tumor cells in GI\u2010NECs first gain clonal mutations in\n                      <jats:italic toggle=\"yes\">TP53<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">RB1<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">NOTCH1<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">APC<\/jats:italic>\n                      , followed by subsequent whole\u2010genome doubling (WGD) and post\u2010WGD clonal mutations in\n                      <jats:italic toggle=\"yes\">LRP1B<\/jats:italic>\n                      , CUB and Sushi multiple domains 3 (\n                      <jats:italic toggle=\"yes\">CSMD3<\/jats:italic>\n                      ), FAT tumor suppressor homolog 4 (\n                      <jats:italic toggle=\"yes\">FAT4<\/jats:italic>\n                      ) and erb\u2010b2 receptor tyrosine kinase 4 (\n                      <jats:italic toggle=\"yes\">ERBB4<\/jats:italic>\n                      ), and finally develop subclonal mutations.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">GI\u2010NECs harbor distinct genomic landscapes and demonstrate significant genetic heterogeneity across different anatomic locations. Moreover, potentially actionable alterations and prognostic factors were revealed for GI\u2010NECs.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cac2.12372","type":"journal-article","created":{"date-parts":[[2022,10,20]],"date-time":"2022-10-20T10:55:17Z","timestamp":1666263317000},"page":"1367-1386","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Genomic characterization reveals distinct mutation landscapes and therapeutic implications in neuroendocrine carcinomas of the gastrointestinal tract"],"prefix":"10.34133","volume":"42","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3996-3176","authenticated-orcid":false,"given":"Huanwen","family":"Wu","sequence":"first","affiliation":[{"name":"Chinese Academy of Medical Sciences and Peking Union Medical College","place":["Beijing, P. R. 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