{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T10:23:39Z","timestamp":1788863019092,"version":"build-2803163510"},"reference-count":51,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2017,11,17]],"date-time":"2017-11-17T00:00:00Z","timestamp":1510876800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["1ZIABCO11275\u20107"],"award-info":[{"award-number":["1ZIABCO11275\u20107"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancer"],"published-print":{"date-parts":[[2018,2]]},"abstract":"<jats:sec><jats:title>BACKGROUND<\/jats:title><jats:p>Nonfunctioning pancreatic neuroendocrine tumors (NFPanNETs) may be sporadic or inherited because of germline mutations associated with von Hippel\u2010Lindau disease (VHL) or multiple endocrine neoplasia type 1 (MEN1). The clinical behavior of NFPanNETs is difficult to predict, even in tumors of the same stage and grade. The authors analyzed genotype\u2010specific patterns of transcriptional messenger RNA (mRNA) levels of NFPanNETs to understand the molecular features that determine PanNET phenotype.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>Thirty\u2010two samples were included for genome\u2010wide mRNA gene expression analysis (9 VHL\u2010associated, 10 MEN1\u2010associated, and 9 sporadic NFPanNETs and 4 purified normal islet cell [NIC] samples). Validation of genes was performed by real\u2010time polymerase chain reaction analysis and immunohistochemistry. Gene expression profiles were analyzed by tumor genotype, and pathway analysis was curated.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>Consensus clustering of mRNA expression revealed separate clustering of NICs, VHL\u2010associated NFPanNETs, and MEN1\u2010associated NFPanNETs; whereas some sporadic tumors clustered with MEN1. Four of 5 MEN1\u2010like sporadic PanNET subtypes had loss of heterozygosity at the <jats:italic>MEN1<\/jats:italic> gene locus. Pathway analysis demonstrated subtype\u2010specific pathway activation, comprising angiogenesis and immune response in VHL; neuronal development in MEN1; protein ubiquitination in the new MEN1\/sporadic subtype; and cytokinesis and cilium\/microtubule development in sporadic NFPanNETs. Among many genes, platelet\u2010derived growth factor receptor \u03b2 (PDGFRB), lymphoid enhancer\u2010binding factor\u20101 (Lef\u20101), cyclin\u2010dependent kinase 4 (CDK4), and CDK6 were upregulated in VHL or MEN1 NFPanNETs, providing potential subtype\u2010specific treatment targets.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p>Distinct mRNA expression patterns were identified in sporadic\u2010associated, VHL\u2010associated, and MEN1\u2010associated NFPanNETs. The current results uncover new pathways involved in NFPanNETs that are subtype\u2010specific and provide potential new diagnostic or therapeutic targets based on tumor subtype. <jats:bold><jats:italic>Cancer<\/jats:italic> 2018;124:636\u201047<\/jats:bold>. \u00a9 <jats:italic>2017 American Cancer Society<\/jats:italic>.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cncr.31057","type":"journal-article","created":{"date-parts":[[2017,11,17]],"date-time":"2017-11-17T11:56:40Z","timestamp":1510919800000},"page":"636-647","source":"Crossref","is-referenced-by-count":10,"title":["Transcriptional alterations in hereditary and sporadic nonfunctioning pancreatic neuroendocrine tumors according to genotype"],"prefix":"10.1002","volume":"124","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4627-3560","authenticated-orcid":false,"given":"Xavier M.","family":"Keutgen","sequence":"first","affiliation":[{"name":"Endocrine Oncology Branch, Center for Cancer Research National Cancer Institute, National Institutes of Health Bethesda Maryland"},{"name":"Division of Surgical Oncology, Department of Surgery Rush University Medical Center Chicago Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suresh","family":"Kumar","sequence":"additional","affiliation":[{"name":"Endocrine Oncology Branch, Center for Cancer Research National Cancer Institute, National Institutes of Health Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sudheer","family":"Gara","sequence":"additional","affiliation":[{"name":"Endocrine Oncology Branch, Center for Cancer Research National Cancer Institute, National Institutes of Health Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myriem","family":"Boufraqech","sequence":"additional","affiliation":[{"name":"Endocrine Oncology Branch, Center for Cancer Research National Cancer Institute, National Institutes of Health Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunita","family":"Agarwal","sequence":"additional","affiliation":[{"name":"Metabolic Diseases Branch National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralph H.","family":"Hruban","sequence":"additional","affiliation":[{"name":"The Sol Goldman Pancreatic Cancer Research Center, Departments of Pathology and Oncology Johns Hopkins University School of Medicine Baltimore Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naris","family":"Nilubol","sequence":"additional","affiliation":[{"name":"Endocrine Oncology Branch, Center for Cancer Research National Cancer Institute, National Institutes of Health Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martha","family":"Quezado","sequence":"additional","affiliation":[{"name":"Department of Pathology National Cancer Institute, National Institutes of Health Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Finney","sequence":"additional","affiliation":[{"name":"Collaborative Bioinformatics Resource, Center for Cancer Research National Cancer Institute, National Institutes of Health Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maggie","family":"Cam","sequence":"additional","affiliation":[{"name":"Collaborative Bioinformatics Resource, Center for Cancer Research National Cancer Institute, National Institutes of Health Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5254-1456","authenticated-orcid":false,"given":"Electron","family":"Kebebew","sequence":"additional","affiliation":[{"name":"Endocrine Oncology Branch, Center for Cancer Research National Cancer Institute, National Institutes of Health Bethesda Maryland"},{"name":"Department of Surgery The George Washington University School of Medicine and Health Sciences Washington District of Columbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,11,17]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1677\/ERC-07-0221"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11605-007-0263-3"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.1976.03630070017007"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2016.37"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1294.002"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2015-3684"},{"key":"e_1_2_8_8_1","first-page":"63","article-title":"Management of pancreatic neuroendocrine tumors in patients with MEN 1","volume":"4","author":"Sadowski SM","year":"2015","journal-title":"Gland Surg"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1097\/SLA.0000000000000856"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.surg.2007.09.012"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11605-012-1847-0"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1053\/gast.2000.18143"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1067\/msy.1998.91823"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1200609"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-11-2105"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1677\/ERC-08-0297"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djt135"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(03)13643-4"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv007"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq170"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2796.1995.tb00929.x"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s004390050595"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2015.394"},{"key":"e_1_2_8_24_1","first-page":"2842","article-title":"Integrative microRNA\u2010mRNA and protein\u2010protein interaction analysis in pancreatic neuroendocrine tumors","volume":"20","author":"Zhou HQ","year":"2016","journal-title":"Eur Rev Med Pharmacol Sci"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.3171\/2011.5.JNS11271"},{"key":"e_1_2_8_26_1","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1159\/000444280","article-title":"Effects of somatostatin analogs and dopamine agonists on insulin\u2010like growth factor 2\u2010induced insulin receptor isoform A activation by gastroenteropancreatic neuroendocrine tumor cells","volume":"103","author":"Adrichem RC","year":"2016","journal-title":"Neuroendocrinology"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.03-1280fje"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2008.21.5988"},{"key":"e_1_2_8_29_1","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1677\/ERC-10-0037","article-title":"Systematic comparison of sporadic and syndromic pancreatic islet cell tumors","volume":"17","author":"Erlic Z","year":"2010","journal-title":"Endocrine Relat Cancer"},{"key":"e_1_2_8_30_1","first-page":"3367","article-title":"Microarray based analysis of gene expression patterns in pancreatic neuroendocrine tumors","volume":"19","author":"Wang DD","year":"2015","journal-title":"Eur Rev Med Pharmacol Sci"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.2337\/db05-0450"},{"key":"e_1_2_8_32_1","doi-asserted-by":"crossref","first-page":"2838","DOI":"10.1158\/1078-0432.CCR-11-2759","article-title":"Molecular profiling of pancreatic neuroendocrine tumors in sporadic and von Hippel\u2010Lindau patients","volume":"18","author":"Speisky D","year":"2012","journal-title":"Clin Cancer Res"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms3612"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-15-0068"},{"key":"e_1_2_8_35_1","first-page":"413","article-title":"Identification of molecular markers specific for pancreatic neuroendocrine tumors by genetic profiling of core biopsies. Ann Surg","volume":"11","author":"Bloomston M","year":"2004","journal-title":"Oncol"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1677\/ERC-07-0194"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2007-0331TR"},{"key":"e_1_2_8_38_1","first-page":"2120","article-title":"Tumor\u2010infiltrating regulatory T cells are positively correlated with angiogenic status in renal cell carcinoma","volume":"125","author":"Ning H","year":"2012","journal-title":"Chin Med J (Engl)"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10555-011-9281-4"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.4161\/cbt.25643"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.29947"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1080\/02841860601048388"},{"key":"e_1_2_8_43_1","first-page":"3584","article-title":"Inhibition of platelet\u2010derived growth factor\u2010mediated proliferation of osteosarcoma cells by the novel tyrosine kinase inhibitor STI571","volume":"8","author":"McGary EC","year":"2002","journal-title":"Clin Cancer Res"},{"issue":"10","key":"e_1_2_8_44_1","first-page":"3779","article-title":"STI571 enhances the therapeutic index of epothilone B by a tumor\u2010selective increase of drug uptake","volume":"9","author":"Pietras K","year":"2003","journal-title":"Clin Cancer Res"},{"key":"e_1_2_8_45_1","first-page":"1469","article-title":"Expression of molecular targets for tyrosine kinase receptor antagonists in malignant endocrine pancreatic tumors","volume":"9","author":"Fjallskog ML","year":"2003","journal-title":"Clin Cancer Res"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.2014.40"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1593\/neo.91972"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2347"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-11-3264"},{"key":"e_1_2_8_50_1","first-page":"909","article-title":"Knockdown of CDK6 enhances glioma sensitivity to chemotherapy","volume":"28","author":"Li B","year":"2012","journal-title":"Oncol Rep"},{"key":"e_1_2_8_51_1","first-page":"247","article-title":"Outcomes of patients treated with capecitabine and temozolamide for advanced pancreatic neuroendocrine tumors (PNETs) and non\u2010PNETs","volume":"5","author":"Peixoto RD","year":"2014","journal-title":"J Gastrointest Oncol"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201540946"}],"container-title":["Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fcncr.31057","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acsjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cncr.31057","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T21:39:23Z","timestamp":1760305163000},"score":1,"resource":{"primary":{"URL":"https:\/\/acsjournals.onlinelibrary.wiley.com\/doi\/10.1002\/cncr.31057"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,11,17]]},"references-count":51,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2018,2]]}},"alternative-id":["10.1002\/cncr.31057"],"URL":"https:\/\/doi.org\/10.1002\/cncr.31057","archive":["Portico"],"relation":{},"ISSN":["0008-543X","1097-0142"],"issn-type":[{"value":"0008-543X","type":"print"},{"value":"1097-0142","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,11,17]]}}}