PMID- 29149451 OWN - NLM STAT- MEDLINE DCOM- 20190611 LR - 20210109 IS - 1097-0142 (Electronic) IS - 0008-543X (Print) IS - 0008-543X (Linking) VI - 124 IP - 3 DP - 2018 Feb 1 TI - Transcriptional alterations in hereditary and sporadic nonfunctioning pancreatic neuroendocrine tumors according to genotype. PG - 636-647 LID - 10.1002/cncr.31057 [doi] AB - BACKGROUND: Nonfunctioning pancreatic neuroendocrine tumors (NFPanNETs) may be sporadic or inherited because of germline mutations associated with von Hippel-Lindau 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-specific patterns of transcriptional messenger RNA (mRNA) levels of NFPanNETs to understand the molecular features that determine PanNET phenotype. METHODS: Thirty-two samples were included for genome-wide mRNA gene expression analysis (9 VHL-associated, 10 MEN1-associated, and 9 sporadic NFPanNETs and 4 purified normal islet cell [NIC] samples). Validation of genes was performed by real-time polymerase chain reaction analysis and immunohistochemistry. Gene expression profiles were analyzed by tumor genotype, and pathway analysis was curated. RESULTS: Consensus clustering of mRNA expression revealed separate clustering of NICs, VHL-associated NFPanNETs, and MEN1-associated NFPanNETs; whereas some sporadic tumors clustered with MEN1. Four of 5 MEN1-like sporadic PanNET subtypes had loss of heterozygosity at the MEN1 gene locus. Pathway analysis demonstrated subtype-specific 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-derived growth factor receptor beta (PDGFRB), lymphoid enhancer-binding factor-1 (Lef-1), cyclin-dependent kinase 4 (CDK4), and CDK6 were upregulated in VHL or MEN1 NFPanNETs, providing potential subtype-specific treatment targets. CONCLUSIONS: Distinct mRNA expression patterns were identified in sporadic-associated, VHL-associated, and MEN1-associated NFPanNETs. The current results uncover new pathways involved in NFPanNETs that are subtype-specific and provide potential new diagnostic or therapeutic targets based on tumor subtype. Cancer 2018;124:636-47. (c) 2017 American Cancer Society. CI - (c) 2017 American Cancer Society. FAU - Keutgen, Xavier M AU - Keutgen XM AUID- ORCID: 0000-0002-4627-3560 AD - Endocrine Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. AD - Division of Surgical Oncology, Department of Surgery, Rush University Medical Center, Chicago, Illinois. FAU - Kumar, Suresh AU - Kumar S AD - Endocrine Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. FAU - Gara, Sudheer Kumar AU - Gara SK AD - Endocrine Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. FAU - Boufraqech, Myriem AU - Boufraqech M AD - Endocrine Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. FAU - Agarwal, Sunita AU - Agarwal S AD - Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland. FAU - Hruban, Ralph H AU - Hruban RH AD - The Sol Goldman Pancreatic Cancer Research Center, Departments of Pathology and Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. FAU - Nilubol, Naris AU - Nilubol N AD - Endocrine Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. FAU - Quezado, Martha AU - Quezado M AD - Department of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. FAU - Finney, Richard AU - Finney R AD - Collaborative Bioinformatics Resource, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. FAU - Cam, Maggie AU - Cam M AD - Collaborative Bioinformatics Resource, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. FAU - Kebebew, Electron AU - Kebebew E AUID- ORCID: 0000-0001-5254-1456 AD - Endocrine Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. AD - Department of Surgery, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia. LA - eng GR - P50 CA174521/CA/NCI NIH HHS/United States GR - ZIA BC011275/ImNIH/Intramural NIH HHS/United States GR - ZIA BC011275-07/ImNIH/Intramural NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Intramural DEP - 20171117 PL - United States TA - Cancer JT - Cancer JID - 0374236 RN - EC 2.3.2.27 (Von Hippel-Lindau Tumor Suppressor Protein) RN - EC 2.7.10.1 (PDGFRB protein, human) RN - EC 2.7.10.1 (Receptor, Platelet-Derived Growth Factor beta) RN - EC 2.7.11.22 (CDK6 protein, human) RN - EC 2.7.11.22 (Cyclin-Dependent Kinase 6) RN - Non functioning pancreatic endocrine tumor SB - IM EIN - Cancer. 2018 Apr 1;124(7):1518. Gara, Sudheer [corrected to Gara, Sudheer Kumar]. PMID: 29574707 MH - Cluster Analysis MH - Cyclin-Dependent Kinase 6/antagonists & inhibitors/genetics MH - Gene Ontology MH - Genotype MH - Humans MH - Pancreatic Neoplasms/*genetics/pathology MH - Receptor, Platelet-Derived Growth Factor beta/genetics MH - *Transcription, Genetic MH - Von Hippel-Lindau Tumor Suppressor Protein/genetics PMC - PMC5780230 MID - NIHMS907489 OTO - NOTNLM OT - multiple endocrine neoplasia type 1 (MEN1) OT - neuroendocrine OT - pancreas OT - sporadic OT - von Hippel-Lindau syndrome (VHL) COIS- Conflict of interest: There are no conflict of interest disclosures from any authors. EDAT- 2017/11/18 06:00 MHDA- 2019/06/14 06:00 PMCR- 2019/02/01 CRDT- 2017/11/18 06:00 PHST- 2017/05/22 00:00 [received] PHST- 2017/07/19 00:00 [revised] PHST- 2017/08/24 00:00 [accepted] PHST- 2017/11/18 06:00 [pubmed] PHST- 2019/06/14 06:00 [medline] PHST- 2017/11/18 06:00 [entrez] PHST- 2019/02/01 00:00 [pmc-release] AID - 10.1002/cncr.31057 [doi] PST - ppublish SO - Cancer. 2018 Feb 1;124(3):636-647. doi: 10.1002/cncr.31057. Epub 2017 Nov 17.