Amit Tirosh1,2, Sanjit Mukherjee1, Justin Lack1, Sudheer Kumar Gara1, Sophie Wang1, Martha M Quezado1, Xavier M Keutgen3, Xiaolin Wu4, Maggie Cam1, Suresh Kumar1, Dhaval Patel1, Naris Nilubol1, Monica Varun Tyagi5,6, Electron Kebebew5,6. 1. Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. 2. Endocrine Oncology Bioinformatics Lab, Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. 3. Division of Surgical Oncology, Department of Surgery, Rush University Medical Center, Chicago, Illinois. 4. Cancer Research Technology Program, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland. 5. Department of Surgery, Stanford University, Stanford, California. 6. Stanford Cancer Institute, Stanford University, Stanford, California.
Abstract
BACKGROUND: Aberrant methylation is a known cause of cancer initiation and/or progression. There are scant data on the genome-wide methylation pattern of nonfunctioning pancreatic neuroendocrine tumors (NFPanNETs) and sporadic and hereditary NFPanNETs. METHODS: Thirty-three tissue samples were analyzed: they included samples from sporadic (n = 9), von Hippel-Lindau (VHL)-related (n = 10), and multiple endocrine neoplasia type 1 (MEN1)-related NFPanNETs (n = 10) as well as normal islet cells (n = 4) for comparison. Genome-wide CpG methylation profiling was performed with the Infinium MethylationEPIC BeadChip assay and was analyzed with R-based tools. RESULTS: In unsupervised hierarchical clustering, sporadic and MEN1-related NFPanNETs clustered together, and the VHL group was in a separate cluster. MEN1-related NFPanNETs had a higher rate of hypermethylated CpG sites in comparison with sporadic and VHL-related tumor groups. Differentially methylated region analysis confirmed the higher rate of hypermethylation in MEN1-related tumors. Moreover, in an integrated analysis of gene expression data for the same tumor samples, downregulated gene expression was found in most genes that were hypermethylated. In a CpG island methylator phenotype analysis, 3 genes were identified and confirmed to have downregulated gene expression: secreted frizzle-related protein 5 (SFRP5) in sporadic NFPanNETs and cell division cycle-associated 7-like (CDCA7L) and RNA binding motif 47 (RBM47) in MEN1-related NFPanNETs. CONCLUSIONS: MEN1 NFPanNETs have a higher rate of geno me-wide hypermethylation than other NFPanNET subtypes. The similarity between the pathways enriched in a methylation analysis of known genes involved in NFPanNET tumorigenesis suggests a key role for aberrant methylation in the pathogenesis of NFPanNETs.
BACKGROUND: Aberrant methylation is a known cause of cancer initiation and/or progression. There are scant data on the genome-wide methylation pattern of nonfunctioning pancreatic neuroendocrine tumors (NFPanNETs) and sporadic and hereditary NFPanNETs. METHODS: Thirty-three tissue samples were analyzed: they included samples from sporadic (n = 9), von Hippel-Lindau (VHL)-related (n = 10), and multiple endocrine neoplasia type 1 (MEN1)-related NFPanNETs (n = 10) as well as normal islet cells (n = 4) for comparison. Genome-wide CpG methylation profiling was performed with the Infinium MethylationEPIC BeadChip assay and was analyzed with R-based tools. RESULTS: In unsupervised hierarchical clustering, sporadic and MEN1-related NFPanNETs clustered together, and the VHL group was in a separate cluster. MEN1-related NFPanNETs had a higher rate of hypermethylated CpG sites in comparison with sporadic and VHL-related tumor groups. Differentially methylated region analysis confirmed the higher rate of hypermethylation in MEN1-related tumors. Moreover, in an integrated analysis of gene expression data for the same tumor samples, downregulated gene expression was found in most genes that were hypermethylated. In a CpG island methylator phenotype analysis, 3 genes were identified and confirmed to have downregulated gene expression: secreted frizzle-related protein 5 (SFRP5) in sporadic NFPanNETs and cell division cycle-associated 7-like (CDCA7L) and RNA binding motif 47 (RBM47) in MEN1-related NFPanNETs. CONCLUSIONS:MEN1 NFPanNETs have a higher rate of geno me-wide hypermethylation than other NFPanNET subtypes. The similarity between the pathways enriched in a methylation analysis of known genes involved in NFPanNET tumorigenesis suggests a key role for aberrant methylation in the pathogenesis of NFPanNETs.
Authors: P R Hammel; V Vilgrain; B Terris; A Penfornis; A Sauvanet; J M Correas; D Chauveau; A Balian; C Beigelman; D O'Toole; P Bernades; P Ruszniewski; S Richard Journal: Gastroenterology Date: 2000-10 Impact factor: 22.682
Authors: Ville Sallinen; Tessa Y S Le Large; Shamil Galeev; Zahar Kovalenko; Elke Tieftrunk; Raphael Araujo; Güralp O Ceyhan; Sebastien Gaujoux Journal: HPB (Oxford) Date: 2017-02-21 Impact factor: 3.647
Authors: Amit Tirosh; Samira M Sadowski; W Marston Linehan; Steven K Libutti; Dhaval Patel; Naris Nilubol; Electron Kebebew Journal: JAMA Oncol Date: 2018-01-01 Impact factor: 31.777
Authors: J Lu; Q Li; H Xie; Z J Chen; A E Borovitskaya; N K Maclaren; A L Notkins; M S Lan Journal: Proc Natl Acad Sci U S A Date: 1996-03-19 Impact factor: 11.205
Authors: T Sakurai; K Isogaya; S Sakai; M Morikawa; Y Morishita; S Ehata; K Miyazono; D Koinuma Journal: Oncogene Date: 2016-02-29 Impact factor: 9.867
Authors: Sakari Vanharanta; Christina B Marney; Weiping Shu; Manuel Valiente; Yilong Zou; Aldo Mele; Robert B Darnell; Joan Massagué Journal: Elife Date: 2014-06-04 Impact factor: 8.140
Authors: Davide Gentilini; Stefania Scala; Germano Gaudenzi; Paolo Garagnani; Miriam Capri; Matteo Cescon; Gian Luca Grazi; Maria Giulia Bacalini; Serena Pisoni; Alessandra Dicitore; Luisa Circelli; Sara Santagata; Francesco Izzo; Anna Maria Di Blasio; Luca Persani; Claudio Franceschi; Giovanni Vitale Journal: Oncotarget Date: 2017-06-27
Authors: Chandra K Maharjan; Po Hien Ear; Catherine G Tran; James R Howe; Chandrikha Chandrasekharan; Dawn E Quelle Journal: Cancers (Basel) Date: 2021-10-12 Impact factor: 6.639
Authors: Amit Tirosh; Jonathan Keith Killian; David Petersen; Yuelin Jack Zhu; Robert L Walker; Jenny E Blau; Naris Nilubol; Dhaval Patel; Sunita K Agarwal; Lee Scott Weinstein; Paul Meltzer; Electron Kebebew Journal: J Clin Endocrinol Metab Date: 2020-10-01 Impact factor: 5.958
Authors: Oleg I Kit; Vladimir S Trifanov; Nataliya A Petrusenko; Dmitry Y Gvaldin; Denis S Kutilin; Nataliya N Timoshkina Journal: Mol Biol Rep Date: 2020-05-25 Impact factor: 2.742
Authors: Maria Luisa Brandi; Sunita K Agarwal; Nancy D Perrier; Kate E Lines; Gerlof D Valk; Rajesh V Thakker Journal: Endocr Rev Date: 2021-03-15 Impact factor: 19.871