A genome-wide investigation of microRNA expression identifies biologically-meaningful microRNAs that distinguish between high-risk and low-risk intraductal papillary mucinous neoplasms of the pancreas
Intraductal papillary mucinous neoplasms (IPMNs) are pancreatic ductal adenocarcinoma (PDAC) precursors. Differentiating between high-risk IPMNs that warrant surgical resection and low-risk IPMNs that can be monitored is a significant clinical problem, and we sought to discover a panel of mi(cro)RNA...
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| Veröffentlicht in: | PloS one 2015-01, Vol.10 (1), p.e0116869-e0116869 |
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| creator | Permuth-Wey, Jennifer Chen, Y Ann Fisher, Kate McCarthy, Susan Qu, Xiaotao Lloyd, Mark C Kasprzak, Agnieszka Fournier, Michelle Williams, Vonetta L Ghia, Kavita M Yoder, Sean J Hall, Laura Georgeades, Christina Olaoye, Funmilayo Husain, Kazim Springett, Gregory M Chen, Dung-Tsa Yeatman, Timothy Centeno, Barbara Ann Klapman, Jason Coppola, Domenico Malafa, Mokenge |
| description | Intraductal papillary mucinous neoplasms (IPMNs) are pancreatic ductal adenocarcinoma (PDAC) precursors. Differentiating between high-risk IPMNs that warrant surgical resection and low-risk IPMNs that can be monitored is a significant clinical problem, and we sought to discover a panel of mi(cro)RNAs that accurately classify IPMN risk status.
In a discovery phase, genome-wide miRNA expression profiling was performed on 28 surgically-resected, pathologically-confirmed IPMNs (19 high-risk, 9 low-risk) using Taqman MicroRNA Arrays. A validation phase was performed in 21 independent IPMNs (13 high-risk, 8 low-risk). We also explored associations between miRNA expression level and various clinical and pathological factors and examined genes and pathways regulated by the identified miRNAs by integrating data from bioinformatic analyses and microarray analysis of miRNA gene targets. Six miRNAs (miR-100, miR-99b, miR-99a, miR-342-3p, miR-126, miR-130a) were down-regulated in high-risk versus low-risk IPMNs and distinguished between groups (P |
| doi_str_mv | 10.1371/journal.pone.0116869 |
| format | Article |
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In a discovery phase, genome-wide miRNA expression profiling was performed on 28 surgically-resected, pathologically-confirmed IPMNs (19 high-risk, 9 low-risk) using Taqman MicroRNA Arrays. A validation phase was performed in 21 independent IPMNs (13 high-risk, 8 low-risk). We also explored associations between miRNA expression level and various clinical and pathological factors and examined genes and pathways regulated by the identified miRNAs by integrating data from bioinformatic analyses and microarray analysis of miRNA gene targets. Six miRNAs (miR-100, miR-99b, miR-99a, miR-342-3p, miR-126, miR-130a) were down-regulated in high-risk versus low-risk IPMNs and distinguished between groups (P<10-3, area underneath the curve (AUC) = 87%). The same trend was observed in the validation phase (AUC = 74%). Low miR-99b expression was associated with main pancreatic duct involvement (P = 0.021), and serum albumin levels were positively correlated with miR-99a (r = 0.52, P = 0.004) and miR-100 expression (r = 0.49, P = 0.008). Literature, validated miRNA:target gene interactions, and pathway enrichment analysis supported the candidate miRNAs as tumor suppressors and regulators of PDAC development. Microarray analysis revealed that oncogenic targets of miR-130a (ATG2B, MEOX2), miR-342-3p (DNMT1), and miR-126 (IRS-1) were up-regulated in high- versus low-risk IPMNs (P<0.10).
This pilot study highlights miRNAs that may aid in preoperative risk stratification of IPMNs and provides novel insights into miRNA-mediated progression to pancreatic malignancy. The miRNAs identified here and in other recent investigations warrant evaluation in biofluids in a well-powered prospective cohort of individuals newly-diagnosed with IPMNs and other pancreatic cysts and those at increased genetic risk for these lesions.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0116869</identifier><identifier>PMID: 25607660</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adenocarcinoma ; Adenocarcinoma, Mucinous - genetics ; Adenocarcinoma, Mucinous - pathology ; Adenocarcinoma, Papillary - genetics ; Adenocarcinoma, Papillary - pathology ; Aged ; Aged, 80 and over ; Bioinformatics ; Carcinoma, Pancreatic Ductal - genetics ; Carcinoma, Pancreatic Ductal - pathology ; Cellular biology ; Cysts ; Data processing ; Deoxyribonucleic acid ; Diagnosis, Differential ; DNA ; DNA microarrays ; DNMT1 protein ; Epidemiology ; Female ; Gene expression ; Gene Expression Profiling - methods ; Gene Expression Regulation, Neoplastic ; Gene Regulatory Networks ; Genomes ; Genomics ; Humans ; Insulin receptor substrate 1 ; Investigations ; Kinases ; Lesions ; Male ; Malignancy ; Medical diagnosis ; Medical imaging ; Medical prognosis ; MicroRNA ; MicroRNAs ; MicroRNAs - genetics ; Microscopy ; Middle Aged ; miRNA ; Mortality ; Neoplasms ; Oligonucleotide Array Sequence Analysis - methods ; Oncology ; Pancreas ; Pancreatic cancer ; Pancreatic Neoplasms - genetics ; Pancreatic Neoplasms - pathology ; Pathology ; Pilot Projects ; Proteins ; Regulators ; Ribonucleic acid ; Risk ; RNA ; Serum albumin ; Serum Albumin - metabolism ; Suppressors ; Surgery ; Tumors</subject><ispartof>PloS one, 2015-01, Vol.10 (1), p.e0116869-e0116869</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Permuth-Wey et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 Permuth-Wey et al 2015 Permuth-Wey et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-1d358f7c5175f623c1d7aec280ca83d1309df28b7b1215bf5d7a1de91f0f0b693</citedby><cites>FETCH-LOGICAL-c692t-1d358f7c5175f623c1d7aec280ca83d1309df28b7b1215bf5d7a1de91f0f0b693</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4301643/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4301643/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25607660$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Permuth-Wey, Jennifer</creatorcontrib><creatorcontrib>Chen, Y Ann</creatorcontrib><creatorcontrib>Fisher, Kate</creatorcontrib><creatorcontrib>McCarthy, Susan</creatorcontrib><creatorcontrib>Qu, Xiaotao</creatorcontrib><creatorcontrib>Lloyd, Mark C</creatorcontrib><creatorcontrib>Kasprzak, Agnieszka</creatorcontrib><creatorcontrib>Fournier, Michelle</creatorcontrib><creatorcontrib>Williams, Vonetta L</creatorcontrib><creatorcontrib>Ghia, Kavita M</creatorcontrib><creatorcontrib>Yoder, Sean J</creatorcontrib><creatorcontrib>Hall, Laura</creatorcontrib><creatorcontrib>Georgeades, Christina</creatorcontrib><creatorcontrib>Olaoye, Funmilayo</creatorcontrib><creatorcontrib>Husain, Kazim</creatorcontrib><creatorcontrib>Springett, Gregory M</creatorcontrib><creatorcontrib>Chen, Dung-Tsa</creatorcontrib><creatorcontrib>Yeatman, Timothy</creatorcontrib><creatorcontrib>Centeno, Barbara Ann</creatorcontrib><creatorcontrib>Klapman, Jason</creatorcontrib><creatorcontrib>Coppola, Domenico</creatorcontrib><creatorcontrib>Malafa, Mokenge</creatorcontrib><title>A genome-wide investigation of microRNA expression identifies biologically-meaningful microRNAs that distinguish between high-risk and low-risk intraductal papillary mucinous neoplasms of the pancreas</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Intraductal papillary mucinous neoplasms (IPMNs) are pancreatic ductal adenocarcinoma (PDAC) precursors. Differentiating between high-risk IPMNs that warrant surgical resection and low-risk IPMNs that can be monitored is a significant clinical problem, and we sought to discover a panel of mi(cro)RNAs that accurately classify IPMN risk status.
In a discovery phase, genome-wide miRNA expression profiling was performed on 28 surgically-resected, pathologically-confirmed IPMNs (19 high-risk, 9 low-risk) using Taqman MicroRNA Arrays. A validation phase was performed in 21 independent IPMNs (13 high-risk, 8 low-risk). We also explored associations between miRNA expression level and various clinical and pathological factors and examined genes and pathways regulated by the identified miRNAs by integrating data from bioinformatic analyses and microarray analysis of miRNA gene targets. Six miRNAs (miR-100, miR-99b, miR-99a, miR-342-3p, miR-126, miR-130a) were down-regulated in high-risk versus low-risk IPMNs and distinguished between groups (P<10-3, area underneath the curve (AUC) = 87%). The same trend was observed in the validation phase (AUC = 74%). Low miR-99b expression was associated with main pancreatic duct involvement (P = 0.021), and serum albumin levels were positively correlated with miR-99a (r = 0.52, P = 0.004) and miR-100 expression (r = 0.49, P = 0.008). Literature, validated miRNA:target gene interactions, and pathway enrichment analysis supported the candidate miRNAs as tumor suppressors and regulators of PDAC development. Microarray analysis revealed that oncogenic targets of miR-130a (ATG2B, MEOX2), miR-342-3p (DNMT1), and miR-126 (IRS-1) were up-regulated in high- versus low-risk IPMNs (P<0.10).
This pilot study highlights miRNAs that may aid in preoperative risk stratification of IPMNs and provides novel insights into miRNA-mediated progression to pancreatic malignancy. The miRNAs identified here and in other recent investigations warrant evaluation in biofluids in a well-powered prospective cohort of individuals newly-diagnosed with IPMNs and other pancreatic cysts and those at increased genetic risk for these lesions.</description><subject>Adenocarcinoma</subject><subject>Adenocarcinoma, Mucinous - genetics</subject><subject>Adenocarcinoma, Mucinous - pathology</subject><subject>Adenocarcinoma, Papillary - genetics</subject><subject>Adenocarcinoma, Papillary - pathology</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Bioinformatics</subject><subject>Carcinoma, Pancreatic Ductal - genetics</subject><subject>Carcinoma, Pancreatic Ductal - pathology</subject><subject>Cellular biology</subject><subject>Cysts</subject><subject>Data processing</subject><subject>Deoxyribonucleic acid</subject><subject>Diagnosis, Differential</subject><subject>DNA</subject><subject>DNA microarrays</subject><subject>DNMT1 protein</subject><subject>Epidemiology</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gene Expression Profiling - methods</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Gene Regulatory Networks</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Humans</subject><subject>Insulin receptor substrate 1</subject><subject>Investigations</subject><subject>Kinases</subject><subject>Lesions</subject><subject>Male</subject><subject>Malignancy</subject><subject>Medical diagnosis</subject><subject>Medical imaging</subject><subject>Medical prognosis</subject><subject>MicroRNA</subject><subject>MicroRNAs</subject><subject>MicroRNAs - genetics</subject><subject>Microscopy</subject><subject>Middle Aged</subject><subject>miRNA</subject><subject>Mortality</subject><subject>Neoplasms</subject><subject>Oligonucleotide Array Sequence Analysis - methods</subject><subject>Oncology</subject><subject>Pancreas</subject><subject>Pancreatic cancer</subject><subject>Pancreatic Neoplasms - genetics</subject><subject>Pancreatic Neoplasms - pathology</subject><subject>Pathology</subject><subject>Pilot Projects</subject><subject>Proteins</subject><subject>Regulators</subject><subject>Ribonucleic acid</subject><subject>Risk</subject><subject>RNA</subject><subject>Serum albumin</subject><subject>Serum Albumin - metabolism</subject><subject>Suppressors</subject><subject>Surgery</subject><subject>Tumors</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk8lu1TAUhiMEoqXwBggsISFY5GJncJIN0lXFUKmiUhm2lmMfJy6OncZOhzfksXB6b6te1AXKIsnxd36fMUleErwieUU-nLl5stysRmdhhQmhNW0eJfukybOUZjh_fO97L3nm_RnGZV5T-jTZy0qKK0rxfvJnjTqwboD0UktA2l6AD7rjQTuLnEKDFpM7_bZGcDVO4P1ijqANWmnwqNXOuE4Lbsx1OgC32nZqNnduHoWeByR1FLXdrH2PWgiXABb1uuvTSfvfiFuJjLvc_GgbJi5nEbhBIx-1MXy6RsMstHWzRxbcaLgf_BJc6CEyVkzA_fPkieLGw4vt-yD5-fnTj8Ov6fHJl6PD9XEqaJOFlMi8rFUlSlKVima5ILLiILIaC17nkuS4kSqr26olGSlbVcZjIqEhCivc0iY_SF5vdEfjPNs2wTNCy5pg2pR1JI42hHT8jI2THmIGzHHNbgxu6hifghYGmGraEmqJVVu3BW2LpoyRNRlAE4MRIKPWx-1tczuAFLBUx-yI7p5Y3bPOXbAix4QWeRR4txWY3Pkce8sG7QXEqsZKzjdxZwUmuKwi-uYf9OHstlTHYwLaKhfvFYsoWxdZRhuaN0uVVg9Q8ZEQRyNOrNLRvuPwfschMgGuQsdn79nR99P_Z09-7bJv77E9cBN678y8zLffBYsNGAfX-wnUXZEJZsvC3VaDLQvHtgsX3V7db9Cd0-2G5X8ByFIsfg</recordid><startdate>20150121</startdate><enddate>20150121</enddate><creator>Permuth-Wey, Jennifer</creator><creator>Chen, Y Ann</creator><creator>Fisher, Kate</creator><creator>McCarthy, Susan</creator><creator>Qu, Xiaotao</creator><creator>Lloyd, Mark C</creator><creator>Kasprzak, Agnieszka</creator><creator>Fournier, Michelle</creator><creator>Williams, Vonetta L</creator><creator>Ghia, Kavita M</creator><creator>Yoder, Sean J</creator><creator>Hall, Laura</creator><creator>Georgeades, Christina</creator><creator>Olaoye, Funmilayo</creator><creator>Husain, Kazim</creator><creator>Springett, Gregory M</creator><creator>Chen, Dung-Tsa</creator><creator>Yeatman, Timothy</creator><creator>Centeno, Barbara Ann</creator><creator>Klapman, Jason</creator><creator>Coppola, Domenico</creator><creator>Malafa, Mokenge</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20150121</creationdate><title>A genome-wide investigation of microRNA expression identifies biologically-meaningful microRNAs that distinguish between high-risk and low-risk intraductal papillary mucinous neoplasms of the pancreas</title><author>Permuth-Wey, Jennifer ; Chen, Y Ann ; Fisher, Kate ; McCarthy, Susan ; Qu, Xiaotao ; Lloyd, Mark C ; Kasprzak, Agnieszka ; Fournier, Michelle ; Williams, Vonetta L ; Ghia, Kavita M ; Yoder, Sean J ; Hall, Laura ; Georgeades, Christina ; Olaoye, Funmilayo ; Husain, Kazim ; Springett, Gregory M ; Chen, Dung-Tsa ; Yeatman, Timothy ; Centeno, Barbara Ann ; Klapman, Jason ; Coppola, Domenico ; Malafa, Mokenge</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-1d358f7c5175f623c1d7aec280ca83d1309df28b7b1215bf5d7a1de91f0f0b693</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Adenocarcinoma</topic><topic>Adenocarcinoma, Mucinous - genetics</topic><topic>Adenocarcinoma, Mucinous - pathology</topic><topic>Adenocarcinoma, Papillary - genetics</topic><topic>Adenocarcinoma, Papillary - pathology</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Bioinformatics</topic><topic>Carcinoma, Pancreatic Ductal - genetics</topic><topic>Carcinoma, Pancreatic Ductal - pathology</topic><topic>Cellular biology</topic><topic>Cysts</topic><topic>Data processing</topic><topic>Deoxyribonucleic acid</topic><topic>Diagnosis, Differential</topic><topic>DNA</topic><topic>DNA microarrays</topic><topic>DNMT1 protein</topic><topic>Epidemiology</topic><topic>Female</topic><topic>Gene expression</topic><topic>Gene Expression Profiling - methods</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Gene Regulatory Networks</topic><topic>Genomes</topic><topic>Genomics</topic><topic>Humans</topic><topic>Insulin receptor substrate 1</topic><topic>Investigations</topic><topic>Kinases</topic><topic>Lesions</topic><topic>Male</topic><topic>Malignancy</topic><topic>Medical diagnosis</topic><topic>Medical imaging</topic><topic>Medical prognosis</topic><topic>MicroRNA</topic><topic>MicroRNAs</topic><topic>MicroRNAs - genetics</topic><topic>Microscopy</topic><topic>Middle Aged</topic><topic>miRNA</topic><topic>Mortality</topic><topic>Neoplasms</topic><topic>Oligonucleotide Array Sequence Analysis - methods</topic><topic>Oncology</topic><topic>Pancreas</topic><topic>Pancreatic cancer</topic><topic>Pancreatic Neoplasms - genetics</topic><topic>Pancreatic Neoplasms - pathology</topic><topic>Pathology</topic><topic>Pilot Projects</topic><topic>Proteins</topic><topic>Regulators</topic><topic>Ribonucleic acid</topic><topic>Risk</topic><topic>RNA</topic><topic>Serum albumin</topic><topic>Serum Albumin - metabolism</topic><topic>Suppressors</topic><topic>Surgery</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Permuth-Wey, Jennifer</creatorcontrib><creatorcontrib>Chen, Y Ann</creatorcontrib><creatorcontrib>Fisher, Kate</creatorcontrib><creatorcontrib>McCarthy, Susan</creatorcontrib><creatorcontrib>Qu, Xiaotao</creatorcontrib><creatorcontrib>Lloyd, Mark C</creatorcontrib><creatorcontrib>Kasprzak, Agnieszka</creatorcontrib><creatorcontrib>Fournier, Michelle</creatorcontrib><creatorcontrib>Williams, Vonetta L</creatorcontrib><creatorcontrib>Ghia, Kavita M</creatorcontrib><creatorcontrib>Yoder, Sean J</creatorcontrib><creatorcontrib>Hall, Laura</creatorcontrib><creatorcontrib>Georgeades, Christina</creatorcontrib><creatorcontrib>Olaoye, Funmilayo</creatorcontrib><creatorcontrib>Husain, Kazim</creatorcontrib><creatorcontrib>Springett, Gregory M</creatorcontrib><creatorcontrib>Chen, Dung-Tsa</creatorcontrib><creatorcontrib>Yeatman, Timothy</creatorcontrib><creatorcontrib>Centeno, Barbara Ann</creatorcontrib><creatorcontrib>Klapman, Jason</creatorcontrib><creatorcontrib>Coppola, Domenico</creatorcontrib><creatorcontrib>Malafa, Mokenge</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Permuth-Wey, Jennifer</au><au>Chen, Y Ann</au><au>Fisher, Kate</au><au>McCarthy, Susan</au><au>Qu, Xiaotao</au><au>Lloyd, Mark C</au><au>Kasprzak, Agnieszka</au><au>Fournier, Michelle</au><au>Williams, Vonetta L</au><au>Ghia, Kavita M</au><au>Yoder, Sean J</au><au>Hall, Laura</au><au>Georgeades, Christina</au><au>Olaoye, Funmilayo</au><au>Husain, Kazim</au><au>Springett, Gregory M</au><au>Chen, Dung-Tsa</au><au>Yeatman, Timothy</au><au>Centeno, Barbara Ann</au><au>Klapman, Jason</au><au>Coppola, Domenico</au><au>Malafa, Mokenge</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A genome-wide investigation of microRNA expression identifies biologically-meaningful microRNAs that distinguish between high-risk and low-risk intraductal papillary mucinous neoplasms of the pancreas</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-01-21</date><risdate>2015</risdate><volume>10</volume><issue>1</issue><spage>e0116869</spage><epage>e0116869</epage><pages>e0116869-e0116869</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Intraductal papillary mucinous neoplasms (IPMNs) are pancreatic ductal adenocarcinoma (PDAC) precursors. Differentiating between high-risk IPMNs that warrant surgical resection and low-risk IPMNs that can be monitored is a significant clinical problem, and we sought to discover a panel of mi(cro)RNAs that accurately classify IPMN risk status.
In a discovery phase, genome-wide miRNA expression profiling was performed on 28 surgically-resected, pathologically-confirmed IPMNs (19 high-risk, 9 low-risk) using Taqman MicroRNA Arrays. A validation phase was performed in 21 independent IPMNs (13 high-risk, 8 low-risk). We also explored associations between miRNA expression level and various clinical and pathological factors and examined genes and pathways regulated by the identified miRNAs by integrating data from bioinformatic analyses and microarray analysis of miRNA gene targets. Six miRNAs (miR-100, miR-99b, miR-99a, miR-342-3p, miR-126, miR-130a) were down-regulated in high-risk versus low-risk IPMNs and distinguished between groups (P<10-3, area underneath the curve (AUC) = 87%). The same trend was observed in the validation phase (AUC = 74%). Low miR-99b expression was associated with main pancreatic duct involvement (P = 0.021), and serum albumin levels were positively correlated with miR-99a (r = 0.52, P = 0.004) and miR-100 expression (r = 0.49, P = 0.008). Literature, validated miRNA:target gene interactions, and pathway enrichment analysis supported the candidate miRNAs as tumor suppressors and regulators of PDAC development. Microarray analysis revealed that oncogenic targets of miR-130a (ATG2B, MEOX2), miR-342-3p (DNMT1), and miR-126 (IRS-1) were up-regulated in high- versus low-risk IPMNs (P<0.10).
This pilot study highlights miRNAs that may aid in preoperative risk stratification of IPMNs and provides novel insights into miRNA-mediated progression to pancreatic malignancy. The miRNAs identified here and in other recent investigations warrant evaluation in biofluids in a well-powered prospective cohort of individuals newly-diagnosed with IPMNs and other pancreatic cysts and those at increased genetic risk for these lesions.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25607660</pmid><doi>10.1371/journal.pone.0116869</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2015-01, Vol.10 (1), p.e0116869-e0116869 |
| issn | 1932-6203 1932-6203 |
| language | eng |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Adenocarcinoma Adenocarcinoma, Mucinous - genetics Adenocarcinoma, Mucinous - pathology Adenocarcinoma, Papillary - genetics Adenocarcinoma, Papillary - pathology Aged Aged, 80 and over Bioinformatics Carcinoma, Pancreatic Ductal - genetics Carcinoma, Pancreatic Ductal - pathology Cellular biology Cysts Data processing Deoxyribonucleic acid Diagnosis, Differential DNA DNA microarrays DNMT1 protein Epidemiology Female Gene expression Gene Expression Profiling - methods Gene Expression Regulation, Neoplastic Gene Regulatory Networks Genomes Genomics Humans Insulin receptor substrate 1 Investigations Kinases Lesions Male Malignancy Medical diagnosis Medical imaging Medical prognosis MicroRNA MicroRNAs MicroRNAs - genetics Microscopy Middle Aged miRNA Mortality Neoplasms Oligonucleotide Array Sequence Analysis - methods Oncology Pancreas Pancreatic cancer Pancreatic Neoplasms - genetics Pancreatic Neoplasms - pathology Pathology Pilot Projects Proteins Regulators Ribonucleic acid Risk RNA Serum albumin Serum Albumin - metabolism Suppressors Surgery Tumors |
| title | A genome-wide investigation of microRNA expression identifies biologically-meaningful microRNAs that distinguish between high-risk and low-risk intraductal papillary mucinous neoplasms of the pancreas |
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