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Association of Genetic Variants Affecting microRNAs and Pancreatic Cancer Risk
Y. Lu, C. Corradi, M. Gentiluomo, E. López de Maturana, GE. Theodoropoulos, S. Roth, E. Maiello, L. Morelli, L. Archibugi, JR. Izbicki, P. Sarlós, V. Kiudelis, M. Oliverius, MN. Aoki, Y. Vashist, CHJ. van Eijck, M. Gazouli, R. Talar-Wojnarowska,...
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- Journal Article MeSH
Genetic factors play an important role in the susceptibility to pancreatic cancer (PC). However, established loci explain a small proportion of genetic heritability for PC; therefore, more progress is needed to find the missing ones. We aimed at identifying single nucleotide polymorphisms (SNPs) affecting PC risk through effects on micro-RNA (miRNA) function. We searched in silico the genome for SNPs in miRNA seed sequences or 3 prime untranslated regions (3'UTRs) of miRNA target genes. Genome-wide association data of PC cases and controls from the Pancreatic Cancer Cohort (PanScan) Consortium and the Pancreatic Cancer Case-Control (PanC4) Consortium were re-analyzed for discovery, and genotyping data from two additional consortia (PanGenEU and PANDoRA) were used for replication, for a total of 14,062 cases and 11,261 controls. None of the SNPs reached genome-wide significance in the meta-analysis, but for three of them the associations were in the same direction in all the study populations and showed lower value of p in the meta-analyses than in the discovery phase. Specifically, rs7985480 was consistently associated with PC risk (OR = 1.12, 95% CI 1.07-1.17, p = 3.03 × 10-6 in the meta-analysis). This SNP is in linkage disequilibrium (LD) with rs2274048, which modulates binding of various miRNAs to the 3'UTR of UCHL3, a gene involved in PC progression. In conclusion, our results expand the knowledge of the genetic PC risk through miRNA-related SNPs and show the usefulness of functional prioritization to identify genetic polymorphisms associated with PC risk.
1st Department of Medicine Medical School University of Pécs Pécs Hungary
1st Faculty of Medicine Institute of Biology and Medical Genetics Charles University Prague Czechia
ARC NET Centre for Applied Research on Cancer University and Hospital Trust of Verona Verona Italy
Biomedical Center Faculty of Medicine in Pilsen Charles University Pilsen Czechia
Blood Transfusion Service Azienda Ospedaliero Universitaria Meyer Children's Hospital Florence Italy
Department for Determinants of Chronic Diseases Bilthoven Netherlands
Department of Biology University of Pisa Pisa Italy
Department of Biomedical Sciences Humanitas University Milan Italy
Department of Digestive Tract Diseases Medical University of Lodz Lodz Poland
Department of Gastroenterology San Carlo Hospital Potenza Italy
Department of General Surgery University of Heidelberg Heidelberg Germany
Department of Hematology Institute of Hematology and Transfusion Medicine Warsaw Poland
Department of Medicine Centre for Translational Medicine University of Szeged Szeged Hungary
Department of Medicine DIMED Padua University Hospital Padua Italy
Department of Radiology and Oncology Institute of Cancer of São Paulo São Paulo Brazil
Department of Surgery DiSCOG Padua University Hospital Padua Italy
Department of Surgery Erasmus Medical Center Erasmus University Rotterdam Netherlands
Digestive and Liver Disease Unit Sant'Andrea Hospital Rome Italy
Division of General and Transplant Surgery University of Pisa Pisa Italy
Division of Preventive Oncology German Cancer Research Center Heidelberg Germany
Endoscopic Surgery Department Hippocratio General Hospital of Athens Athens Greece
Faculty of Medicine and Psychology Sapienza University of Rome Rome Italy
Faculty of Medicine University of São Paulo São Paulo Brazil
Fundeni Clinical Institute Bucharest Romania
Genetic and Molecular Epidemiology Group Spanish National Cancer Research Centre Madrid Spain
Genomic Epidemiology Group German Cancer Research Center Heidelberg Germany
German Cancer Consortium Heidelberg Germany
Institute for Risk Assessment Sciences Utrecht University Utrecht Netherlands
Institute for Translational Medicine Medical School University of Pécs Pécs Hungary
Laboratory for Applied Science and Technology in Health Carlos Chagas Institute Curitiba Brazil
Laboratory of Biology Medical School National and Kapodistrian University of Athens Athens Greece
Medical Faculty Heidelberg University of Heidelberg Heidelberg Germany
Pancreatic Surgery Unit Humanitas Clinical and Research Center IRCCS Milan Italy
Szent György University Teaching Hospital of County Fejér Székesfehérvár Hungary
References provided by Crossref.org
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- $a Lu, Ye $u Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany $u Medical Faculty Heidelberg, University of Heidelberg, Heidelberg, Germany
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- $a Association of Genetic Variants Affecting microRNAs and Pancreatic Cancer Risk / $c Y. Lu, C. Corradi, M. Gentiluomo, E. López de Maturana, GE. Theodoropoulos, S. Roth, E. Maiello, L. Morelli, L. Archibugi, JR. Izbicki, P. Sarlós, V. Kiudelis, M. Oliverius, MN. Aoki, Y. Vashist, CHJ. van Eijck, M. Gazouli, R. Talar-Wojnarowska, A. Mambrini, R. Pezzilli, B. Bueno-de-Mesquita, P. Hegyi, P. Souček, JP. Neoptolemos, G. Di Franco, C. Sperti, EF. Kauffmann, V. Hlaváč, FG. Uzunoğlu, S. Ermini, E. Małecka-Panas, M. Lucchesi, G. Vanella, F. Dijk, B. Mohelníková-Duchoňová, F. Bambi, MC. Petrone, K. Jamroziak, F. Guo, K. Kolarova, G. Capretti, AC. Milanetto, L. Ginocchi, M. Loveček, M. Puzzono, HWM. van Laarhoven, S. Carrara, A. Ivanauskas, K. Papiris, D. Basso, PG. Arcidiacono, F. Izbéki, R. Chammas, P. Vodicka, T. Hackert, C. Pasquali, ML. Piredda, E. Costello-Goldring, GM. Cavestro, A. Szentesi, F. Tavano, B. Włodarczyk, H. Brenner, E. Kreivenaite, X. Gao, S. Bunduc, RCH. Vermeulen, MA. Schneider, A. Latiano, D. Gioffreda, SGG. Testoni, J. Kupcinskas, RT. Lawlor, G. Capurso, N. Malats, D. Campa, F. Canzian
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- $a Genetic factors play an important role in the susceptibility to pancreatic cancer (PC). However, established loci explain a small proportion of genetic heritability for PC; therefore, more progress is needed to find the missing ones. We aimed at identifying single nucleotide polymorphisms (SNPs) affecting PC risk through effects on micro-RNA (miRNA) function. We searched in silico the genome for SNPs in miRNA seed sequences or 3 prime untranslated regions (3'UTRs) of miRNA target genes. Genome-wide association data of PC cases and controls from the Pancreatic Cancer Cohort (PanScan) Consortium and the Pancreatic Cancer Case-Control (PanC4) Consortium were re-analyzed for discovery, and genotyping data from two additional consortia (PanGenEU and PANDoRA) were used for replication, for a total of 14,062 cases and 11,261 controls. None of the SNPs reached genome-wide significance in the meta-analysis, but for three of them the associations were in the same direction in all the study populations and showed lower value of p in the meta-analyses than in the discovery phase. Specifically, rs7985480 was consistently associated with PC risk (OR = 1.12, 95% CI 1.07-1.17, p = 3.03 × 10-6 in the meta-analysis). This SNP is in linkage disequilibrium (LD) with rs2274048, which modulates binding of various miRNAs to the 3'UTR of UCHL3, a gene involved in PC progression. In conclusion, our results expand the knowledge of the genetic PC risk through miRNA-related SNPs and show the usefulness of functional prioritization to identify genetic polymorphisms associated with PC risk.
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