Association of Genetic Variants Affecting microRNAs and Pancreatic Cancer Risk
Lu, Y.; Corradi, C.; Gentiluomo, M.; López de Maturana, E.; Theodoropoulos, G.E.; Roth, S.; Maiello, E.; Morelli, L.; Archibugi, L.; Izbicki, J.R.; Sarlós, P.; Kiudelis, V.; Oliverius, M.; Aoki, M.N.; Vashist, Y.; van Eijck, C.H.J.; Gazouli, M.; Talar-Wojnarowska, R.; Mambrini, A.; Pezzilli, R.; Bueno-de-Mesquita, B.; Hegyi, P.; Souček, P.; Neoptolemos, J.P.; Di Franco, G.; Sperti, C.; Kauffmann, E.F.; Hlaváč, V.; Uzunoğlu, F.G.; Ermini, S.; Małecka-Panas, E.; Lucchesi, M.; Vanella, G.; Dijk, F.; Mohelníková-Duchoňová, B.; Bambi, F.; Petrone, M.C.; Jamroziak, K.; Guo, F.; Kolarova, K.; Capretti, G.; Milanetto, A.C.; Ginocchi, L.; Loveček, M.; Puzzono, M.; van Laarhoven, H.W.M.; Carrara, S.; Ivanauskas, A.; Papiris, K.; Basso, D.; Arcidiacono, P.G.; Izbéki, F.; Chammas, R.; Vodicka, P.; Hackert, T.; Pasquali, C.; Piredda, M.L.; Costello-Goldring, E.; Cavestro, G.M.; Szentesi, A.; Tavano, F.; Włodarczyk, B.; Brenner, H.; Kreivenaite, E.; Gao, X.; Bunduc, S.; Vermeulen, R.C.H.; Schneider, M.A.; Latiano, A.; Gioffreda, D.; Testoni, S.G.G.; Kupcinskas, J.; Lawlor, R.T.; Capurso, G.; Malats, N.; Campa, D.; Canzian, F.
(2021) Frontiers in Genetics, volume 12, pp. 1 - 11
(Article)
Abstract
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
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(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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Keywords: genetic polymorphisms, miRNA, pancreatic cancer, pancreatic ductal adenocarcinoma, susceptibility, Molecular Medicine, Genetics, Genetics(clinical)
ISSN: 1664-8021
Publisher: Frontiers Media S.A.
Note: Funding Information: The research used the genotyping data provided by the EPIC, we would like to thank the contributors from the United Kingdom. The EPIC-Norfolk study (DOI 10.22025/2019.10.105.00004) has received funding from the Medical Research Council (MR/N003284/1 and MC-UU_12015/1) and Cancer Research United Kingdom (C864/A14136). We are grateful to all the participants who have been part of the project and to the many members of the study teams at the University of Cambridge who have enabled this research. Funding. This work was supported by intramural funding of DKFZ; Fondazione Tizzi (www.fondazionetizzi.it); Fondazione Arpa (www.fondazionearpa.it); the Italian Ministry of Health grants (5 ? 1000); Associazione Italiana per la Ricerca sul Cancro (AIRC 5 ? 1000; 12182); Fondazione Italiana Malattie Pancreas ? Ministero Salute (FIMPCUP_J38D19000690001); Fondazione Cariverona: Oncology Biobank Project ?Antonio Schiavi? (prot. 203885/2017); the Ministry of Health of the Czechia grants (NV19-09-00088 and NV19-08-00113); Palacky University Olomouc grant (IGA_LF_2020_005); and the Ministry of Education, Youth and Sports of the Czechia project INTER-COST (LTC19015). The PanGenEU has been partially supported by Fondo de Investigaciones Sanitarias (FIS), Instituto de Salud Carlos III, Spain (PI0902102, PI12/01635, PI12/00815, PI15/01573, and PI18/01347), and EU-6FP (018771-MOLDIAG-PACA) and EU-FP7-HEALTH (259737-CANCERALIAand 256974-EPC-TM-Net) projects and in the UK by funding of EUROPAC by Pancreatic Cancer United Kingdom. The ESTHER study was funded by the Baden-W?rttemberg State Ministry of Science, Research and Arts (Stuttgart, Germany). Publisher Copyright: © Copyright © 2021 Lu, Corradi, Gentiluomo, López de Maturana, Theodoropoulos, Roth, Maiello, Morelli, Archibugi, Izbicki, Sarlós, Kiudelis, Oliverius, Aoki, Vashist, van Eijck, Gazouli, Talar-Wojnarowska, Mambrini, Pezzilli, Bueno-de-Mesquita, Hegyi, Souček, Neoptolemos, Di Franco, Sperti, Kauffmann, Hlaváč, Uzunoğlu, Ermini, Małecka-Panas, Lucchesi, Vanella, Dijk, Mohelníková-Duchoňová, Bambi, Petrone, Jamroziak, Guo, Kolarova, Capretti, Milanetto, Ginocchi, Loveček, Puzzono, van Laarhoven, Carrara, Ivanauskas, Papiris, Basso, Arcidiacono, Izbéki, Chammas, Vodicka, Hackert, Pasquali, Piredda, Costello-Goldring, Cavestro, Szentesi, Tavano, Włodarczyk, Brenner, Kreivenaite, Gao, Bunduc, Vermeulen, Schneider, Latiano, Gioffreda, Testoni, Kupcinskas, Lawlor, Capurso, Malats, Campa and Canzian.
(Peer reviewed)
