Association of Genetic Variants Affecting microRNAs and Pancreatic Cancer Risk

Ye Lu, Chiara Corradi, Manuel Gentiluomo, Evangelina López de Maturana, George E. Theodoropoulos, Susanne Roth, Evaristo Maiello, Luca Morelli, Livia Archibugi, Jakob R. Izbicki, Patricia Sarlós, Vytautas Kiudelis, Martin Oliverius, Mateus Nóbrega Aoki, Yogesh Vashist, Casper H.J. van Eijck, Maria Gazouli, Renata Talar-Wojnarowska, Andrea Mambrini, Raffaele PezzilliBas Bueno-de-Mesquita, Péter Hegyi, Pavel Souček, John P. Neoptolemos, Gregorio Di Franco, Cosimo Sperti, Emanuele F. Kauffmann, Viktor Hlaváč, Faik G. Uzunoğlu, Stefano Ermini, Ewa Małecka-Panas, Maurizio Lucchesi, Giuseppe Vanella, Frederike Dijk, Beatrice Mohelníková-Duchoňová, Franco Bambi, Maria Chiara Petrone, Krzysztof Jamroziak, Feng Guo, Katerina Kolarova, Giovanni Capretti, Anna Caterina Milanetto, Laura Ginocchi, Martin Loveček, Marta Puzzono, Hanneke W.M. van Laarhoven, Silvia Carrara, Audrius Ivanauskas, Konstantinos Papiris, Daniela Basso, Paolo G. Arcidiacono, Ferenc Izbéki, Roger Chammas, Pavel Vodicka, Thilo Hackert, Claudio Pasquali, Maria L. Piredda, Eithne Costello-Goldring, Giulia Martina Cavestro, Andrea Szentesi, Francesca Tavano, Barbara Włodarczyk, Hermann Brenner, Edita Kreivenaite, Xin Gao, Stefania Bunduc, Roel C.H. Vermeulen, Martin A. Schneider, Anna Latiano, Domenica Gioffreda, Sabrina G.G. Testoni, Juozas Kupcinskas, Rita T. Lawlor, Gabriele Capurso, Núria Malats, Daniele Campa, Federico Canzian*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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 (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.
Original languageEnglish
Article number693933
JournalFrontiers in Genetics
Volume12
DOIs
Publication statusPublished - 30 Aug 2021

Bibliographical note

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-Württemberg State Ministry of Science, Research and Arts (Stuttgart, Germany).

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