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 Pezzilli; Bas 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

doi:10.3389/fgene.2021.693933

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 Pezzilli

Bas 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

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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 language	English
Article number	693933
Journal	Frontiers in Genetics
Volume	12
DOIs	https://doi.org/10.3389/fgene.2021.693933 https://doi.org/10.3389/fgene.2021.693933
Publication status	Published - 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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10.3389/fgene.2021.693933

Association of Genetic Variants Affecting microRNAs and Pancreatic Cancer RiskFinal published version, 1.43 MBLicence: CC BY
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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., ... Canzian, F. (2021). Association of Genetic Variants Affecting microRNAs and Pancreatic Cancer Risk. Frontiers in Genetics, 12, Article 693933. https://doi.org/10.3389/fgene.2021.693933, https://doi.org/10.3389/fgene.2021.693933

@article{a0345604dbca42c68e24df79baab250b,

title = "Association of Genetic Variants Affecting microRNAs and Pancreatic Cancer Risk",

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.",

author = "Ye Lu and Chiara Corradi and Manuel Gentiluomo and \{L{\'o}pez de Maturana\}, Evangelina and Theodoropoulos, \{George E.\} and Susanne Roth and Evaristo Maiello and Luca Morelli and Livia Archibugi and Izbicki, \{Jakob R.\} and Patricia Sarl{\'o}s and Vytautas Kiudelis and Martin Oliverius and Aoki, \{Mateus N{\'o}brega\} and Yogesh Vashist and \{van Eijck\}, \{Casper H.J.\} and Maria Gazouli and Renata Talar-Wojnarowska and Andrea Mambrini and Raffaele Pezzilli and Bas Bueno-de-Mesquita and P{\'e}ter Hegyi and Pavel Sou{\v c}ek and Neoptolemos, \{John P.\} and \{Di Franco\}, Gregorio and Cosimo Sperti and Kauffmann, \{Emanuele F.\} and Viktor Hlav{\'a}{\v c} and Uzunoğlu, \{Faik G.\} and Stefano Ermini and Ewa Ma{\l}ecka-Panas and Maurizio Lucchesi and Giuseppe Vanella and Frederike Dijk and Beatrice Moheln{\'i}kov{\'a}-Ducho{\v n}ov{\'a} and Franco Bambi and Petrone, \{Maria Chiara\} and Krzysztof Jamroziak and Feng Guo and Katerina Kolarova and Giovanni Capretti and Milanetto, \{Anna Caterina\} and Laura Ginocchi and Martin Love{\v c}ek and Marta Puzzono and \{van Laarhoven\}, \{Hanneke W.M.\} and Silvia Carrara and Audrius Ivanauskas and Konstantinos Papiris and Daniela Basso and Arcidiacono, \{Paolo G.\} and Ferenc Izb{\'e}ki and Roger Chammas and Pavel Vodicka and Thilo Hackert and Claudio Pasquali and Piredda, \{Maria L.\} and Eithne Costello-Goldring and Cavestro, \{Giulia Martina\} and Andrea Szentesi and Francesca Tavano and Barbara W{\l}odarczyk and Hermann Brenner and Edita Kreivenaite and Xin Gao and Stefania Bunduc and Vermeulen, \{Roel C.H.\} and Schneider, \{Martin A.\} and Anna Latiano and Domenica Gioffreda and Testoni, \{Sabrina G.G.\} and Juozas Kupcinskas and Lawlor, \{Rita T.\} and Gabriele Capurso and N{\'u}ria Malats and Daniele Campa and Federico Canzian",

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-W{\"u}rttemberg State Ministry of Science, Research and Arts (Stuttgart, Germany).",

year = "2021",

month = aug,

day = "30",

doi = "10.3389/fgene.2021.693933",

language = "English",

volume = "12",

journal = "Frontiers in Genetics",

issn = "1664-8021",

publisher = "Frontiers Media SA",

}

Lu, Y, Corradi, C, Gentiluomo, M, López de Maturana, E, Theodoropoulos, GE, Roth, S, Maiello, E, Morelli, L, Archibugi, L, Izbicki, JR, Sarlós, P, Kiudelis, V, Oliverius, M, Aoki, MN, Vashist, Y, van Eijck, CHJ, Gazouli, M, Talar-Wojnarowska, R, Mambrini, A, Pezzilli, R, Bueno-de-Mesquita, B, Hegyi, P, Souček, P, Neoptolemos, JP, Di Franco, G, Sperti, C, Kauffmann, EF, Hlaváč, V, Uzunoğlu, FG, Ermini, S, Małecka-Panas, E, Lucchesi, M, Vanella, G, Dijk, F, Mohelníková-Duchoňová, B, Bambi, F, Petrone, MC, Jamroziak, K, Guo, F, Kolarova, K, Capretti, G, Milanetto, AC, Ginocchi, L, Loveček, M, Puzzono, M, van Laarhoven, HWM, Carrara, S, Ivanauskas, A, Papiris, K, Basso, D, Arcidiacono, PG, Izbéki, F, Chammas, R, Vodicka, P, Hackert, T, Pasquali, C, Piredda, ML, Costello-Goldring, E, Cavestro, GM, Szentesi, A, Tavano, F, Włodarczyk, B, Brenner, H, Kreivenaite, E, Gao, X, Bunduc, S, Vermeulen, RCH, Schneider, MA, Latiano, A, Gioffreda, D, Testoni, SGG, Kupcinskas, J, Lawlor, RT, Capurso, G, Malats, N, Campa, D & Canzian, F 2021, 'Association of Genetic Variants Affecting microRNAs and Pancreatic Cancer Risk', Frontiers in Genetics, vol. 12, 693933. https://doi.org/10.3389/fgene.2021.693933, https://doi.org/10.3389/fgene.2021.693933

TY - JOUR

T1 - Association of Genetic Variants Affecting microRNAs and Pancreatic Cancer Risk

AU - Lu, Ye

AU - Corradi, Chiara

AU - Gentiluomo, Manuel

AU - López de Maturana, Evangelina

AU - Theodoropoulos, George E.

AU - Roth, Susanne

AU - Maiello, Evaristo

AU - Morelli, Luca

AU - Archibugi, Livia

AU - Izbicki, Jakob R.

AU - Sarlós, Patricia

AU - Kiudelis, Vytautas

AU - Oliverius, Martin

AU - Aoki, Mateus Nóbrega

AU - Vashist, Yogesh

AU - van Eijck, Casper H.J.

AU - Gazouli, Maria

AU - Talar-Wojnarowska, Renata

AU - Mambrini, Andrea

AU - Pezzilli, Raffaele

AU - Bueno-de-Mesquita, Bas

AU - Hegyi, Péter

AU - Souček, Pavel

AU - Neoptolemos, John P.

AU - Di Franco, Gregorio

AU - Sperti, Cosimo

AU - Kauffmann, Emanuele F.

AU - Hlaváč, Viktor

AU - Uzunoğlu, Faik G.

AU - Ermini, Stefano

AU - Małecka-Panas, Ewa

AU - Lucchesi, Maurizio

AU - Vanella, Giuseppe

AU - Dijk, Frederike

AU - Mohelníková-Duchoňová, Beatrice

AU - Bambi, Franco

AU - Petrone, Maria Chiara

AU - Jamroziak, Krzysztof

AU - Guo, Feng

AU - Kolarova, Katerina

AU - Capretti, Giovanni

AU - Milanetto, Anna Caterina

AU - Ginocchi, Laura

AU - Loveček, Martin

AU - Puzzono, Marta

AU - van Laarhoven, Hanneke W.M.

AU - Carrara, Silvia

AU - Ivanauskas, Audrius

AU - Papiris, Konstantinos

AU - Basso, Daniela

AU - Arcidiacono, Paolo G.

AU - Izbéki, Ferenc

AU - Chammas, Roger

AU - Vodicka, Pavel

AU - Hackert, Thilo

AU - Pasquali, Claudio

AU - Piredda, Maria L.

AU - Costello-Goldring, Eithne

AU - Cavestro, Giulia Martina

AU - Szentesi, Andrea

AU - Tavano, Francesca

AU - Włodarczyk, Barbara

AU - Brenner, Hermann

AU - Kreivenaite, Edita

AU - Gao, Xin

AU - Bunduc, Stefania

AU - Vermeulen, Roel C.H.

AU - Schneider, Martin A.

AU - Latiano, Anna

AU - Gioffreda, Domenica

AU - Testoni, Sabrina G.G.

AU - Kupcinskas, Juozas

AU - Lawlor, Rita T.

AU - Capurso, Gabriele

AU - Malats, Núria

AU - Campa, Daniele

AU - Canzian, Federico

N1 - 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).

PY - 2021/8/30

Y1 - 2021/8/30

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85114813099

U2 - 10.3389/fgene.2021.693933

DO - 10.3389/fgene.2021.693933

M3 - Article

C2 - 34527018

AN - SCOPUS:85114813099

SN - 1664-8021

VL - 12

JO - Frontiers in Genetics

JF - Frontiers in Genetics

M1 - 693933

ER -

Association of Genetic Variants Affecting microRNAs and Pancreatic Cancer Risk

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Bibliographical note

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