Polymorphic variants involved in methylation regulation: a strategy to discover risk loci for pancreatic ductal adenocarcinoma

Chiara Corradi; Giulia Lencioni; Manuel Gentiluomo; Alessio Felici; Anna Latiano; Gediminas Kiudelis; Casper H. J. van Eijck; Katalin Marta; Rita T. Lawlor; Francesca Tavano; Ugo Boggi; Frederike Dijk; Giulia Martina Cavestro; Roel C. H. Vermeulen; Thilo Hackert; Maria Chiara Petrone; Faik G. ntac Uzunoğ lu; Livia Archibugi; Jakob R. Izbicki; Luca Morelli; Alessandro Zerbi; Stefano Landi; Hannah Stocker; Renata Talar-Wojnarowska; Gregorio di Franco; P. ter Hegyi; Cosimo Sperti; Silvia Carrara; Gabriele Capurso; Maria Gazouli; Hermann Brenner; Stefania Bunduc; Olivier Busch; Francesco Perri; Martin Oliverius; P. ter Jeno Hegyi; Mara Goetz; Pasquale Scognamiglio; Andrea Mambrini; Paolo Giorgio Arcidiacono; Edita Kreivenaite; Juozas Kupcinskas; Tamas Hussein; Stefano Ermini; Anna Caterina Milanetto; Pavel Vodicka; Vytautas Kiudelis; Viktor Hlaváč; Pavel Soucek; George E. Theodoropoulos; Daniela Basso; John P. Neoptolemos; Mateus Nóbrega Aoki; Raffaele Pezzilli; Claudio Pasquali; Roger Chammas; Sabrina Gloria Giulia Testoni; Beatrice Mohelnikova-Duchonova; Maurizio Lucchesi; Cosmeri Rizzato; Federico Canzian; Daniele Campa

doi:https://doi.org/10.1136/jmg-2022-108910

Polymorphic variants involved in methylation regulation: a strategy to discover risk loci for pancreatic ductal adenocarcinoma

Chiara Corradi, Giulia Lencioni, Manuel Gentiluomo, Alessio Felici, Anna Latiano, Gediminas Kiudelis, Casper H. J. van Eijck, Katalin Marta, Rita T. Lawlor, Francesca Tavano, Ugo Boggi, Frederike Dijk, Giulia Martina Cavestro, Roel C. H. Vermeulen, Thilo Hackert, Maria Chiara Petrone, Faik G. ntac Uzunoğ lu, Livia Archibugi, Jakob R. Izbicki, Luca MorelliAlessandro Zerbi, Stefano Landi, Hannah Stocker, Renata Talar-Wojnarowska, Gregorio di Franco, P. ter Hegyi, Cosimo Sperti, Silvia Carrara, Gabriele Capurso, Maria Gazouli, Hermann Brenner, Stefania Bunduc, Olivier Busch, Francesco Perri, Martin Oliverius, P. ter Jeno Hegyi, Mara Goetz, Pasquale Scognamiglio, Andrea Mambrini, Paolo Giorgio Arcidiacono, Edita Kreivenaite, Juozas Kupcinskas, Tamas Hussein, Stefano Ermini, Anna Caterina Milanetto, Pavel Vodicka, Vytautas Kiudelis, Viktor Hlaváč, Pavel Soucek, George E. Theodoropoulos, Daniela Basso, John P. Neoptolemos, Mateus Nóbrega Aoki, Raffaele Pezzilli, Claudio Pasquali, Roger Chammas, Sabrina Gloria Giulia Testoni, Beatrice Mohelnikova-Duchonova, Maurizio Lucchesi, Cosmeri Rizzato, Federico Canzian, Daniele Campa

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Introduction: Only a small number of risk factors for pancreatic ductal adenocarcinoma (PDAC) has been established. Several studies identified a role of epigenetics and of deregulation of DNA methylation. DNA methylation is variable across a lifetime and in different tissues; nevertheless, its levels can be regulated by genetic variants like methylation quantitative trait loci (mQTLs), which can be used as a surrogate. Materials and methods: We scanned the whole genome for mQTLs and performed an association study in 14 705 PDAC cases and 246 921 controls. The methylation data were obtained from whole blood and pancreatic cancer tissue through online databases. We used the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case-Control Consortium genome-wide association study (GWAS) data as discovery phase and the Pancreatic Disease Research consortium, the FinnGen project and the Japan Pancreatic Cancer Research consortium GWAS as replication phase. Results: The C allele of 15q26.1-rs12905855 showed an association with a decreased risk of PDAC (OR=0.90, 95% CI 0.87 to 0.94, p=4.93×10-8 in the overall meta-analysis), reaching genome-level statistical significance. 15q26.1-rs12905855 decreases the methylation of a 'C-phosphate-G' (CpG) site located in the promoter region of the RCCD1 antisense (RCCD1-AS1) gene which, when expressed, decreases the expression of the RCC1 domain-containing (RCCD1) gene (part of a histone demethylase complex). Thus, it is possible that the rs12905855 C-allele has a protective role in PDAC development through an increase of RCCD1 gene expression, made possible by the inactivity of RCCD1-AS1. Conclusion: We identified a novel PDAC risk locus which modulates cancer risk by controlling gene expression through DNA methylation.

Original language	English
Article number	108910
Pages (from-to)	980-986
Number of pages	7
Journal	Journal of medical genetics
Volume	60
Issue number	10
Early online date	2023
DOIs	https://doi.org/10.1136/jmg-2022-108910
Publication status	Published - 1 Oct 2023

Keywords

DNA Methylation
Genetic Variation
Genetics
Germ-Line Mutation
Molecular Epidemiology

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https://doi.org/10.1136/jmg-2022-108910

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Corradi, C., Lencioni, G., Gentiluomo, M., Felici, A., Latiano, A., Kiudelis, G., van Eijck, C. H. J., Marta, K., Lawlor, R. T., Tavano, F., Boggi, U., Dijk, F., Cavestro, G. M., Vermeulen, R. C. H., Hackert, T., Petrone, M. C., Uzunoğ lu, F. G. N., Archibugi, L., Izbicki, J. R., ... Campa, D. (2023). Polymorphic variants involved in methylation regulation: a strategy to discover risk loci for pancreatic ductal adenocarcinoma. Journal of medical genetics, 60(10), 980-986. Article 108910. https://doi.org/10.1136/jmg-2022-108910

@article{f9c651e56c3c481e8e13f799a95de572,

title = "Polymorphic variants involved in methylation regulation: a strategy to discover risk loci for pancreatic ductal adenocarcinoma",

abstract = "Introduction: Only a small number of risk factors for pancreatic ductal adenocarcinoma (PDAC) has been established. Several studies identified a role of epigenetics and of deregulation of DNA methylation. DNA methylation is variable across a lifetime and in different tissues; nevertheless, its levels can be regulated by genetic variants like methylation quantitative trait loci (mQTLs), which can be used as a surrogate. Materials and methods: We scanned the whole genome for mQTLs and performed an association study in 14 705 PDAC cases and 246 921 controls. The methylation data were obtained from whole blood and pancreatic cancer tissue through online databases. We used the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case-Control Consortium genome-wide association study (GWAS) data as discovery phase and the Pancreatic Disease Research consortium, the FinnGen project and the Japan Pancreatic Cancer Research consortium GWAS as replication phase. Results: The C allele of 15q26.1-rs12905855 showed an association with a decreased risk of PDAC (OR=0.90, 95% CI 0.87 to 0.94, p=4.93×10-8 in the overall meta-analysis), reaching genome-level statistical significance. 15q26.1-rs12905855 decreases the methylation of a 'C-phosphate-G' (CpG) site located in the promoter region of the RCCD1 antisense (RCCD1-AS1) gene which, when expressed, decreases the expression of the RCC1 domain-containing (RCCD1) gene (part of a histone demethylase complex). Thus, it is possible that the rs12905855 C-allele has a protective role in PDAC development through an increase of RCCD1 gene expression, made possible by the inactivity of RCCD1-AS1. Conclusion: We identified a novel PDAC risk locus which modulates cancer risk by controlling gene expression through DNA methylation.",

keywords = "DNA Methylation, Genetic Variation, Genetics, Germ-Line Mutation, Molecular Epidemiology",

author = "Chiara Corradi and Giulia Lencioni and Manuel Gentiluomo and Alessio Felici and Anna Latiano and Gediminas Kiudelis and {van Eijck}, {Casper H. J.} and Katalin Marta and Lawlor, {Rita T.} and Francesca Tavano and Ugo Boggi and Frederike Dijk and Cavestro, {Giulia Martina} and Vermeulen, {Roel C. H.} and Thilo Hackert and Petrone, {Maria Chiara} and {Uzunoğ lu}, {Faik G. ntac} and Livia Archibugi and Izbicki, {Jakob R.} and Luca Morelli and Alessandro Zerbi and Stefano Landi and Hannah Stocker and Renata Talar-Wojnarowska and {di Franco}, Gregorio and Hegyi, {P. ter} and Cosimo Sperti and Silvia Carrara and Gabriele Capurso and Maria Gazouli and Hermann Brenner and Stefania Bunduc and Olivier Busch and Francesco Perri and Martin Oliverius and Hegyi, {P. ter Jeno} and Mara Goetz and Pasquale Scognamiglio and Andrea Mambrini and Arcidiacono, {Paolo Giorgio} and Edita Kreivenaite and Juozas Kupcinskas and Tamas Hussein and Stefano Ermini and Milanetto, {Anna Caterina} and Pavel Vodicka and Vytautas Kiudelis and Viktor Hlav{\'a}{\v c} and Pavel Soucek and Theodoropoulos, {George E.} and Daniela Basso and Neoptolemos, {John P.} and {N{\'o}brega Aoki}, Mateus and Raffaele Pezzilli and Claudio Pasquali and Roger Chammas and Testoni, {Sabrina Gloria Giulia} and Beatrice Mohelnikova-Duchonova and Maurizio Lucchesi and Cosmeri Rizzato and Federico Canzian and Daniele Campa",

note = "Funding Information: This work was supported by intramural funding of DKFZ (to FC); Fondazione Tizzi ( www.fondazionetizzi.it ); Fondazione Arpa ( www.fondazionearpa.it , to DC); and Associazione Italiana per la Ricerca sul Cancro (AIRC IG 2021-26201, to GC). This work was supported by Italian Ministry of Health grants (Ricerca Corrente 2022-2024) to Fondazione 'Casa Sollievo della Sofferenza' IRCCS Hospital, San Giovanni Rotondo (FGU), Italy and by the '5x1000' voluntary contribution. Publisher Copyright: {\textcopyright} 2023 Authors. All rights reserved.",

year = "2023",

month = oct,

day = "1",

doi = "https://doi.org/10.1136/jmg-2022-108910",

language = "English",

volume = "60",

pages = "980--986",

journal = "Journal of medical genetics",

issn = "0022-2593",

publisher = "BMJ Publishing Group",

number = "10",

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Corradi, C, Lencioni, G, Gentiluomo, M, Felici, A, Latiano, A, Kiudelis, G, van Eijck, CHJ, Marta, K, Lawlor, RT, Tavano, F, Boggi, U, Dijk, F, Cavestro, GM, Vermeulen, RCH, Hackert, T, Petrone, MC, Uzunoğ lu, FGN, Archibugi, L, Izbicki, JR, Morelli, L, Zerbi, A, Landi, S, Stocker, H, Talar-Wojnarowska, R, di Franco, G, Hegyi, PT, Sperti, C, Carrara, S, Capurso, G, Gazouli, M, Brenner, H, Bunduc, S, Busch, O, Perri, F, Oliverius, M, Hegyi, PTJ, Goetz, M, Scognamiglio, P, Mambrini, A, Arcidiacono, PG, Kreivenaite, E, Kupcinskas, J, Hussein, T, Ermini, S, Milanetto, AC, Vodicka, P, Kiudelis, V, Hlaváč, V, Soucek, P, Theodoropoulos, GE, Basso, D, Neoptolemos, JP, Nóbrega Aoki, M, Pezzilli, R, Pasquali, C, Chammas, R, Testoni, SGG, Mohelnikova-Duchonova, B, Lucchesi, M, Rizzato, C, Canzian, F & Campa, D 2023, 'Polymorphic variants involved in methylation regulation: a strategy to discover risk loci for pancreatic ductal adenocarcinoma', Journal of medical genetics, vol. 60, no. 10, 108910, pp. 980-986. https://doi.org/10.1136/jmg-2022-108910

TY - JOUR

T1 - Polymorphic variants involved in methylation regulation

T2 - a strategy to discover risk loci for pancreatic ductal adenocarcinoma

AU - Corradi, Chiara

AU - Lencioni, Giulia

AU - Gentiluomo, Manuel

AU - Felici, Alessio

AU - Latiano, Anna

AU - Kiudelis, Gediminas

AU - van Eijck, Casper H. J.

AU - Marta, Katalin

AU - Lawlor, Rita T.

AU - Tavano, Francesca

AU - Boggi, Ugo

AU - Dijk, Frederike

AU - Cavestro, Giulia Martina

AU - Vermeulen, Roel C. H.

AU - Hackert, Thilo

AU - Petrone, Maria Chiara

AU - Uzunoğ lu, Faik G. ntac

AU - Archibugi, Livia

AU - Izbicki, Jakob R.

AU - Morelli, Luca

AU - Zerbi, Alessandro

AU - Landi, Stefano

AU - Stocker, Hannah

AU - Talar-Wojnarowska, Renata

AU - di Franco, Gregorio

AU - Hegyi, P. ter

AU - Sperti, Cosimo

AU - Carrara, Silvia

AU - Capurso, Gabriele

AU - Gazouli, Maria

AU - Brenner, Hermann

AU - Bunduc, Stefania

AU - Busch, Olivier

AU - Perri, Francesco

AU - Oliverius, Martin

AU - Hegyi, P. ter Jeno

AU - Goetz, Mara

AU - Scognamiglio, Pasquale

AU - Mambrini, Andrea

AU - Arcidiacono, Paolo Giorgio

AU - Kreivenaite, Edita

AU - Kupcinskas, Juozas

AU - Hussein, Tamas

AU - Ermini, Stefano

AU - Milanetto, Anna Caterina

AU - Vodicka, Pavel

AU - Kiudelis, Vytautas

AU - Hlaváč, Viktor

AU - Soucek, Pavel

AU - Theodoropoulos, George E.

AU - Basso, Daniela

AU - Neoptolemos, John P.

AU - Nóbrega Aoki, Mateus

AU - Pezzilli, Raffaele

AU - Pasquali, Claudio

AU - Chammas, Roger

AU - Testoni, Sabrina Gloria Giulia

AU - Mohelnikova-Duchonova, Beatrice

AU - Lucchesi, Maurizio

AU - Rizzato, Cosmeri

AU - Canzian, Federico

AU - Campa, Daniele

N1 - Funding Information: This work was supported by intramural funding of DKFZ (to FC); Fondazione Tizzi ( www.fondazionetizzi.it ); Fondazione Arpa ( www.fondazionearpa.it , to DC); and Associazione Italiana per la Ricerca sul Cancro (AIRC IG 2021-26201, to GC). This work was supported by Italian Ministry of Health grants (Ricerca Corrente 2022-2024) to Fondazione 'Casa Sollievo della Sofferenza' IRCCS Hospital, San Giovanni Rotondo (FGU), Italy and by the '5x1000' voluntary contribution. Publisher Copyright: © 2023 Authors. All rights reserved.

PY - 2023/10/1

Y1 - 2023/10/1

N2 - Introduction: Only a small number of risk factors for pancreatic ductal adenocarcinoma (PDAC) has been established. Several studies identified a role of epigenetics and of deregulation of DNA methylation. DNA methylation is variable across a lifetime and in different tissues; nevertheless, its levels can be regulated by genetic variants like methylation quantitative trait loci (mQTLs), which can be used as a surrogate. Materials and methods: We scanned the whole genome for mQTLs and performed an association study in 14 705 PDAC cases and 246 921 controls. The methylation data were obtained from whole blood and pancreatic cancer tissue through online databases. We used the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case-Control Consortium genome-wide association study (GWAS) data as discovery phase and the Pancreatic Disease Research consortium, the FinnGen project and the Japan Pancreatic Cancer Research consortium GWAS as replication phase. Results: The C allele of 15q26.1-rs12905855 showed an association with a decreased risk of PDAC (OR=0.90, 95% CI 0.87 to 0.94, p=4.93×10-8 in the overall meta-analysis), reaching genome-level statistical significance. 15q26.1-rs12905855 decreases the methylation of a 'C-phosphate-G' (CpG) site located in the promoter region of the RCCD1 antisense (RCCD1-AS1) gene which, when expressed, decreases the expression of the RCC1 domain-containing (RCCD1) gene (part of a histone demethylase complex). Thus, it is possible that the rs12905855 C-allele has a protective role in PDAC development through an increase of RCCD1 gene expression, made possible by the inactivity of RCCD1-AS1. Conclusion: We identified a novel PDAC risk locus which modulates cancer risk by controlling gene expression through DNA methylation.

AB - Introduction: Only a small number of risk factors for pancreatic ductal adenocarcinoma (PDAC) has been established. Several studies identified a role of epigenetics and of deregulation of DNA methylation. DNA methylation is variable across a lifetime and in different tissues; nevertheless, its levels can be regulated by genetic variants like methylation quantitative trait loci (mQTLs), which can be used as a surrogate. Materials and methods: We scanned the whole genome for mQTLs and performed an association study in 14 705 PDAC cases and 246 921 controls. The methylation data were obtained from whole blood and pancreatic cancer tissue through online databases. We used the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case-Control Consortium genome-wide association study (GWAS) data as discovery phase and the Pancreatic Disease Research consortium, the FinnGen project and the Japan Pancreatic Cancer Research consortium GWAS as replication phase. Results: The C allele of 15q26.1-rs12905855 showed an association with a decreased risk of PDAC (OR=0.90, 95% CI 0.87 to 0.94, p=4.93×10-8 in the overall meta-analysis), reaching genome-level statistical significance. 15q26.1-rs12905855 decreases the methylation of a 'C-phosphate-G' (CpG) site located in the promoter region of the RCCD1 antisense (RCCD1-AS1) gene which, when expressed, decreases the expression of the RCC1 domain-containing (RCCD1) gene (part of a histone demethylase complex). Thus, it is possible that the rs12905855 C-allele has a protective role in PDAC development through an increase of RCCD1 gene expression, made possible by the inactivity of RCCD1-AS1. Conclusion: We identified a novel PDAC risk locus which modulates cancer risk by controlling gene expression through DNA methylation.

KW - DNA Methylation

KW - Genetic Variation

KW - Genetics

KW - Germ-Line Mutation

KW - Molecular Epidemiology

UR - http://www.scopus.com/inward/record.url?scp=85159235636&partnerID=8YFLogxK

U2 - https://doi.org/10.1136/jmg-2022-108910

DO - https://doi.org/10.1136/jmg-2022-108910

M3 - Article

C2 - 37130759

SN - 0022-2593

VL - 60

SP - 980

EP - 986

JO - Journal of medical genetics

JF - Journal of medical genetics

IS - 10

M1 - 108910

ER -

Polymorphic variants involved in methylation regulation: a strategy to discover risk loci for pancreatic ductal adenocarcinoma

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