Polymorphic variants involved in methylation regulation: a strategy to discover risk loci for pancreatic ductal adenocarcinoma
Chiara Corradi
1, 2
,
Giulia Lencioni
1, 2
,
Manuel Gentiluomo
1, 2
,
Alessio Felici
1, 2
,
Anna Latiano
3, 4
,
Gediminas Kiudelis
5, 6
,
Casper H. J. van Eijck
7, 8
,
Katalin Marta
9, 10, 11
,
Rita T. Lawlor
12, 13
,
Francesca Tavano
3, 4
,
Ugo Boggi
14, 15
,
Frederike Dijk
16, 17
,
Giulia Martina Cavestro
18, 19
,
Roel C. H. Vermeulen
20
,
Thilo Hackert
21, 22
,
Maria Chiara Petrone
23, 24
,
Faik Güntac Uzunoğlu
25, 26
,
Livia Archibugi
23, 24, 27, 28
,
Jakob R. Izbicki
25, 26
,
Luca Morelli
29, 30
,
Alessandro Zerbi
31, 32, 33, 34
,
Stefano Landi
1, 2
,
Hannah Stocker
35, 36, 37, 38
,
Renata Talar-Wojnarowska
39, 40
,
Gregorio Di Franco
29, 30
,
Péter Hegyi
9, 10, 11, 41, 42, 43, 44
,
Cosimo Sperti
45, 46
,
Silvia Carrara
32, 47
,
Gabriele Capurso
23, 24, 27, 28
,
Maria Gazouli
48, 49
,
Hermann Brenner
35, 36, 50, 51
,
Stefania Bunduc
9, 10, 11, 52
,
Olivier Busch
17, 53
,
Francesco Perri
3, 4
,
Martin Oliverius
54, 55
,
Péter Jeno Hegyi
9, 10, 11
,
Mara Goetz
25, 26
,
Pasquale Scognamiglio
25, 26
,
Andrea Mambrini
56, 57
,
Paolo Giorgio Arcidiacono
23, 24
,
Edita Kreivenaite
5, 6
,
Juozas Kupcinskas
5, 6
,
Tamas Hussein
9, 10, 11
,
Stefano Ermini
58, 59
,
Anna Caterina Milanetto
45, 46
,
Pavel Vodicka
60, 61, 62, 63, 64
,
Vytautas Kiudelis
5, 6
,
Viktor Hlaváč
63, 65
,
Pavel Soucek
63, 65
,
George E. Theodoropoulos
49, 66
,
Daniela Basso
46, 67
,
John P. Neoptolemos
21, 22
,
Mateus Nóbrega Aoki
68, 69
,
Raffaele Pezzilli
70
,
Claudio Pasquali
45, 46
,
Roger Chammas
68, 69
,
Sabrina Gloria Giulia Testoni
23, 24
,
Beatrice Mohelnikova-Duchonova
71, 72
,
Lucchesi Maurizio
56, 57
,
Cosmeri Rizzato
2, 73
,
Federico Canzian
36, 74
,
Daniele Campa
1, 2
1
Department of Biology
3
Division of Gastroenterology and Research Laboratory
4
5
Department of Gastroenterology, Institute for Digestive Research, Medical Academy
6
Lithuanian University of Health Sciences
|
7
Department of surgery
9
Center for Traslational Medicine
11
Division of Pancreatic Disease, Heart and Vascular Center
12
ARC-NET, Centre for Applied Research on Cancer
13
University and Hospital Trust of Verona
14
Division of General and Transplant Surgery
18
Division of Experimental Oncology, Gastroenterology and Gastrointestinal Endoscopy Unit
20
University of Utrect
21
Department of general surgery
23
Pancreato-Biliary Endoscopy and Endoscopic Ultrasound, Pancreas Translational and Clinical Research Center
25
Department of General, Visceral and Thoracic Surgery
27
Digestive and Liver Disease Unit
29
General Surgery, Department of Translational Research and New Technologies in Medicine and Surgery
31
Pancreatic Unit
33
Department of Biomedical Sciences
35
Division of Clinical Epidemiology and Aging Research
37
Network Aging Research (NAR)
39
Department of Digestive Tract Diseases
41
Institute for Translational Medicine, Medical School
43
Janos Szentagothai Research Center
45
Department of Surgery-DiSCOG
47
Endoscopic Unit, Department of Gastroenterology
48
Laboratory of Biology, Medical School
51
German Cancer Consortium (DKTK)
54
Department of Surgery, Third Faculty of Medicine
56
Oncology of Massa Carrara, Oncological Department
|
57
Azienda USL Toscana Nord Ovest
58
Blood Transfusion Service
59
Azienda Ospedaliero Universitaria Meyer
60
Department of Molecular Biology of Cancer
62
Biomedical Centre and Department of Surgery, Faculty of Medicine in Pilsen
|
64
First Faculty of Medicine, Institute of Biology and Medical Genetics
65
Biomedical Center, Faculty of Medicine in Pilsen
|
66
First Propaedeutic University Surgery Clinic, Hippocratio General Hospital, Medical School
67
Department of Medicine-DIMED
68
Laboratory for Applied Science and Technology in Health, Carlos Chagas Institute
70
County Medical Association of Potenza
|
71
Department of Oncology, Faculty of Medicine and Dentistry
73
Department of Translational Research and New Technologies in Medicine and Surgery
74
Genomic Epidemiology Group
Publication type: Journal Article
Publication date: 2023-05-02
scimago Q1
wos Q2
SJR: 1.620
CiteScore: 7.9
Impact factor: 3.7
ISSN: 00222593, 14686244
PubMed ID:
37130759
Genetics
Genetics (clinical)
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=4.93×10−8in 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 theRCCD1antisense (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 ofRCCD1gene expression, made possible by the inactivity ofRCCD1-AS1.
Conclusion
We identified a novel PDAC risk locus which modulates cancer risk by controlling gene expression through DNA methylation.
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Corradi C. et al. Polymorphic variants involved in methylation regulation: a strategy to discover risk loci for pancreatic ductal adenocarcinoma // Journal of Medical Genetics. 2023. Vol. 60. No. 10. p. jmg-2022-108910.
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Corradi C. et al. Polymorphic variants involved in methylation regulation: a strategy to discover risk loci for pancreatic ductal adenocarcinoma // Journal of Medical Genetics. 2023. Vol. 60. No. 10. p. jmg-2022-108910.
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@article{2023_Corradi,
author = {Chiara Corradi and Giulia Lencioni and Manuel Gentiluomo and Alessio Felici and Anna Latiano and Gediminas Kiudelis and Casper H. J. van Eijck and Katalin Marta and Rita T. Lawlor and Francesca Tavano and Ugo Boggi and Frederike Dijk and Giulia Martina Cavestro and Roel C. H. Vermeulen and Thilo Hackert and Maria Chiara Petrone and Faik Güntac Uzunoğlu and Livia Archibugi and Jakob R. Izbicki and Luca Morelli and Alessandro Zerbi and Stefano Landi and Hannah Stocker and Renata Talar-Wojnarowska and Gregorio Di Franco and Péter Hegyi 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 Péter Jeno Hegyi and Mara Goetz and Pasquale Scognamiglio and Andrea Mambrini and Paolo Giorgio Arcidiacono and Edita Kreivenaite and Juozas Kupcinskas and Tamas Hussein and Stefano Ermini and Anna Caterina Milanetto and Pavel Vodicka and Vytautas Kiudelis and Viktor Hlaváč and Pavel Soucek and George E. Theodoropoulos and others},
title = {Polymorphic variants involved in methylation regulation: a strategy to discover risk loci for pancreatic ductal adenocarcinoma},
journal = {Journal of Medical Genetics},
year = {2023},
volume = {60},
publisher = {BMJ},
month = {may},
url = {https://doi.org/10.1136/jmg-2022-108910},
number = {10},
pages = {jmg--2022--108910},
doi = {10.1136/jmg-2022-108910}
}
Cite this
MLA
Copy
Corradi, Chiara, et al. “Polymorphic variants involved in methylation regulation: a strategy to discover risk loci for pancreatic ductal adenocarcinoma.” Journal of Medical Genetics, vol. 60, no. 10, May. 2023, pp. jmg-2022-108910. https://doi.org/10.1136/jmg-2022-108910.