A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer
López de Maturana, Evangelina (Centro de Investigación Biomédica en Red de Cáncer)
Rodríguez, Juan Antonio (Centre de Regulació Genòmica)
Alonso, Lola (Centro de Investigación Biomédica en Red de Cáncer)
Lao, Oscar (Centre de Regulació Genòmica)
Molina-Montes, Esther (Centro de Investigación Biomédica en Red de Cáncer)
Martín-Antoniano, Isabel Adoración (Centro de Investigación Biomédica en Red de Cáncer)
Gómez-Rubio, Paulina (Centro de Investigación Biomédica en Red de Cáncer)
Lawlor, Rita (University and Hospital Trust of Verona. ARC-Net Centre for Applied Research on Cancer and Department of Pathology and Diagnostics)
Carrato, Alfredo (Instituto Ramón y Cajal de Investigación Sanitaria (Madrid))
Hidalgo, Manuel (Weill Cornell Medicine)
Iglesias, Mar (Parc de Salut MAR de Barcelona)
Molero, Xavier (Universitat Autònoma de Barcelona. Departament de Medicina)
Löhr, Matthias (Gastrocentrum, Karolinska Institutet and University Hospital)
Michalski, Christopher (Martin-Luther-University Halle-WittenberHalle (Saale). Department of Visceral, Vascular and Endocrine Surgery)
Perea, José (Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz)
O'Rorke, Michael (The University of Iowa. College of Public Health)
Barberà, Victor Manuel (Hospital General Universitario de Elche)
Tardón, Adonina (Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública)
Farré, Antoni (Institut d'Investigació Biomèdica Sant Pau)
Muñoz-Bellvís, Luís (Instituto de Investigación Biomédica de Salamanca)
Crnogorac-Jurcevic, Tanja (Queen Mary University of London. Barts Cancer Institute, Centre for Molecular Oncology)
Domínguez-Muñoz, Enrique (Complejo Hospitalario Universitario de Santiago de Compostela)
Gress, Thomas (University Hospital of Giessen and Marburg (Alemanya))
Greenhalf, William (University of Liverpool. Department of Molecular and Clinical Cancer Medicine)
Sharp, Linda (Newcastle University, Institute of Health & Society)
Arnes, Luís (Columbia University Medical Center. Department of Systems Biology)
Cecchini, Lluís (Parc de Salut MAR de Barcelona)
Balsells, Joaquim (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas)
Costello, Eithne (University of Liverpool. Department of Molecular and Clinical Cancer Medicine)
Ilzarbe, Lucas (Parc de Salut MAR de Barcelona)
Kleeff, Jörg (Martin-Luther-University Halle-WittenberHalle (Saale). Department of Visceral, Vascular and Endocrine Surgery)
Kong, Bo (Technical University of Munich. Department of Surgery)
Márquez, Mirari (Centro de Investigación Biomédica en Red de Cáncer)
Mora Brugués, Josefina (Institut d'Investigació Biomèdica Sant Pau)
O'Driscoll, Damian (University College Cork. National Cancer Registry Ireland and HRB Clinical Research Facility)
Scarpa, Aldo (University and Hospital Trust of Verona. ARC-Net Centre for Applied Research on Cancer and Department of Pathology and Diagnostics)
Ye, Weimin (Karolinska Institutet (Estocolm, Suècia). Department of Medical Epidemiology and Biostatistics)
Yu, Jingru (Karolinska Institutet (Estocolm, Suècia). Department of Medical Epidemiology and Biostatistics)
García-Closas, Montserrat (Centro Nacional de Investigaciones Oncológicas)
Kogevinas, M.. (Hospital del Mar (Barcelona, Catalunya))
Rothman, Nathaniel (Centro Nacional de Investigaciones Oncológicas)
Silverman, Debra T. (Centro Nacional de Investigaciones Oncológicas)
Albanes, Demetrius (Centro Nacional de Investigaciones Oncológicas)
Arslan, Alan A. (New York University School of Medicine. Department of Population Health)
Beane-Freeman, Laura (Centro Nacional de Investigaciones Oncológicas)
Bracci, Paige M. (University of California. Department of Epidemiology and Biostatistics)
Brennan, Paul (International Agency for Research on Cancer (IARC))
Bueno-de-Mesquita, Bas (National Institute for Public Health and the Environment (RIVM). Deparment for Determinants of Chronic Diseases (DCD))
Buring, Julie (Brigham and Women's Hospital (Boston, Estats Units d'Amèrica))
Canzian, Federico (German Cancer Research Center (DKFZ. Genomic Epidemiology Group)
Du, Margaret (Memorial Sloan Kettering Cancer Center)
Gallinger, Steven (Sinai Health System. Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute)
Gaziano, J. Michael (Brigham and Women's Hospital (Boston, Estats Units d'Amèrica))
Goodman, Phyllis J. (SWOG Statistical Center, Fred Hutchinson Cancer Research Center)
Gunter, Marc (International Agency for Research on Cancer (IARC))
LeMarchand, Loic (University of Hawaii Cancer Center. Cancer Epidemiology Program)
Li, Donghui (University of Texas MD Anderson Cancer Center)
Neale, Rachael E. (QIMR Berghofer Medical Research Institute (Brisbane, Austràlia). Population Health Department)
Peters, Ulrika (Fred Hutchinson Cancer Research Center. Division of Public Health Sciences)
Petersen, Gloria M. (Mayo Clinic College of Medicine. Department of Health Sciences Research)
Risch, Harvey A. (Yale School of Public Health. Department of Chronic Disease Epidemiology)
Sánchez, Maria José (Universidad de Granada)
Shu, Xiao-Ou (Vanderbilt University School of Medicine. Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center)
Thornquist, Mark D. (Fred Hutchinson Cancer Research Center. Division of Public Health Sciences)
Visvanathan, Kala (Mayo Clinic College of Medicine. Department of Health Sciences Research)
Zheng, Wei (Vanderbilt University School of Medicine. Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center)
Chanock, Stephen (Centro Nacional de Investigaciones Oncológicas)
Easton, Douglas F (University of Cambridge. Centre for Cancer Genetic Epidemiology)
Wolpin, Brian M. (Dana-Farber Cancer Institute (Boston, Estats Units d'Amèrica))
Stolzenberg-Solomon, Rachael Z. (Centro Nacional de Investigaciones Oncológicas)
Klein, Alison P. (Johns Hopkins School of Medicine. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center)
Amundadottir, Laufey T. (National Cancer Institute (Bethesda, Estats Units d'Amèrica))
Marti-Renom, Marc A. (Universitat Pompeu Fabra. Centre de Regulació Genòmica (CRG-UPF))
Real, Francisco X (Universitat Pompeu Fabra. Departament de Ciències Experimentals i de la Salut)
Malats, Núria (Centro de Investigación Biomédica en Red de Cáncer)

Date:	2021
Abstract:	Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors interplay. To date, 40 GWAS hits have been associated with PC risk in individuals of European descent, explaining 4. 1% of the phenotypic variance. We complemented a new conventional PC GWAS (1D) with genome spatial autocorrelation analysis (2D) permitting to prioritize low frequency variants not detected by GWAS. These were further expanded via Hi-C map (3D) interactions to gain additional insight into the inherited basis of PC. In silico functional analysis of public genomic information allowed prioritization of potentially relevant candidate variants. We identified several new variants located in genes for which there is experimental evidence of their implication in the biology and function of pancreatic acinar cells. Among them is a novel independent variant in NR5A2 (rs3790840) with a meta-analysis p value = 5. 91E−06 in 1D approach and a Local Moran's Index (LMI) = 7. 76 in 2D approach. We also identified a multi-hit region in CASC8 -a lncRNA associated with pancreatic carcinogenesis-with a lowest p value = 6. 91E−05. Importantly, two new PC loci were identified both by 2D and 3D approaches: SIAH3 (LMI = 18. 24), CTRB2/BCAR1 (LMI = 6. 03), in addition to a chromatin interacting region in XBP1 -a major regulator of the ER stress and unfolded protein responses in acinar cells-identified by 3D; all of them with a strong in silico functional support. This multi-step strategy, combined with an in-depth in silico functional analysis, offers a comprehensive approach to advance the study of PC genetic susceptibility and could be applied to other diseases. The online version contains supplementary material available at 10. 1186/s13073-020-00816-4.
Grants:	Instituto de Salud Carlos III PI06-1614 Instituto de Salud Carlos III PI11-01542 Instituto de Salud Carlos III PI09-02102 Instituto de Salud Carlos III PI12-01635 Instituto de Salud Carlos III PI12-00815 Instituto de Salud Carlos III PI15-01573 Instituto de Salud Carlos III PI18-01347 Ministerio de Ciencia e Innovación BFU2017-85926-P European Commission 609989 European Commission 256974
Note:	Altres ajuts: The work was partially supported by Red Temática de Investigación Cooperativa en Cáncer, Spain (#RD12/0036/0034, #RD12/0036/0050, #RD12/0036/0073); Fundación Científica de la AECC, Spain; European Cooperation in Science and Technology COST action #BM1204
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Pancreatic cancer risk ; Genome-wide association analysis ; Genetic susceptibility ; 3D genomic structure ; Local indices of genome spatial autocorrelation
Published in:	Genome Medicine, Vol. 13 (february 2021) , ISSN 1756-994X

DOI: 10.1186/s13073-020-00816-4
PMID: 33517887

18 p, 6.6 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Recerca Sant Pau
Articles > Research articles
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