Genome Medicine (Feb 2021)
A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer
- Evangelina López de Maturana,
- Juan Antonio Rodríguez,
- Lola Alonso,
- Oscar Lao,
- Esther Molina-Montes,
- Isabel Adoración Martín-Antoniano,
- Paulina Gómez-Rubio,
- Rita Lawlor,
- Alfredo Carrato,
- Manuel Hidalgo,
- Mar Iglesias,
- Xavier Molero,
- Matthias Löhr,
- Christopher Michalski,
- José Perea,
- Michael O’Rorke,
- Victor Manuel Barberà,
- Adonina Tardón,
- Antoni Farré,
- Luís Muñoz-Bellvís,
- Tanja Crnogorac-Jurcevic,
- Enrique Domínguez-Muñoz,
- Thomas Gress,
- William Greenhalf,
- Linda Sharp,
- Luís Arnes,
- Lluís Cecchini,
- Joaquim Balsells,
- Eithne Costello,
- Lucas Ilzarbe,
- Jörg Kleeff,
- Bo Kong,
- Mirari Márquez,
- Josefina Mora,
- Damian O’Driscoll,
- Aldo Scarpa,
- Weimin Ye,
- Jingru Yu,
- PanGenEU Investigators,
- Montserrat García-Closas,
- Manolis Kogevinas,
- Nathaniel Rothman,
- Debra T Silverman,
- SBC/EPICURO Investigators,
- Demetrius Albanes,
- Alan A Arslan,
- Laura Beane-Freeman,
- Paige M Bracci,
- Paul Brennan,
- Bas Bueno-de-Mesquita,
- Julie Buring,
- Federico Canzian,
- Margaret Du,
- Steve Gallinger,
- J Michael Gaziano,
- Phyllis J Goodman,
- Marc Gunter,
- Loic LeMarchand,
- Donghui Li,
- Rachael E Neale,
- Ulrika Peters,
- Gloria M Petersen,
- Harvey A Risch,
- Maria José Sánchez,
- Xiao-Ou Shu,
- Mark D Thornquist,
- Kala Visvanathan,
- Wei Zheng,
- Stephen J Chanock,
- Douglas Easton,
- Brian M Wolpin,
- Rachael Z Stolzenberg-Solomon,
- Alison P Klein,
- Laufey T Amundadottir,
- Marc A Marti-Renom,
- Francisco X Real,
- Núria Malats
Affiliations
- Evangelina López de Maturana
- Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center (CNIO)
- Juan Antonio Rodríguez
- CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST)
- Lola Alonso
- Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center (CNIO)
- Oscar Lao
- CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST)
- Esther Molina-Montes
- Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center (CNIO)
- Isabel Adoración Martín-Antoniano
- Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center (CNIO)
- Paulina Gómez-Rubio
- Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center (CNIO)
- Rita Lawlor
- ARC-Net Centre for Applied Research on Cancer and Department of Pathology and Diagnostics, University and Hospital Trust of Verona
- Alfredo Carrato
- CIBERONC
- Manuel Hidalgo
- Madrid-Norte-Sanchinarro Hospital
- Mar Iglesias
- CIBERONC
- Xavier Molero
- Hospital Universitari Vall d’Hebron, Vall d’Hebron Research Institute (VHIR)
- Matthias Löhr
- Gastrocentrum, Karolinska Institutet and University Hospital
- Christopher Michalski
- Department of Surgery, Technical University of Munich
- José Perea
- Department of Surgery, Hospital 12 de Octubre, and Department of Surgery and Health Research Institute, Fundación Jiménez Díaz
- Michael O’Rorke
- Centre for Public Health, Queen’s University Belfast
- Victor Manuel Barberà
- Molecular Genetics Laboratory, General University Hospital of Elche
- Adonina Tardón
- Department of Medicine, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Instituto de Investigación Sanitaria del Principado de Asturias (ISPA)
- Antoni Farré
- Department of Gastroenterology and Clinical Biochemistry, Hospital de la Santa Creu i Sant Pau
- Luís Muñoz-Bellvís
- CIBERONC
- Tanja Crnogorac-Jurcevic
- Barts Cancer Institute, Centre for Molecular Oncology, Queen Mary University of London
- Enrique Domínguez-Muñoz
- Department of Gastroenterology, University Clinical Hospital of Santiago de Compostela
- Thomas Gress
- Department of Gastroenterology, University Hospital of Giessen and Marburg
- William Greenhalf
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool
- Linda Sharp
- National Cancer Registry Ireland and HRB Clinical Research Facility, University College Cork
- Luís Arnes
- Centre for Stem Cell Research and Developmental Biology, University of Copenhagen
- Lluís Cecchini
- CIBERONC
- Joaquim Balsells
- Hospital Universitari Vall d’Hebron, Vall d’Hebron Research Institute (VHIR)
- Eithne Costello
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool
- Lucas Ilzarbe
- CIBERONC
- Jörg Kleeff
- Department of Surgery, Technical University of Munich
- Bo Kong
- Department of Surgery, Technical University of Munich
- Mirari Márquez
- Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center (CNIO)
- Josefina Mora
- Department of Gastroenterology and Clinical Biochemistry, Hospital de la Santa Creu i Sant Pau
- Damian O’Driscoll
- National Cancer Registry Ireland and HRB Clinical Research Facility, University College Cork
- Aldo Scarpa
- ARC-Net Centre for Applied Research on Cancer and Department of Pathology and Diagnostics, University and Hospital Trust of Verona
- Weimin Ye
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet
- Jingru Yu
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet
- PanGenEU Investigators
- Montserrat García-Closas
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health
- Manolis Kogevinas
- CIBERESP
- Nathaniel Rothman
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health
- Debra T Silverman
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health
- SBC/EPICURO Investigators
- Demetrius Albanes
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health
- Alan A Arslan
- Department of Obstetrics and Gynecology, New York University School of Medicine
- Laura Beane-Freeman
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health
- Paige M Bracci
- Department of Epidemiology and Biostatistics, University of California
- Paul Brennan
- International Agency for Research on Cancer (IARC)
- Bas Bueno-de-Mesquita
- Deparment for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM)
- Julie Buring
- Division of Preventive Medicine, Brigham and Women’s Hospital
- Federico Canzian
- Genomic Epidemiology Group, German Cancer Research Center (DKFZ
- Margaret Du
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center
- Steve Gallinger
- Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health System
- J Michael Gaziano
- Departments of Medicine, Brigham and Women’s Hospital, VA Boston and Harvard Medical School
- Phyllis J Goodman
- SWOG Statistical Center, Fred Hutchinson Cancer Research Center
- Marc Gunter
- International Agency for Research on Cancer (IARC)
- Loic LeMarchand
- Cancer Epidemiology Program, University of Hawaii Cancer Center
- Donghui Li
- University of Texas MD Anderson Cancer Center
- Rachael E Neale
- Population Health Department, QIMR Berghofer Medical Research Institute
- Ulrika Peters
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center
- Gloria M Petersen
- Department of Health Sciences Research, Mayo Clinic College of Medicine
- Harvey A Risch
- Department of Chronic Disease Epidemiology, Yale School of Public Health
- Maria José Sánchez
- Escuela Andaluza de Salud Pública (EASP)
- Xiao-Ou Shu
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine
- Mark D Thornquist
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center
- Kala Visvanathan
- Department of Health Sciences Research, Mayo Clinic College of Medicine
- Wei Zheng
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine
- Stephen J Chanock
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health
- Douglas Easton
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge
- Brian M Wolpin
- Department Medical Oncology, Dana-Farber Cancer Institute
- Rachael Z Stolzenberg-Solomon
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health
- Alison P Klein
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine
- Laufey T Amundadottir
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health
- Marc A Marti-Renom
- National Centre for Genomic Analysis (CNAG), Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Universitat Pompeu Fabra (UPF), ICREA
- Francisco X Real
- CIBERONC
- Núria Malats
- Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center (CNIO)
- DOI
- https://doi.org/10.1186/s13073-020-00816-4
- Journal volume & issue
-
Vol. 13,
no. 1
pp. 1 – 18
Abstract
Abstract Background 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. Methods 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. Results 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. Conclusions 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.
Keywords
- Pancreatic cancer risk
- Genome-wide association analysis
- Genetic susceptibility
- 3D genomic structure
- Local indices of genome spatial autocorrelation
