Journal article
A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer
Genome medicine, Vol.13(1), pp.15-15
02/01/2021
DOI: 10.1186/s13073-020-00816-4
PMCID: PMC7849104
PMID: 33517887
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.
Details
- Title: Subtitle
- A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer
- Creators
- Evangelina López de Maturana - CIBERONC, Madrid, SpainJuan Antonio Rodríguez - CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, SpainLola Alonso - CIBERONC, Madrid, SpainOscar Lao - CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, SpainEsther Molina-Montes - CIBERONC, Madrid, SpainIsabel Adoración Martín-Antoniano - CIBERONC, Madrid, SpainPaulina Gómez-Rubio - CIBERONC, Madrid, SpainRita Lawlor - ARC-Net Centre for Applied Research on Cancer and Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, ItalyAlfredo Carrato - Department of Oncology, Ramón y Cajal University Hospital, IRYCIS, Alcala University, Madrid, SpainManuel Hidalgo - Weill Cornell Medicine, New York, USAMar Iglesias - Hospital del Mar-Parc de Salut Mar, Barcelona, SpainXavier Molero - Universitat Autònoma de Barcelona and CIBEREHD, Barcelona, SpainMatthias Löhr - Gastrocentrum, Karolinska Institutet and University Hospital, Stockholm, SwedenChristopher Michalski - Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-University Halle-WittenberHalle (Saale), Halle, GermanyJosé Perea - Department of Surgery, Hospital 12 de Octubre, and Department of Surgery and Health Research Institute, Fundación Jiménez Díaz, Madrid, SpainMichael O'Rorke - College of Public Health, The University of Iowa, Iowa City, IA, USAVictor Manuel Barberà - Molecular Genetics Laboratory, General University Hospital of Elche, Elche, SpainAdonina Tardón - CIBERESP, Madrid, SpainAntoni Farré - Department of Gastroenterology and Clinical Biochemistry, Hospital de la Santa Creu i Sant Pau, Barcelona, SpainLuís Muñoz-Bellvís - Department of Surgery, Hospital Universitario de Salamanca - IBSAL, Universidad de Salamanca, Salamanca, SpainTanja Crnogorac-Jurcevic - Barts Cancer Institute, Centre for Molecular Oncology, Queen Mary University of London, London, UKEnrique Domínguez-Muñoz - Department of Gastroenterology, University Clinical Hospital of Santiago de Compostela, Santiago de Compostela, SpainThomas Gress - Department of Gastroenterology, University Hospital of Giessen and Marburg, Marburg, GermanyWilliam Greenhalf - Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UKLinda Sharp - Newcastle University, Institute of Health & Society, Newcastle, UKLuís Arnes - Department of Systems Biology, Columbia University Medical Center, New York, NY, USALluís Cecchini - Hospital del Mar-Parc de Salut Mar, Barcelona, SpainJoaquim Balsells - Universitat Autònoma de Barcelona and CIBEREHD, Barcelona, SpainEithne Costello - Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UKLucas Ilzarbe - Hospital del Mar-Parc de Salut Mar, Barcelona, SpainJörg Kleeff - Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-University Halle-WittenberHalle (Saale), Halle, GermanyBo Kong - Department of Surgery, Technical University of Munich, Munich, GermanyMirari Márquez - CIBERONC, Madrid, SpainJosefina Mora - Department of Gastroenterology and Clinical Biochemistry, Hospital de la Santa Creu i Sant Pau, Barcelona, SpainDamian O'Driscoll - National Cancer Registry Ireland and HRB Clinical Research Facility, University College Cork, Cork, IrelandAldo Scarpa - ARC-Net Centre for Applied Research on Cancer and Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, ItalyWeimin Ye - Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stokholm, SwedenJingru Yu - Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stokholm, SwedenMontserrat García-Closas - Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USAManolis Kogevinas - Institut Municipal d'Investigació Mèdica - Hospital del Mar, Centre de Recerca en Epidemiologia Ambiental (CREAL), Barcelona, SpainNathaniel Rothman - Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USADebra T Silverman - Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USADemetrius Albanes - Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USAAlan A Arslan - Department of Population Health, New York University School of Medicine, New York, NY, USALaura Beane-Freeman - Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USAPaige M Bracci - Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USAPaul Brennan - International Agency for Research on Cancer (IARC), Lyon, FranceBas Bueno-de-Mesquita - Deparment for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The NetherlandsJulie Buring - Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USAFederico Canzian - Genomic Epidemiology Group, German Cancer Research Center (DKFZ, Heidelberg, GermanyMargaret Du - Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USASteve Gallinger - Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, CanadaJ Michael Gaziano - Departments of Medicine, Brigham and Women's Hospital, VA Boston and Harvard Medical School, Boston, MA, USAPhyllis J Goodman - SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USAMarc Gunter - International Agency for Research on Cancer (IARC), Lyon, FranceLoic LeMarchand - Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USADonghui Li - University of Texas MD Anderson Cancer Center, Houston, TX, USARachael E Neale - Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, AustraliaUlrika Peters - Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USAGloria M Petersen - Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN, USAHarvey A Risch - Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USAMaria José Sánchez - Universidad de Granada, Granada, SpainXiao-Ou Shu - Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USAMark D Thornquist - Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USAKala Visvanathan - Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN, USAWei Zheng - Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USAStephen J Chanock - Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USADouglas Easton - Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UKBrian M Wolpin - Department Medical Oncology, Dana-Farber Cancer Institute, Boston, USARachael Z Stolzenberg-Solomon - Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USAAlison P Klein - Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USALaufey T Amundadottir - Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USAMarc 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, Baldiri Reixac 4, 08028, Barcelona, Spain. martirenom@cnag.crg.euFrancisco X Real - Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, SpainNúria Malats - CIBERONC, Madrid, Spain. nmalats@cnio.esSBC/EPICURO Investigators
- Resource Type
- Journal article
- Publication Details
- Genome medicine, Vol.13(1), pp.15-15
- DOI
- 10.1186/s13073-020-00816-4
- PMID
- 33517887
- PMCID
- PMC7849104
- NLM abbreviation
- Genome Med
- ISSN
- 1756-994X
- eISSN
- 1756-994X
- Grant note
- UM1 CA182910 / NCI NIH HHS U10 CA037429 / NCI NIH HHS P50 CA062924 / NCI NIH HHS U01 CA182883 / NCI NIH HHS UG1 CA189974 / NCI NIH HHS P30 CA008748 / NCI NIH HHS P30 CA086862 / NCI NIH HHS R01 CA154823 / NCI NIH HHS HHSN261200800001E / NCI NIH HHS
- Language
- English
- Date published
- 02/01/2021
- Academic Unit
- Epidemiology; Pathology
- Record Identifier
- 9984214831002771
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