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dc.contributorVall d'Hebron Barcelona Hospital Campus
dc.contributor.authorLópez de Maturana, Evangelina
dc.contributor.authorRodríguez, Juan Antonio
dc.contributor.authorAlonso, Lola
dc.contributor.authorLao, Oscar
dc.contributor.authorMolina-Montes, Esther
dc.contributor.authorMartín-Antoniano, Isabel Adoración
dc.contributor.authorMolero Richard, Francesc Xavier
dc.contributor.authorBalsells Valls, Joaquin
dc.date.accessioned2021-06-01T11:53:38Z
dc.date.available2021-06-01T11:53:38Z
dc.date.issued2021-02-01
dc.identifier.citationLópez de Maturana E, Rodríguez JA, Alonso L, Lao O, Molina-Montes E, Martín-Antoniano IA, et al. A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer. Genome Med. 2021 Feb 1;13:15.
dc.identifier.issn1756-994X
dc.identifier.urihttp://hdl.handle.net/11351/6003
dc.description3D genomic structure; Genetic susceptibility; Pancreatic cancer risk
dc.description.abstractBackground 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.
dc.language.isoeng
dc.publisherBMC
dc.relation.ispartofseriesGenome Medicine;13
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourceScientia
dc.subjectPàncrees - Càncer
dc.subjectMalalties congènites
dc.subject.meshPancreatic Neoplasms
dc.subject.meshGenetic Predisposition to Disease
dc.subject.meshGenome-Wide Association Study
dc.titleA multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer
dc.typeinfo:eu-repo/semantics/article
dc.identifier.doi10.1186/s13073-020-00816-4
dc.subject.decsneoplasias pancreáticas
dc.subject.decspredisposición genética a la enfermedad
dc.subject.decsestudio de asociación genómica completa
dc.relation.publishversionhttps://doi.org/10.1186/s13073-020-00816-4
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dc.audienceProfessionals
dc.contributor.organismesInstitut Català de la Salut
dc.contributor.authoraffiliation[López de Maturana E, Alonso L, Molina-Montes E, Martín-Antoniano IA] Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center (CNIO), C/Melchor Fernandez Almagro 3, 28029 Madrid, Spain. CIBERONC, Madrid, Spain. [Rodríguez JA, Lao O] CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain. [Molero X, Balsells J] Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. CIBEREHD, Barcelona, Spain
dc.identifier.pmid33517887
dc.identifier.wos000616492900001
dc.relation.projectidinfo:eu-repo/grantAgreement/ES/1PN/2008-2011/PI11%2F01542
dc.relation.projectidinfo:eu-repo/grantAgreement/ES/PE2013-2016/PI12%2F01635
dc.relation.projectidinfo:eu-repo/grantAgreement/ES/PE2013-2016/PI15%2F01573
dc.relation.projectidinfo:eu-repo/grantAgreement/ES/PE2013-2016/PI18%2F01347
dc.relation.projectidinfo:eu-repo/grantAgreement/ES/2PN/2008-2011/RD12%2F0036%2F0034
dc.relation.projectidinfo:eu-repo/grantAgreement/ES/3PN/2008-2011/RD12%2F0036%2F0050
dc.relation.projectidinfo:eu-repo/grantAgreement/ES/4PN/2008-2011/RD12%2F0036%2F0073
dc.relation.projectidinfo:eu-repo/grantAgreement/ES/PE2013-2016/BFU2017-85926-P
dc.relation.projectidinfo:eu-repo/grantAgreement/EC/FP7/259737
dc.relation.projectidinfo:eu-repo/grantAgreement/EC/FP7/256974
dc.relation.projectidinfo:eu-repo/grantAgreement/EC/FP7/609989
dc.rights.accessrightsinfo:eu-repo/semantics/openAccess


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