A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer

Mostra el registre complet Registre parcial de l'ítem

• dc.contributor.author López De Maturana, Evangelina
• dc.contributor.author Rodríguez, Juan Antonio
• dc.contributor.author Lao Grueso, Oscar, 1976-
• dc.contributor.author Iglesias Coma, Mar
• dc.contributor.author Cecchini Rosell, Lluís
• dc.contributor.author Ilzarbe Sánchez, Lucas
• dc.contributor.author Real, Francisco X.
• dc.contributor.author Malats i Riera, Núria
• dc.date.accessioned 2021-03-08T06:54:29Z
• dc.date.available 2021-03-08T06:54:29Z
• dc.date.issued 2021
• dc.description.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.
• dc.description.sponsorship The work was partially supported by Fondo de Investigaciones Sanitarias (FIS), Instituto de Salud Carlos III, Spain (#PI061614, #PI11/01542, #PI0902102, #PI12/01635, #PI12/00815, #PI15/01573, #PI18/01347); Red Temática de Investigación Cooperativa en Cáncer, Spain (#RD12/0036/0034, #RD12/0036/0050, #RD12/0036/0073); Spanish Ministerio de Ciencia, Innovación y Universidades (#BFU2017-85926-P); Fundación Científica de la AECC, Spain; European Cooperation in Science and Technology - COST Action #BM1204: EUPancreas. EU-6FP Integrated Project (#018771-MOLDIAG-PACA), EU-FP7-HEALTH (#259737-CANCERALIA, #256974-EPC-TM-Net), EU-FP7-ERC (#609989); Associazione Italiana Ricerca sul Cancro (#12182); Cancer Focus Northern Ireland and Department for Employment and Learning; and ALF (#SLL20130022), Sweden; Pancreatic Cancer Collective (PCC): Lustgarten Foundation & Stand-Up to Cancer (SU2C #6179); Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, USA; PANC4 GWAS RO1CA154823; NCI, US-NIH (#HHSN261200800001E).
• dc.format.mimetype application/pdf
• dc.identifier.citation López 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; 13(1):15. DOI: 10.1186/s13073-020-00816-4
• dc.identifier.doi http://dx.doi.org/10.1186/s13073-020-00816-4
• dc.identifier.issn 1756-994X
• dc.identifier.uri http://hdl.handle.net/10230/46684
• dc.language.iso eng
• dc.publisher BioMed Central
• dc.relation.ispartof Genome Med. 2021; 13(1):15
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/259737
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/BFU2017-85926-P
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/256974
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/609989
• dc.rights © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data ma
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword 3D genomic structure
• dc.subject.keyword Genetic susceptibility
• dc.subject.keyword Genome-wide association analysis
• dc.subject.keyword Local indices of genome spatial autocorrelation
• dc.subject.keyword Pancreatic cancer risk
• dc.title A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion