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

Estructura genòmica 3D; Predisposició genètica; Risc de càncer de pàncreesEstructura genómica 3D; Predisposición genética; Riesgo de cáncer de páncreas3D genomic structure; Genetic susceptibility; Pancreatic cancer riskBackground 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.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)