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

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.

Associations between pancreatic expression quantitative traits and risk of pancreatic ductal adenocarcinoma

“…These SNPs are strong eQTLs and splicing QTLs for a number of genes in multiple tissues, including the pancreas. Among the genes whose expression is associated with the eQTLs on chromosome 16, there are CTRB1 and CTRB2 (51), two chymotripsinogens that are precursors of pancreatic proteolytic enzymes. Genetic variation at this locus is associated also with susceptibility to chronic pancreatitis (52), which is a strong risk factor for PDAC.…”

UEG position paper on pancreatic cancer. Bringing pancreatic cancer to the 21st century: Prevent, detect, and treat the disease earlier and better

“…In this regard, a recent multi‐step GWAS strategy conducted solely in European population, combined with an in‐depth in silico functional analysis, allowed to identify further low‐penetrance loci. 26 A number of consortia comprising pre‐existing studies have already been formed to facilitate the identification of further low‐penetrance variants and gene‐environment interaction through meta‐GWAS strategies. However, these approaches do not substitute for the design of novel, sufficiently powered studies that apply uniform criteria to case selection, the acquisition of environmental exposure information, and to biological sample collection.…”

“…More comprehensive approaches are needed to make progress, including global analyses of biologically relevant pathways and genome‐wide association studies. In this regard, a recent multi‐step GWAS strategy conducted solely in European population, combined with an in‐depth in silico functional analysis, allowed to identify further low‐penetrance loci 26 . A number of consortia comprising pre‐existing studies have already been formed to facilitate the identification of further low‐penetrance variants and gene‐environment interaction through meta‐GWAS strategies.…”

Association of Genetic Variants Affecting microRNAs and Pancreatic Cancer Risk

“…IRB approval and written informed consent were obtained from all participating centers and study participants, respectively. DNA samples were genotyped using the Infinium OncoArray-500 K, and genotype imputation was performed using IMPUTE2 with 1,000 Genomes-phase 3 as reference panel (López de Maturana et al, 2021).…”

“…Several epidemiologic PC risk factors have been identified, including cigarette smoking, heavy alcohol intake, type two diabetes mellitus, high BMI, and chronic pancreatitis (Maisonneuve and Lowenfels, 2015;Barone et al, 2016;Principe and Rana, 2020). The genetic susceptibility to PC is explained by rare high penetrance mutations identified through sequencing approaches (Hu et al, 2018) and common low penetrance variants discovered through genome-wide association studies (GWAS; Amundadottir et al, 2009;Low et al, 2010;Petersen et al, 2010;Wu et al, 2012;Wolpin et al, 2014;Childs et al, 2015;Zhang et al, 2016;Klein et al, 2018;Campa et al, 2020;Gentiluomo et al, 2020;Lin et al, 2020;López de Maturana et al, 2021) or candidate gene approaches (Campa et al, 2013a(Campa et al, , 2015(Campa et al, , 2016b Genetic factors play an important role in the susceptibility to pancreatic cancer (PC). However, established loci explain a small proportion of genetic heritability for PC; therefore, more progress is needed to find the missing ones.…”