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

Pangeneu Study Investigators ,Epicuro Investigators

doi:10.1186/s13073-020-00816-4

Abstract

BackgroundPancreatic 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.MethodsWe 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.ResultsWe 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.ConclusionsThis 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.

Highlights

Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors interplay
We identified a multi-hit region in CASC8—a Long non-coding RNA (lncRNA) associated with pancreatic carcinogenesis—with a lowest p value = 6.91E−05
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 endoplasmic reticulum (ER) stress and unfolded protein responses in acinar cells—identified by 3D; all of them with a strong in silico functional support

Summary

Introduction

Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors interplay. In comparison with other major cancers, fewer genome-wide association studies (GWAS) have been carried out and the number of patients included in them is relatively small (N = 9040). According to the GWAS Catalog (January 2019) [5], 40 common germline variants sited in 32 loci and associated with PC risk have been identified in individuals of European descent [6,7,8,9,10,11]. These variants only explain 4.1% of the phenotypic variance for PC [12]. Given the challenges in performing new PC case-control studies with adequate clinical, epidemiological, and genetic information, the field is far from reaching the statistical power that has been achieved in other more common cancers such as breast, colorectal, or prostate cancers with > 100,000 subjects included in GWAS, yielding a much larger number of genetic variants associated with them [5]

Results

Discussion

Conclusion