Walsh, Naomi

Abstract Registry-based epidemiologic studies suggest associations between chronic inflammatory intestinal diseases and pancreatic ductal adenocarcinoma (PDAC). As genetic susceptibility contributes to a large proportion of chronic inflammatory intestinal diseases, we hypothesize that the genomic regions surrounding established genome-wide associated variants for these chronic inflammatory diseases are associated with PDAC. We examined the association between PDAC and genomic regions (±500 kb) surrounding established common susceptibility variants for ulcerative colitis, Crohn's disease, inflammatory bowel disease, celiac disease, chronic pancreatitis, and primary sclerosing cholangitis. We analyzed summary statistics from genome-wide association studies data for 8,384 cases and 11,955 controls of European descent from two large consortium studies using the summary data-based adaptive rank truncated product method to examine the overall association of combined genomic regions for each inflammatory disease group. Combined genomic susceptibility regions for ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis were associated with PDAC at P values < 0.05 (0.0040, 0.0057, 0.011, and 3.4 × 10−6, respectively). After excluding the 20 PDAC susceptibility regions (±500 kb) previously identified by GWAS, the genomic regions for ulcerative colitis, Crohn disease, and inflammatory bowel disease remained associated with PDAC (P = 0.0029, 0.0057, and 0.0098, respectively). Genomic regions for celiac disease (P = 0.22) and primary sclerosing cholangitis (P = 0.078) were not associated with PDAC. Our results support the hypothesis that genomic regions surrounding variants associated with inflammatory intestinal diseases, particularly, ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis are associated with PDAC. Significance: The joint effects of common variants in genomic regions containing susceptibility loci for inflammatory bowel disease and chronic pancreatitis are associated with PDAC and may provide insights to understanding pancreatic cancer etiology.

Abstract Objective Genome-wide association studies (GWAS) identify associations of individual SNPs with cancer risk but usually only explain a fraction of the inherited variability. Pathway analysis of genetic variants has been shown for many disorders to be a powerful tool in discovering novel networks of susceptibility genes. Design We have conducted a large agnostic pathway-based meta-analysis of GWAS data using the summary-based adaptive rank truncated product (sARTP) method to identify novel gene sets and pathways associated with pancreatic ductal adenocarcinoma (PDA) in 9,040 cases and 12,495 controls. We performed expression quantitative trait loci (eQTL) analysis and functional annotation of the top SNPs in genes identified in PDA-associated gene sets and pathways. Results We identified 14 gene sets and pathways associated with PDA at FDR < 0.05. Five of the strongest signals (P-value ≤ 1.3x10-5 Bonferroni corrected) were in genes from KEGG maturity onset diabetes of the young, Reactome regulation of beta cell development, Biocarta role of epidermal growth factor (EGF) receptor transactivation by G-protein-coupled receptors in cardiac hypertrophy pathway, Nikolsky breast cancer chr17q11-q21 amplicon gene set, and Pujana ATM Pearson correlation coefficient (PCC) network gene set. We identified and validated rs876493 and three correlated SNPs (PGAP3) and rs3124737 (CASP7) as eQTLs in two normal derived pancreas tissue datasets. Conclusion Our agnostic gene set and pathway analysis integrated with functional annotation and eQTL analysis provides novel insight into genes and pathways that may be biologically relevant for risk of PDA. Citation Format: Naomi Walsh, Han Zhang, Paula L. Hyland, Qi Yang, Evelina Mocci, Mingfeng Zhang, Erica J. Childs, Zhaoming Wang, Stephen Chanock, Patricia Hartge, Robert Hoover, Peter Kraft, Donghui Li, Eric J. Jacobs, Gloria M. Petersen, Brian M. Wolpin, Harvey A. Risch, Laufey T. Amundadottir, Kai Yu, Alison P. Klein, Rachael Z. Stolzenberg-Solomon. Large pathway and gene set analysis of GWAS data identifies novel associations for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 242.

Abstract Background Although a number of cancer chemopreventive agents have now been evaluated in phase II and phase III clinical trials that assess their efficacy and tolerability in both high risk and general populations, few have shown clear efficacy and uptake of approved agents has been disappointingly low. Therefore, chemopreventive agents should undergo rigorous screening prior to clinical trial evaluation in order to improve the selection of suitable agents for testing in large, expensive multi-center phase III trials. The aim of this study is to develop a descriptive method for prioritizing candidate agents for further development. Methods This framework was developed through a systematic literature review of Pubmed/Medline, Embase and The Cochrane Library. A semi-quantitative assessment focusing on efficacy and toxicity/tolerability was established based on expert input. Data from clinical trials, cancer epidemiological, observational and preclinical studies, including in vivo and in vitro basic research, was used to retrospectively evaluate the clinical application and effectiveness of cancer chemopreventive agents. Two chemopreventive agents with either a positive (aromatase inhibitors (AIs) for breast cancer) or negative (selenium for lung cancer) phase III clinical trial outcome were subsequently evaluated to determine the usefulness of the framework. Results Chemopreventive agents must reduce or reverse the process of carcinogenesis in normal or pre-malignant tissue with minimal toxicity. Evaluation of efficacy included data from preclinical and animal models, epidemiological studies, and clinical trials (both early phase trials in the organ of interest as well as secondary endpoints from other relevant studies). Agent suitability evaluation included assessment of toxicities, tolerability, and agent specific attributes (PK/PD, bioavailability, dosing, etc.). Examination of selenium and AI historical data in these categories revealed strong concordance with phase III outcomes. The detailed descriptive evaluation of the agents will be presented. Conclusion This framework provides a descriptive paradigm for cancer chemopreventive agent evaluation through systematic and rigorous interrogation. Thorough, standardized evaluation of all available preclinical, epidemiological, and clinical data should be strongly encouraged to better inform the investments required for clinical trials. Citation Format: Naomi Walsh, David S. Alberts, Powel Brown, Paul Limburg, Mark Sherman, Eva Szabo. Framework for clinical evaluation of chemopreventive agents: Defining criteria for future assessment. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4662. doi:10.1158/1538-7445.AM2015-4662