Pancreatic Cancer Case-Control Consortium Research Articles

Physical Activity, Sedentary Behavior, and Pancreatic Cancer Risk: A Mendelian Randomization Study.

Pancreatic cancer is currently the seventh leading cause of cancer death worldwide. Understanding whether modifiable factors increase or decrease the risk of this disease is central to facilitating primary prevention. Several epidemiological studies have described the benefits of physical activity, and the risks associated with sedentary behavior, in relation to cancer. This study aimed to assess evidence of causal effects of physical activity and sedentary behavior on pancreatic cancer risk. We conducted a two-sample Mendelian randomization study using publicly available data for genetic variants associated with physical activity and sedentary behavior traits and genetic data from the Pancreatic Cancer Cohort Consortium (PanScan), the Pancreatic Cancer Case-Control Consortium (PanC4), and the FinnGen study for a total of 10 018 pancreatic cancer cases and 266 638 controls. We also investigated the role of body mass index (BMI) as a possible mediator between physical activity and sedentary traits and risk of developing pancreatic cancer. We found evidence of a causal association between genetically determined hours spent watching television (hours per day) and increased risk of pancreatic cancer for each hour increment (PanScan-PanC4 odds ratio = 1.52, 95% confidence interval 1.17-1.98, P = .002). Additionally, mediation analysis showed that genetically determined television-watching time was strongly associated with BMI, and the estimated proportion of the effect of television-watching time on pancreatic cancer risk mediated by BMI was 54%. This study reports the first Mendelian randomization-based evidence of a causal association between a measure of sedentary behavior (television-watching time) and risk of pancreatic cancer and that this is strongly mediated by BMI. Summary: Pancreatic cancer is a deadly disease that is predicted to become the second leading cause of cancer-related deaths by 2030. Physical activity and sedentary behaviors have been linked to cancer risk and survival. However, there is limited research on their correlation with pancreatic cancer. To investigate this, we used a Mendelian randomization approach to examine the genetic predisposition to physical activity and sedentariness and their relation to pancreatic cancer risk, while excluding external confounders. Our findings revealed a causal link between the time spent watching television and an increased risk of pancreatic cancer. Additionally, we determined that over half of the effect of watching television on pancreatic risk is mediated by the individual's BMI.

Evidence for a causal link between intra-pancreatic fat deposition and pancreatic cancer: A prospective cohort and Mendelian randomization study

Prior observational studies suggest an association between intra-pancreatic fat deposition (IPFD) and pancreatic ductal adenocarcinoma (PDAC); however, the causal relationship is unclear. To elucidate causality, we conduct a prospective observational study using magnetic resonance imaging (MRI)-measured IPFD data and also perform a Mendelian randomization study using genetic instruments for IPFD. In the observational study, we use UK Biobank data (N= 29,463, median follow-up: 4.5 years) and find that high IPFD (>10%) is associated with PDAC risk (adjusted hazard ratio [HR]: 3.35, 95% confidence interval [95% CI]: 1.60-7.00). In the Mendelian randomization study, we leverage eight out of nine IPFD-associated genetic variants (p<5×10-8) from a genome-wide association study in the UK Biobank (N= 25,617) and find that genetically determined IPFD is associated with PDAC (odds ratio [OR] per 1-standard deviation [SD] increase in IPFD: 2.46, 95% CI: 1.38-4.40) in the Pancreatic Cancer Cohort Consortium I, II, III (PanScan I-III)/Pancreatic Cancer Case-Control Consortium (PanC4) dataset (8,275 PDAC cases and 6,723 non-cases). This study provides evidencefor a potential causal role of IPFD in the pathogenesis of PDAC. Thus, reducing IPFD may lower PDAC risk.

Elucidating the role of blood metabolites on pancreatic cancer risk using two-sample Mendelian randomization analysis.

Pancreatic ductal adenocarcinoma (PDAC) is an uncommon but highly fatal malignancy. Identifying causal metabolite biomarkers offers an opportunity to facilitate effective risk assessment strategies for PDAC. In this study, we performed a two-sample Mendelian randomization (MR) study to characterize the potential causal effects of metabolites in plasma on PDAC risk. Genetic instruments were determined for a total of 506 metabolites from one set of comprehensive genome-wide association studies (GWAS) involving 913 individuals of European ancestry from the INTERVAL/EPIC-Norfolk cohorts. Another set of genetic instruments was developed for 483 metabolites from an independent GWAS conducted with 8299 individuals of European ancestry from the Canadian Longitudinal Study on Aging (CLSA) cohort. We analyzed GWAS data of the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4), comprising 8275 PDAC cases and 6723 controls of European ancestry. The association of metabolites with PDAC risk was assessed using the inverse-variance weighted (IVW) method, and complemented with sensitivity analyses of MR-Egger and MR-PRESSO tests. Potential side effects of targeting the identified metabolites for PDAC intervention were further evaluated by a phenome-wide MR (Phe-MR) analysis. Forty-four unique metabolites were identified to be significantly associated with PDAC risk, of which four top-ranking metabolites (X: 12798, X: 11787, X: 11308 and X: 19141) showed replication evidence when using instruments developed from both two cohorts. Our results highlight novel blood metabolites related to PDAC risk, which may help prioritize metabolic features for PDAC mechanistic research and further evaluation of their potential role in PDAC risk assessment.

Genetic Susceptibility to Nonalcoholic Fatty Liver Disease and Risk for Pancreatic Cancer: Mendelian Randomization.

There are conflicting data on whether nonalcoholic fatty liver disease (NAFLD) is associated with susceptibility to pancreatic cancer. Using Mendelian randomization (MR), we investigated the relationship between genetic predisposition to NAFLD and risk for pancreatic cancer. Data from genome-wide association studies (GWAS) within the Pancreatic Cancer Cohort Consortium (PanScan; cases n = 5,090, controls n = 8,733) and the Pancreatic Cancer Case Control Consortium (PanC4; cases n = 4,163, controls n = 3,792) were analyzed. We used data on 68 genetic variants with four different MR methods [inverse variance weighting (IVW), MR-Egger, simple median, and penalized weighted median] separately to predict genetic heritability of NAFLD. We then assessed the relationship between each of the four MR methods and pancreatic cancer risk, using logistic regression to calculate ORs and 95% confidence intervals (CI), adjusting for PC risk factors, including obesity and diabetes. No association was found between genetically predicted NAFLD and pancreatic cancer risk in the PanScan or PanC4 samples [e.g., PanScan, IVW OR, 1.04; 95% confidence interval (CI), 0.88-1.22; MR-Egger OR, 0.89; 95% CI, 0.65-1.21; PanC4, IVW OR, 1.07; 95% CI, 0.90-1.27; MR-Egger OR, 0.93; 95% CI, 0.67-1.28]. None of the four MR methods indicated an association between genetically predicted NAFLD and pancreatic cancer risk in either sample. Genetic predisposition to NAFLD is not associated with pancreatic cancer risk. Given the close relationship between NAFLD and metabolic conditions, it is plausible that any association between NAFLD and pancreatic cancer might reflect host metabolic perturbations (e.g., obesity, diabetes, or metabolic syndrome) and does not necessarily reflect a causal relationship between NAFLD and pancreatic cancer.

Polymorphic variants involved in methylation regulation: a strategy to discover risk loci for pancreatic ductal adenocarcinoma

IntroductionOnly a small number of risk factors for pancreatic ductal adenocarcinoma (PDAC) has been established. Several studies identified a role of epigenetics and of deregulation of DNA methylation. DNA methylation...

Abstract 1475: Uncovering the functional variants and target genes of the 7q32 pancreatic cancer risk locus

Abstract In western nations, pancreatic ductal adenocarcinoma (PDAC) is set to become second leading cause of cancer mortality over the next decade. Despite advances in treatment, PDAC has a 5-year survival rate of only ~9%, necessitating a better understanding of its etiology. Risk factors for PDAC are both environmental and genetic, with heritability estimated at around 20%. However, highly penetrant coding variants are rare within the population and have been estimated to account for as little as 1% of the phenotypic variance for PDAC. In an effort to identify common PDAC susceptibility alleles, genome-wide association studies (GWAS) have identified 17 loci at which germline variants associate with PDAC risk. Mostly localizing to non-coding loci, many such risk variants are expected to confer risk via allele-specific changes in transcription factor binding, leading to altered target gene expression over a lifetime. The identification of functional variants from GWAS is complicated by the correlation of alleles through linkage disequilibrium (LD). Here, we have leveraged Bayesian fine mapping to identify a credible set of seven single nucleotide polymorphisms (SNPs) in high LD at the 7q32 risk locus. Fine-mapped variants were annotated using epigenomic datasets we previously generated from a range of pancreatic cell lines, organoids and primary patient samples, encompassing histone modification marks (ChIP-seq), open chromatin (ATAC-seq) and chromatin conformation capture (Capture-HiC, HiChIP). Two variants from the credible set (rs6971499 and rs6970779) were found to consistently lie within regions annotated as super-enhancers and marked by open chromatin within our data. Both SNPs exhibit chromatin looping to the promoters of nearby plausible target genes LINC-PINT and miR29a. Electrophoretic mobility shift assays (EMSA) illustrate that rs6971499-T and rs6970779-G exhibit allele-specific protein binding in PANC-1 and MIA PaCa-2 cell lines, while luciferase reporter assays in the same cell lines demonstrate that both alleles drive significant changes in transcriptional activity. Ongoing proteomic experiments aim to identify the transcription factors differentially bound to these alleles, while CRISPR methods are being employed to validate enhancer variants in their native chromatin context. Future experiments may further characterise these transcription factors and their target genes with an eye toward better understanding their roles in PDAC carcinogenesis. Citation Format: Aidan O'Brien, Jason W. Hoskins, Daina R. Eiser, Katelyn E. Connelly, Jun Zhong, Thorkell Andresson, Irene Collins, Pancreatic Cancer Cohort Consortium, Pancreatic Cancer Case-Control Consortium, Stephen J. Chanock, Alison P. Klein, H. Efsun Arda, Laufey T. Amundadottir. Uncovering the functional variants and target genes of the 7q32 pancreatic cancer risk locus [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1475.

Tobacco, alcohol and pancreatic disease: key findings from global consortia

(RR) were 1.74 (95% confidence interval, CI, 1.39-2.13) for current and 1.32 (95% CI 1.03-1.71) for former smokers [2, 3]. Chronic pancreatitis is associated to heavy alcohol drinking, though the risk estimates remain open to discussion. Epidemiological data are limited, but consistent with clinical ones to indicate that (heavy) drinking is related to chronic pancreatitis [2]. There is consistent evidence that tobacco is also a major factor for chronic pancreatitis. With reference to tobacco, the RRs from a meta-analysis were 2.8 (95% CI 1.7-4.8) for current and 1.4 (95% CI 1.1-1.9) for former smokers and these associations were not totally accounted for by heavy alcohol drinking [4]. Tobacco is responsible for 10 to 20% of all chronic pancreatitis. In non-alcoholic idiopathic chronic pancreatitis, smoking is associated with disease progression [5]. Cigarette smoking is the major risk factor for pancreatic cancer. In the Pancreatic Cancer Consortium (PanScan; 1481 cases, 1539 controls) the pooled RR was 1.77 (95% CI 1.38-2.26) for current and 1.09 (95% CI 0.91-1.30) for former smokers [6]. In the International Pancreatic Cancer Case-Control Consortium (PanC4; 6507 cases, 12,890 controls), the RR was 2.20 (95% CI 1.71-2.83) for current smokers and rose to 3.39 (95% CI 2.36-1.86) for heavy smokers; the RR was 1.17 (95% CI 1.02-2.83) for former smokers [7]. Cigar smoking was also associated with pancreatic cancer (RR 1.62, 95% CI 1.15-2.29), whereas no consistent association was found for smokeless tobacco, nor for pipe smoking [8]. A meta-analysis of 21 case-control and 11 cohort studies provided conclusive evidence that moderate drinking was unrelated to pancreatic cancer, but heavy drinking (3 or more drinks/day) gave a RR of 1.22 (95% CI 1.12-1.34) [9]. In the PanScan collaborative re-analysis of cohort studies (1530 cases, 1520 controls), there was no overall association with total alcohol intake, but the RR was 1.38 (95% CI 0.9-2.3) for drinking ≥60g day and rose to 2.23 (95% CI 1.0-4.9) for male heavy liquors drinkers [10]. In a pooled analysis of 14 cohort studies (2187 cases) the RR for >30g day was 1.22 (95% CI 1.031.45) [11]. In the PanC4 study (5585 cases, 11,822 controls), the RR was 1.46 (95% CI 1.16-1.83) for ≥6 drinks day; no association was observed with moderate drinking [12]. Possible mechanisms of action of alcohol include acetaldehyde, fatty acid ethyl esters, free radicals, DNA damage and inflammation [12]. Possible mechanisms of action of smoking include tobacco specific nitrosamines (NKK), polycyclic aromatic hydrocarbons (PAH) and other smoking-associated chemicals, and smoking as an inflammatory agent and a progressor in carcinogenesis [7].

Identification of Recessively Inherited Genetic Variants Potentially Linked to Pancreatic Cancer Risk.

Although 21 pancreatic cancer susceptibility loci have been identified in individuals of European ancestry through genome-wide association studies (GWASs), much of the heritability of pancreatic cancer risk remains unidentified. A recessive genetic model could be a powerful tool for identifying additional risk variants. To discover recessively inherited pancreatic cancer risk loci, we performed a re-analysis of the largest pancreatic cancer GWAS, the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4), including 8,769 cases and 7,055 controls of European ancestry. Six single nucleotide polymorphisms (SNPs) showed associations with pancreatic cancer risk according to a recessive model of inheritance. We replicated these variants in 3,212 cases and 3,470 controls collected from the PANcreatic Disease ReseArch (PANDoRA) consortium. The results of the meta-analyses confirmed that rs4626538 (7q32.2), rs7008921 (8p23.2) and rs147904962 (17q21.31) showed specific recessive effects (p<10−5) compared with the additive effects (p>10−3), although none of the six SNPs reached the conventional threshold for genome-wide significance (p < 5×10−8). Additional bioinformatic analysis explored the functional annotations of the SNPs and indicated a possible relationship between rs36018702 and expression of the BCL2L11 and BUB1 genes, which are known to be involved in pancreatic biology. Our findings, while not conclusive, indicate the importance of considering non-additive genetic models when performing GWAS analysis. The SNPs associated with pancreatic cancer in this study could be used for further meta-analysis for recessive association of SNPs and pancreatic cancer risk and might be a useful addiction to improve the performance of polygenic risk scores.

Abstract 882: Associations of genetically predicted blood protein biomarkers with pancreatic ductal adenocarcinoma risk: A study using comprehensive protein genetic prediction models

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with few known risk factors and biomarkers. Identification of biomarkers is critical for understanding the pathogenesis of this deadly cancer and identifying high-risk individuals for close surveillance. Several blood protein biomarkers have been linked to PDAC in previous studies, but these studies have assessed only a limited number of protein biomarkers usually in small set(s) of samples. To identify novel circulating protein biomarkers of PDAC, we studied 8,275 cases and 6,723 controls of European descent from the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case-Control Consortium. Leveraging genome and plasma proteome data of 2,841 healthy European descendants included in the INTERVAL study, we established models using four methods (best linear unbiased predictor, elastic net, LASSO, and top1) to predict protein levels based on genetic variants. For each protein, of the four sets of models developed, the model showing the highest prediction performance (R2) was retained. We selected 2,164 built protein models with a prediction performance (R2) of &amp;gt;0.01 for association analyses with PDAC risk. We observed associations between predicted concentrations of 14 proteins and PDAC risk at a false discovery rate of &amp;lt; 0.05, including those of eight proteins that showed a significant association after Bonferroni correction (2.31 × 10-5). These include Histo-blood group ABO system transferase encoded by ABO, which has been previously implicated as a potential target gene of PDAC risk variant identified in GWAS. Besides eight proteins that were previously reported in our earlier study using protein quantitative trait loci as instruments, we identified six novel proteins which have not been identified in previous studies. Six of the identified proteins showed positive associations and eight showed inverse associations (P-values from 2.62 × 10-4 to 5.71 × 10-21). In conclusion, we identified 14 protein biomarker candidates for PDAC risk, which if validated in future studies, may contribute to the etiological understanding of PDAC development. Citation Format: Dalia Ghoneim, Jingjing Zhu, Jihwan Ha, Praveen Surendran, Qizhi Cathy Yao, Tao Liu, Sarah Fahle, Adam Butterworth, Chong Wu, Lang Wu. Associations of genetically predicted blood protein biomarkers with pancreatic ductal adenocarcinoma risk: A study using comprehensive protein genetic prediction models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 882.

Mendelian Randomization Analysis of n-6 Polyunsaturated Fatty Acid Levels and Pancreatic Cancer Risk.

Whether circulating polyunsaturated fatty acid (PUFA) levels are associated with pancreatic cancer risk is uncertain. Mendelian randomization (MR) represents a study design using genetic instruments to better characterize the relationship between exposure and outcome. We utilized data from genome-wide association studies within the Pancreatic Cancer Cohort Consortium and Pancreatic Cancer Case-Control Consortium, involving approximately 9,269 cases and 12,530 controls of European descent, to evaluate associations between pancreatic cancer risk and genetically predicted plasma n-6 PUFA levels. Conventional MR analyses were performed using individual-level and summary-level data. Using genetic instruments, we did not find evidence of associations between genetically predicted plasma n-6 PUFA levels and pancreatic cancer risk [estimates per one SD increase in each PUFA-specific weighted genetic score using summary statistics: linoleic acid odds ratio (OR) = 1.00, 95% confidence interval (CI) = 0.98-1.02; arachidonic acid OR = 1.00, 95% CI = 0.99-1.01; and dihomo-gamma-linolenic acid OR = 0.95, 95% CI = 0.87-1.02]. The OR estimates remained virtually unchanged after adjustment for covariates, using individual-level data or summary statistics, or stratification by age and sex. Our results suggest that variations of genetically determined plasma n-6 PUFA levels are not associated with pancreatic cancer risk. These results suggest that modifying n-6 PUFA levels through food sources or supplementation may not influence risk of pancreatic cancer.

Genome-Wide Gene-Diabetes and Gene-Obesity Interaction Scan in 8,255 Cases and 11,900 Controls from PanScan and PanC4 Consortia.

Obesity and diabetes are major modifiable risk factors for pancreatic cancer. Interactions between genetic variants and diabetes/obesity have not previously been comprehensively investigated in pancreatic cancer at the genome-wide level. We conducted a gene-environment interaction (GxE) analysis including 8,255 cases and 11,900 controls from four pancreatic cancer genome-wide association study (GWAS) datasets (Pancreatic Cancer Cohort Consortium I-III and Pancreatic Cancer Case Control Consortium). Obesity (body mass index ≥30 kg/m2) and diabetes (duration ≥3 years) were the environmental variables of interest. Approximately 870,000 SNPs (minor allele frequency ≥0.005, genotyped in at least one dataset) were analyzed. Case-control (CC), case-only (CO), and joint-effect test methods were used for SNP-level GxE analysis. As a complementary approach, gene-based GxE analysis was also performed. Age, sex, study site, and principal components accounting for population substructure were included as covariates. Meta-analysis was applied to combine individual GWAS summary statistics. No genome-wide significant interactions (departures from a log-additive odds model) with diabetes or obesity were detected at the SNP level by the CC or CO approaches. The joint-effect test detected numerous genome-wide significant GxE signals in the GWAS main effects top hit regions, but the significance diminished after adjusting for the GWAS top hits. In the gene-based analysis, a significant interaction of diabetes with variants in the FAM63A (family with sequence similarity 63 member A) gene (significance threshold P < 1.25 × 10-6) was observed in the meta-analysis (P GxE = 1.2 ×10-6, P Joint = 4.2 ×10-7). This analysis did not find significant GxE interactions at the SNP level but found one significant interaction with diabetes at the gene level. A larger sample size might unveil additional genetic factors via GxE scans. This study may contribute to discovering the mechanism of diabetes-associated pancreatic cancer.

Abstract 1200: Associations between genetically predicted blood protein biomarkers and pancreatic ductal adenocarcinoma risk

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of most lethal malignancies with few known risk factors and biomarkers. Identification of disease biomarkers is critical for understanding the pathogenesis of this cancer and identifying high risk individuals for close surveillance. Several blood protein biomarkers have been linked to PDAC in previous studies, but these studies have assessed only a limited number of biomarkers usually in small samples. To identify novel circulating protein biomarkers of PDAC, we studied 8,280 cases and 6,728 controls of European descent from the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case-Control Consortium, by using genetic instruments. Protein quantitative trait loci (pQTLs) for 1,226 plasma proteins identified in a large INTERVAL study of 3,301 healthy European descendants were used as instruments to evaluate associations between genetically predicted protein levels and PDAC. For proteins showing a significant association, we further conducted conditional analysis with adjustments for previously identified risk variants to assess whether the observed associations between genetically predicted protein concentrations and PDAC risk were independent of the risk variants identified in genome-wide association studies (GWAS). Furthermore, for the proteins that were associated with PDAC risk, we performed an enrichment analysis of the genes encoding these proteins to examine whether they are enriched in specific pathways, functions or networks. We observed associations between predicted concentrations of 38 proteins and PDAC risk at a false discovery rate of &amp;lt; 0.05, including those of 23 proteins that showed a significant association even after Bonferroni correction (4.08 × 10−5). These include Histo-blood group ABO system transferase encoded by ABO, which has been previously implicated as a potential target gene of PDAC risk variant identified in GWAS. Eight of the identified proteins (Beta-crystallin B2, Dedicator of cytokinesis protein 9, VIP36-like protein, Erythrocyte band 7 integral membrane protein, Tensin-2, Transmembrane protease serine 11D, Alcohol dehydrogenase 1B, and C-X-C motif chemokine 10) were associated with PDAC risk after conditioning on previously reported pancreatic cancer risk variants (odds ratios ranged from 0.79 to 1.52, P-values from 1.28 × 10−3 to 6.47 × 10−4). Pathway enrichment analysis showed that the encoding genes for the implicated proteins were significantly enriched in cancer-related pathways, such as STAT3 and IL-15 production. In conclusion, we identified 38 protein biomarker candidates for PDAC risk, which if validated by additional studies, may contribute to the etiological understanding of PDAC tumor development. Citation Format: Jingjing Zhu, Xiang Shu, Xingyi Guo, Duo Liu, Jiandong bao, Roger Milne, Graham G Giles, Chong Wu, Mengmeng Du, Emily White, Harvey A Risch, Nuria Malats, Eric J. Duell, Phyllis J. Goodman, Donghui Li, Paige Bracci, Verena Katzke, Rachel E Neale, Steven Gallinger, Stephen Van Den Eeden, Alan Arslan, Federico Canzian, Charles Kooperberg, Brian Wolpin, Laura Beane-Freeman, Ghislaine Scelo, Kala Visvanatha, Christopher A. Haiman, Loïc Le Marchand, Herbert Yu, Gloria M Petersen, Rachael Stolzenberg-Solomon, Alison P Klein, Laufey T Amundadottir, Qiuyin Cai, Jirong Long, Xiao-Ou Shu, Wei Zheng, Lang Wu. Associations between genetically predicted blood protein biomarkers and pancreatic ductal adenocarcinoma risk [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1200.

Incorporating multiple sets of eQTL weights into gene-by-environment interaction analysis identifies novel susceptibility loci for pancreatic cancer.

It is of great scientific interest to identify interactions between genetic variants and environmental exposures that may modify the risk of complex diseases. However, larger sample sizes are usually required to detect gene-by-environment interaction (G × E) than required to detect genetic main association effects. To boost the statistical power and improve the understanding of the underlying molecular mechanisms, we incorporate functional genomics information, specifically, expression quantitative trait loci (eQTLs), into a data-adaptive G × E test, called aGEw. This test adaptively chooses the best eQTL weights from multiple tissues and provides an extra layer of weighting at the genetic variant level. Extensive simulations show that the aGEw test can control the Type 1 error rate, and the power is resilient to the inclusion of neutral variants and noninformative external weights. We applied the proposed aGEw test to the Pancreatic Cancer Case-Control Consortium (discovery cohort of 3,585 cases and 3,482 controls) and the PanScan II genome-wide association study data (replication cohort of 2,021 cases and 2,105 controls) with smoking as the exposure of interest. Two novel putative smoking-related pancreatic cancer susceptibility genes, TRIP10 and KDM3A, were identified. The aGEw test is implemented in an R package aGE.

Associations between Genetically Predicted Blood Protein Biomarkers and Pancreatic Cancer Risk.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with few known risk factors and biomarkers. Several blood protein biomarkers have been linked to PDAC in previous studies, but these studies have assessed only a limited number of biomarkers, usually in small samples. In this study, we evaluated associations of circulating protein levels and PDAC risk using genetic instruments. To identify novel circulating protein biomarkers of PDAC, we studied 8,280 cases and 6,728 controls of European descent from the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case-Control Consortium, using genetic instruments of protein quantitative trait loci. We observed associations between predicted concentrations of 38 proteins and PDAC risk at an FDR of < 0.05, including 23 of those proteins that showed an association even after Bonferroni correction. These include the protein encoded by ABO, which has been implicated as a potential target gene of PDAC risk variant. Eight of the identified proteins (LMA2L, TM11D, IP-10, ADH1B, STOM, TENC1, DOCK9, and CRBB2) were associated with PDAC risk after adjusting for previously reported PDAC risk variants (OR ranged from 0.79 to 1.52). Pathway enrichment analysis showed that the encoding genes for implicated proteins were significantly enriched in cancer-related pathways, such as STAT3 and IL15 production. We identified 38 candidates of protein biomarkers for PDAC risk. This study identifies novel protein biomarker candidates for PDAC, which if validated by additional studies, may contribute to the etiologic understanding of PDAC development.

Polygenic and multifactorial scores for pancreatic ductal adenocarcinoma risk prediction

BackgroundMost cases of pancreatic ductal adenocarcinoma (PDAC) are asymptomatic in early stages, and the disease is typically diagnosed in advanced phases, resulting in very high mortality. Tools to identify individuals...

Gallbladder disease, cholecystectomy, and pancreatic cancer risk in the International Pancreatic Cancer Case-Control Consortium (PanC4).

The association among gallbladder disease, cholecystectomy, and pancreatic cancer is unclear. Moreover, time interval between gallbladder disease or cholecystectomy and pancreatic cancer diagnosis is not considered in most previous studies. To quantify the association among gallbladder disease, cholecystectomy, and pancreatic cancer, considering time since first diagnosis of gallbladder disease or cholecystectomy. We used data from nine case-control studies within the Pancreatic Cancer Case-Control Consortium, including 5760 cases of adenocarcinoma of the exocrine pancreas and 8437 controls. We estimated pooled odds ratios and the corresponding 95% confidence intervals by estimating study-specific odds ratios through multivariable unconditional logistic regression models, and then pooling the obtained estimates using fixed-effects models. Compared with patients with no history of gallbladder disease, the pooled odds ratio of pancreatic cancer was 1.69 (95% confidence interval, 1.51-1.88) for patients reporting a history of gallbladder disease. The odds ratio was 4.90 (95% confidence interval, 3.45-6.97) for gallbladder disease diagnosed <2 years before pancreatic cancer diagnosis and 1.11 (95% confidence interval, 0.96-1.29) when ≥2 years elapsed. The pooled odds ratio was 1.64 (95% confidence interval, 1.43-1.89) for patients who underwent cholecystectomy, as compared to those without cholecystectomy. The odds ratio was 7.00 (95% confidence interval, 4.13-11.86) for a surgery <2 years before pancreatic cancer diagnosis and 1.28 (95% confidence interval, 1.08-1.53) for a surgery ≥2 years before. There appears to be no long-term effect of gallbladder disease on pancreatic cancer risk, and at most a modest one for cholecystectomy. The strong short-term association can be explained by diagnostic bias and reverse causation.

Mendelian randomisation study of the effects of known and putative risk factors on pancreatic cancer

BackgroundObservational studies have reported multiple risk factors for pancreatic ductal adenocarcinoma (PDAC). Some are well established, like tobacco smoking, alcohol drinking, obesity and type 2 diabetes, whereas some others are...

Analysis of Heritability and Genetic Architecture of Pancreatic Cancer: A PanC4 Study.

Pancreatic cancer is the fourth-leading cause of cancer death in both men and women in the United States. The currently identified common susceptibility loci account for a small fraction of estimated heritability. We sought to estimate overall heritability of pancreatic cancer and partition the heritability by variant frequencies and functional annotations. Analysis using the genome-based restricted maximum likelihood method (GREML) was conducted on Pancreatic Cancer Case-Control Consortium (PanC4) genome-wide association study (GWAS) data from 3,568 pancreatic cancer cases and 3,363 controls of European Ancestry. Applying linkage disequilibrium- and minor allele frequency-stratified GREML (GREML-LDMS) method to imputed GWAS data, we estimated the overall heritability of pancreatic cancer to be 21.2% (SE = 4.8%). Across the functional groups (intronic, intergenic, coding, and regulatory variants), intronic variants account for most of the estimated heritability (12.4%). Previously identified GWAS loci explained 4.1% of the total phenotypic variation of pancreatic cancer. Mutations in hereditary pancreatic cancer susceptibility genes are present in 4% to 10% of patients with pancreatic cancer, yet our GREML-LDMS results suggested these regions explain only 0.4% of total phenotypic variance for pancreatic cancer. Although higher than previous studies, our estimated 21.2% overall heritability may still be downwardly biased due to the inherent limitation that the contribution of rare variants in genes with a substantive overall impact on disease are not captured when applying these commonly used methods to imputed GWAS data. Our work demonstrated the importance of rare and common variants in pancreatic cancer risk.

Abstract 1580: Genetic variability of H3K27me modifier genesEZH2,KDM6AandKDM6Bin association with pancreatic cancer risk

Abstract Background: Several literature reports explain the critical role of epigenetic regulation in relation to different types of cancers, however this is still an emerging research area in pancreatic cancer. Methylation of lysine 27 on histone H3 (H3K27me) plays a critical role in regulating gene expression and this modification has been reported to have oncogenic effects. Specifically, in pancreatic cancer this mechanism has only been demonstrated in relation to patient outcome. The demethylase KDM6A (UTX) or KDM6B (JMJD3, a paralog of KDM6A on a different chromosome), and methyltransferase EZH2 (KMT6A) specifically regulate the alteration level of H3K27me. Based on the hypothesis that genetic variants may influence overall gene function, it is plausible that single nucleotide polymorphisms (SNPs) in these genes may similarly affect the roles of these genes in H3K27me deregulation. Materials and methods: Using the SNPinfo tool, a total of 21 tag SNPs in EZH2, KDM6A and KDM6B were selected from European populations based on 1000 Genome project. SNPs below 80% linkage disequilibrium threshold or less than 5% frequency among Europeans were excluded. These SNPs were analysed in relation to pancreatic cancer susceptibility using logistic regression among up to 8,741 pancreatic cancer cases and 6,957 controls from publically-available GWAS data (Pancreatic Cancer Cohort Consortium (PanScan) and Pancreatic Cancer Case-Control Consortium (PanC4)). Imputation of these data sets were performed according to standard protocol and used for subsequent analyses. Results: Following adjustment for age and gender, we observed promising associations between KDM6B rs12453250 C&amp;gt;A and EZH2 rs2888566 T&amp;gt;C ((OR=0.92 95% CI (0.85-0.99), P=0.018) and (OR=1.09 95% CI (1.03-1.17), P=0.007) respectively) and pancreatic cancer risk. Interestingly, rs12453250 results in an amino acid change from Phenylalanine (F) to Leucine (L) which is predicted to have a probably-damaging effect on the KDM6B protein. Conclusions: The extent to which epigenetic markers can be incorporated into pancreatic cancer risk prediction along with genetic information is unknown. Our novel findings suggest a plausible role of EZH2 and KDM6A SNPs in relation to pancreatic cancer risk among carriers of their minor alleles. These results warrant further validation in independent studies and may enhance systematic risk assessment among Europeans. Citation Format: Ye Lu, Ofure Obazee, Federico Canzian. Genetic variability of H3K27me modifier genesEZH2,KDM6AandKDM6Bin association with pancreatic cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1580.

A Pathway Analysis of Hereditary Hemochromatosis-related Genes and Pancreatic Ductal Adenocarcinoma Risk (FS11-05-19)

ObjectivesHereditary primary hemochromatosis is characterized by dysregulation of iron homeostasis and is caused by a genetic predisposition to absorb too much iron from foods. Hemochromatosis has been associated with some chronic diseases, including hepatocellular carcinoma and type 2 diabetes mellitus. Type 2 diabetes is an established risk factor and high red meat intake has been associated with pancreatic ductal adenocarcinoma (PDAC). We hypothesize that genetic susceptibility to hemochromatosis as determined by known hereditary hemochromatosis-related genes will be associated with PDAC. MethodsWe conducted a pathway analysis of genes known to contribute to hereditary hemochromatosis using the summary-based adaptive rank truncated product (sARTP) method on GWAS summary statistics derived from 9038 PDAC cases and 12,389 controls of European descent collected by the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PANC4). Our analysis included 7 hereditary hemochromatosis genes (HFE, BMP2, HJV, HAMP, TFR2, SLC40A1, and FTH1) and close genomic regions (20 kb upstream and 20 kb downstream) with a total of 176 single nucleotide polymorphisms (SNPs). The sARTP method combines SNP-level associations across SNPs in a gene or a pathway. ResultsThe hereditary hemochromatosis pathway was significantly associated with PDAC (P-value = 0.011). HJV and TFR2 genes contributed the most to the association with PDAC risk (gene level P-values = 0.003 and 0.013, respectively). ConclusionsThis study supports the hypothesis that genetic susceptibility related to hereditary hemochromatosis genes are associated with PDAC. Further studies should evaluate the modifying effect of iron-rich foods and genetic susceptibility of hemochromatosis and PDAC risk. Funding SourcesThis work was supported by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health.