Etiology Of Pancreatic Cancer Research Articles

Genome-wide analysis to assess if heavy alcohol consumption modifies the association between SNPs and pancreatic cancer risk.

Pancreatic cancer is a leading cause of cancer-related death globally. Risk factors for pancreatic cancer include common genetic variants and potentially heavy alcohol consumption. We assessed if genetic variants modify the association between heavy alcohol consumption and pancreatic cancer risk. We conducted a genome-wide interaction analysis of single nucleotide polymorphisms (SNP) by heavy alcohol consumption (more than 3 drinks per day) for pancreatic cancer in European ancestry populations from genome-wide association studies (GWAS). Our analysis included 3,707 cases and 4,167 controls from case-control studies and 1,098 cases and 1,162 controls from cohort studies. Fixed effect meta-analyses were conducted. A potential novel region of association on 10p11.22, lead SNP rs7898449 (Pinteraction = 5.1 x 10-8 in the meta-analysis, Pinteraction = 2.1x10-9 in the case-control studies, Pinteraction = 0.91 cohort studies) was identified. A SNP correlated with this lead SNP is an eQTL for the NRP1 gene. Of the 17 genomic regions with genome-wide significant evidence of association with pancreatic cancer in prior studies, we observed suggestive evidence that heavy alcohol consumption modified the association for one SNP near LINC00673, rs11655237 on 17q25.1 (Pinteraction = 0.004). We identified a novel genomic region that may be associated with pancreatic cancer risk in conjunction with heavy alcohol consumption located near an eQTL for the NRP1, a protein that plays an important role in the development and progression of pancreatic cancer Impact: This work can provide insight into the etiology of pancreatic cancer particularly in heavy drinkers.

Integrating plasma protein-centric multi-omics to identify potential therapeutic targets for pancreatic cancer

BackgroundDeciphering the role of plasma proteins in pancreatic cancer (PC) susceptibility can aid in identifying novel targets for diagnosis and treatment.MethodsWe examined the relationship between genetically determined levels of plasma proteins and PC through a systemic proteome-wide Mendelian randomization (MR) analysis utilizing cis-pQTLs from multiple centers. Rigorous sensitivity analyses, colocalization, reverse MR, replications with varying instrumental variable selections and additional datasets, as well as subsequent meta-analysis, were utilized to confirm the robustness of significant findings. The causative effect of corresponding protein-coding genes’ expression and their expression pattern in single-cell types were then investigated. Enrichment analysis, between-protein interaction and causation, knock-out mice models, and mediation analysis with established PC risk factors were applied to indicate the pathogenetic pathways. These candidate targets were ultimately prioritized upon druggability and potential side effects predicted by a phenome-wide MR.ResultsTwenty-one PC-related circulating proteins were identified in the exploratory phase with no evidence for horizontal pleiotropy or reverse causation. Of these, 11 were confirmed in a meta-analysis integrating external validations. The causality at a transcription level was repeated for neutrophil elastase, hydroxyacylglutathione hydrolase, lipase member N, protein disulfide-isomerase A5, xyloside xylosyltransferase 1. The carbohydrate sulfotransferase 11 and histo-blood group ABO system transferase exhibited high-support genetic colocalization evidence and were found to affect PC carcinogenesis partially through modulating body mass index and type 2 diabetes, respectively. Approved drugs have been established for eight candidate targets, which could potentially be repurposed for PC therapies. The phenome-wide investigation revealed 12 proteins associated with 51 non-PC traits, and interference on protein disulfide-isomerase A5 and cystatin-D would increase the risk of other malignancies.ConclusionsBy employing comprehensive methodologies, this study demonstrated a genetic predisposition linking 21 circulating proteins to PC risk. Our findings shed new light on the PC etiology and highlighted potential targets as priorities for future efforts in early diagnosis and therapeutic strategies of PC.

Abstract 1466: Tobacco carcinogen impacts redox pathway to facilitate pancreatic ductal adenocarcinoma (PDAC) initiation and progression

Abstract The 5-year survival rate for pancreatic ductal adenocarcinoma (PDAC) is only 10%. PDAC is projected to soon become the second leading cause of cancer death. Tobacco is one of the main risk factors for PDAC. Incidence of PDAC increases 2-fold among tobacco users, and 20-35% of PDAC cases are attributed to smoking. However, the specific pathways activated by tobacco carcinogens remain elusive.This research project addresses the impact of carcinogens in pancreatic cancer etiology. We hypothesize that carcinogens in tobacco increase reactive oxygen species (ROS), which elevates the Nrf2 redox pathway to facilitate PDAC initiation and progression. Specifically, we focus on two major subclasses of carcinogens: the heavy metal cadmium (Cd) and the polycyclic aromatic hydrocarbon (PAH) benzo(a)pyrene (BaP). Using mouse pancreatic ductal organoid cultures, we found that acute carcinogen exposure increases Nrf2 activity, which is sustained after "intermediate" exposure (5 passages). Intriguingly, chronic exposure (10 passages) downregulates Nrf2 activity, which has been shown to be associated with acquired metastatic potential. Furthermore, we found an upregulation in NFkB and EGFR signaling after intermediate exposure, which are involved in microenvironment remodeling and increased proliferative potential. Overall, we demonstrate that acute carcinogen exposure elevates ROS levels and activates the Nrf2 pathway, whereas prolonged exposure upregulates NFkB and EGFR pathways. Furthermore, we have established a novel carcinogenesis model using 3D organoid culture to recapitulate each step in pancreatic tumorigenesis. Collectively, this project contributes to our understanding of tobacco-related PDAC pathogenesis. Citation Format: Xiaoxue Lin, McKenna Stamp, Alexandra Fowler, Chelsea Bottomley, Shira Okhovat, Kristina Peck, Dannielle Engle. Tobacco carcinogen impacts redox pathway to facilitate pancreatic ductal adenocarcinoma (PDAC) initiation and progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1466.

Aspirin exposure and its association with metal stent patency in malignant distal biliary obstruction: a large international multicenter propensity score–matched study

Background and AimsStent dysfunction is common following endoscopic retrograde cholangiopancreatography (ERCP) with self-expanding metal stent (SEMS) insertion in malignant distal biliary obstruction (MDBO). Chronic aspirin exposure (ASA-E) has been previously shown to potentially decrease this risk. We aim to further ascertain the protective effect of ASA and to identify other predictors of stent dysfunction. MethodMulticenter retrospective cohort study (9 Canada and 1 US). MDBO who underwent ERCP-SEMS between 01/2014-12/2019 were included and divided into two cohorts: ASA-E and ASA unexposed (ASA-U). Propensity score-matching (PSM) was performed to limit selection bias. Matched variables included: age, sex, tumor stage, and type of metal stent. The primary outcome was the hazard rate of stent dysfunction. A multivariable Cox proportional hazards model was used to identify independent predictors of stent dysfunction. Results1,396 patients were assessed. Following PSM a total of 496 patients were analyzed (248 ASA-E, 248 ASA-U). ERCP-SEMS was associated with high clinical success of 82.2% in ASA-E and 81.2% in ASA-U, p=0.80. A total of 184 patients had stent dysfunction wth a mean stent patency time of 229.9 ± 306.2 days and 245.4 ± 241.4 days in ASA-E and ASA-U, resepectively (p=0.52). On multivariable analysis, ASA-E did not protect against stent dysfunction with a hazard ratio of 1.25 (95% confidence interval, CI: 0.96; 1.63). Pancreatic cancer etiology (HR 1.36, 95% CI:1.15-1.61) predicted stent dysfunction while cancer therapy was protective (HR 0.73, 95% CI: 0.55; 0.96). The use of chronic ASA was not associated with an increased risk for adverse events including bleeding, post-ERCP pancreatitis, and perforation. ConclusionIn this large, multicenter study utilizing propensity score-matching, chronic exposure to ASA did not protect against stent dysfunction in MDBO. Instead, the analysis revealed that the etiology of pancreatic cancer was an independent predictor of stent dysfunction while cancer therapy was protective.

Unveiling the intricate causal nexus between pancreatic cancer and peripheral metabolites through a comprehensive bidirectional two-sample Mendelian randomization analysis.

Aim: Pancreatic cancer (PC) is a devastating malignancy characterized by its aggressive nature and poor prognosis. However, the relationship of PC with peripheral metabolites remains not fully investigated. The study aimed to explore the causal linkage between PC and peripheral metabolite profiles. Methods: Employing publicly accessible genome-wide association studies (GWAS) data, we conducted a bidirectional two-sample Mendelian randomization (MR) analysis. The primary analysis employed the inverse-variance weighted (IVW) method. To address potential concerns about horizontal pleiotropy, we also employed supplementary methods such as maximum likelihood, weighted median, MR-Egger regression, and MR pleiotropy residual sum and outlier (MR-PRESSO). Results: We ascertained 20 genetically determined peripheral metabolites with causal linkages to PC while high-density lipoprotein (HDL) and very low-density lipoprotein (VLDL) particles accounted for the vast majority. Specifically, HDL particles exhibited an elevated PC risk while VLDL particles displayed an opposing pattern. The converse MR analysis underscored a notable alteration in 17 peripheral metabolites due to PC, including branch chain amino acids and derivatives of glycerophospholipid. Cross-referencing the bidirectional MR results revealed a reciprocal causation of PC and X-02269 which might form a self-perpetuating loop in PC development. Additionally, 1-arachidonoylglycerophosphocholine indicated a reduced PC risk and an increase under PC influence, possibly serving as a negative feedback regulator. Conclusion: Our findings suggest a complex interplay between pancreatic cancer and peripheral metabolites, with potential implications for understanding the etiology of pancreatic cancer and identifying novel early diagnosis and therapeutic targets. Moreover, X-02269 may hold a pivotal role in PC onset and progression.

Clinical trial-identified inflammatory biomarkers in breast and pancreatic cancers.

Breast cancer and pancreatic cancer are two common cancer types characterized by high prevalence and high mortality rates, respectively. However, breast cancer has been more well-studied than pancreatic cancer. This narrative review curated inflammation-associated biomarkers from clinical studies that were systematically selected for both breast and pancreatic cancers and discusses some of the common and unique elements between the two endocrine-regulated malignant diseases. Finding common ground between the two cancer types and specifically analyzing breast cancer study results, we hoped to explore potential feasible methods and biomarkers that may be useful also in diagnosing and treating pancreatic cancer. A PubMed MEDLINE search was used to identify articles that were published between 2015-2022 of different kinds of clinical trials that measured immune-modulatory biomarkers and biomarker changes of inflammation defined in diagnosis and treatment of breast cancer and pancreatic cancer patients. A total of 105 papers (pancreatic cancer 23, breast cancer 82) were input into Covidence for the title and abstract screening. The final number of articles included in this review was 73 (pancreatic cancer 19, breast cancer 54). The results showed some of the frequently cited inflammatory biomarkers for breast and pancreatic cancers included IL-6, IL-8, CCL2, CD8+ T cells and VEGF. Regarding unique markers, CA15-3 and TNF-alpha were two of several breast cancer-specific, and CA19 and IL-18 were pancreatic cancer-specific. Moreover, we discussed leptin and MMPs as emerging biomarker targets with potential use for managing pancreatic cancer based on breast cancer studies in the future, based on inflammatory mechanisms. Overall, the similarity in how both types of cancers respond to or result in further disruptive inflammatory signaling, and that point to a list of markers that have been shown useful in diagnosis and/or treatment method response or efficacy in managing breast cancer could potentially provide insights into developing the same or more useful diagnostic and treatment measurement inflammatory biomarkers for pancreatic cancer. More research is needed to investigate the relationship and associated inflammatory markers between the similar immune-associated biological mechanisms that contribute to breast and pancreatic cancer etiology, drive disease progression or that impact treatment response and reflect survival outcomes.

Abstract 6447: Carotenoid and tocopherol intake in relation to pancreatic cancer risk in a population-based case-control study

Abstract Pancreatic cancer is the third leading cause of cancer-related death in the U.S. and has a 5-year relative survival rate of only 11.5%. The etiology of pancreatic cancer is not well understood, with cigarette smoking, type 2 diabetes, and chronic pancreatitis as the only well-established risk factors. Therefore, it is critical to identify modifiable risk factors for primary prevention. Persistent oxidative stress and resultant oxidative damage can lead to accumulated mutations in oncogenes and tumor suppressor genes and subsequent carcinogenesis of the pancreas. Carotenoids are abundant in fruits and vegetables, while tocopherols are rich in oilseeds and nuts. Both carotenoids and tocopherols have antioxidant functions. Thus, it is possible that high intake of these bioactive compounds can reduce risk of pancreatic cancer. The present study sought to investigate this question in a case-control study conducted during 1994-1998 in Minnesota. Cases (n=150), aged 20 years or older, were ascertained from all hospitals in the metropolitan area of the Twin Cities and the Mayo Clinic; from the latter, only cases residing in the Upper Midwest of the US were recruited. Controls (n=459) were randomly selected from the general population and frequency matched to cases by age (within 5 years) and sex. Intake of carotenoids and tocopherols from diet and supplements was estimated from a validated food frequency questionnaire. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using unconditional logistic regression. As lutein and zeaxanthin are isomers that have identical chemical formulas, they are combined into a single variable in the analysis. All dietary variables were adjusted for energy intake with the residual method prior to data analysis. After adjustment for age, sex, race, education, physical activity, cigarette smoking, and alcohol consumption, intake of lutein and zeaxanthin was associated with a significantly reduced risk of pancreatic cancer [OR (95% CI) for quartile 4 (median: 4972 µg/day) vs. quartile 1 (median: 976 µg/day): 0.39 (0.19-0.79); p-trend: 0.06]. This inverse association became slightly weaker but remained statistically significant after additional adjustment for intake of energy, fat, and fiber. No significant associations were observed for intake of α-carotene, β-carotene, lycopene, β-cryptoxanthin, α-tocopherol, β-tocopherol, and δ-tocopherol, although a higher intake of all these nutrients except α-tocopherol and δ-tocopherol tended to confer a lower risk. Our study shows that there is a significant, beneficial effect of lutein and zeaxanthin intake on pancreatic cancer risk, although it may be a chance finding due to multiple comparisons. More epidemiologic studies are warranted to further elucidate the roles of carotenoids and tocopherols in the etiology and prevention of pancreatic cancer. Citation Format: Bronson Dokmanovich, Hao fan, Yunpeng Yu, Kristin Anderson, Jianjun Zhang. Carotenoid and tocopherol intake in relation to pancreatic cancer risk in a population-based case-control study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6447.

Adherence to Mediterranean Diet and Risk of Pancreatic Cancer: Systematic Review and Meta-Analysis.

Pancreatic cancer (PC) represents the 6th cause of cancer death. Although the aetiology of PC is not completely understood, numerous risk factors have been identified in association with this cancer, among them diet. However, little is known about the association between the Mediterranean Diet (MedDiet) and the risk of PC. For this reason, we conducted a systematic review with meta-analysis according to the PRISMA guidelines, searching on three databases (PubMed/MEDLINE, Scopus, and EMBASE). The protocol was registered in PROSPERO. Both fixed and random effect models were performed. The Effect size was reported as a hazard ratio (HR) with a 95% Confidence Interval (CI). A total of eight articles were included. The methodological quality of the included meta-analyses was high. Our results show that a higher adherence to the MedDiet is associated with a lower risk of PC [HR:0.82 (0.76-0.88) p < 0.001, based on 1,301,320 subjects]. The results were also confirmed in sensitivity and subgroups analyses (avoidance of potential overlapping effects, type of tools used to assess dietary intake and the diagnosis of PC, prevalence and incidence of PC risk, country where the studies took place, sex, and cancer site). Promoting a higher adherence to the MedDiet could be an effective approach to reduce the risk of PC.

Circulating gamma-glutamyl transpeptidase and risk of pancreatic cancer: A prospective cohort study in the UK Biobank.

To determine whether serum gamma-glutamyl transpeptidase (GGT) level is associated with pancreatic cancer risk in a large prospective cohort. The study analyzed serum GGT concentration at baseline of 421,032 participants recruited in the UK Biobank since 2006 through 2010. Information on incidence of pancreatic cancer was obtained from cancer and death registers, updated until 2015 in Scotland or 2016 in England and Wales. Adjusted Cox proportional hazards models were used to measure the association between serum GGTand pancreatic cancer risk. The study identified 586 cases of pancreatic cancer over a median follow-up period of 7.16 years. In the multivariable-adjusted Cox model, serum GGT level was associated with 14% higher pancreatic cancer risk (hazard ratio (HR) per one standard deviation increment of log2 GGT level=1.14, 95% confidence interval (CI) 1.02-1.28, p= 0.025). In the total population, the HR for the highest GGT group was 1.68 (95%CI: 1.22-2.30) versus the lowest GGT group. The HR for the highest GGT group in men (≥50.2U/L) was 1.72 (95%CI: 1.14-2.61) and that in women (≥31.6U/L) was 1.75 (95%CI: 1.06-2.88) versus the lowest GGT group. Our findings suggested a positive association of serum GGT in pancreatic cancer etiology, implying the potential of monitoring GGT level for identifying at-risk individuals for pancreatic cancer.

Previous hepatitis B viral infection-an underestimated cause of pancreatic cancer.

BACKGROUNDThe etiology of pancreatic cancer remains unclear. This limits the possibility of prevention and effective treatment. Hepatitis B virus (HBV) is responsible for the development of different types of cancer, but its role in pancreatic cancer is still being discussed.AIMTo assess the prevalence of previous HBV infection and to identify viral biomarkers in patients with pancreatic ductal adenocarcinoma (PDAC) to support the role of the virus in etiology of this cancer.METHODSThe data of 130 hepatitis B surface antigen-negative subjects were available for the final analysis, including 60 patients with PDAC confirmed by cytology or histology and 70 sex- and age-matched controls. All the participants were tested for HBV biomarkers in blood [antibody to hepatitis B core antigen (anti-HBc), antibody to hepatitis B surface antigen (anti-HBs) and HBV DNA], and for those with PDAC, biomarkers in resected pancreatic tissues were tested (HBV DNA, HBV pregenomic RNA and covalently closed circular DNA). We performed immunohistochemistry staining of pancreatic tissues for hepatitis B virus X antigen and Ki-67 protein. Non-parametric statistics were used for the analysis.RESULTSAnti-HBc was detected in 18/60 (30%) patients with PDAC and in 9/70 (13%) participants in the control group (P = 0.029). Accordingly, the odds of PDAC in anti-HBc-positive subjects were higher compared to those with no previous HBV infection (odds ratio: 2.905, 95% confidence interval: 1.191-7.084, standard error 0.455). HBV DNA was detected in 8 cases of PDAC and in 6 of them in the pancreatic tumor tissue samples only (all patients were anti-HBc positive). Blood HBV DNA was negative in all subjects of the control group with positive results of the serum anti-HBc test. Among 9 patients with PDAC, 5 revealed signs of replicative competence of the virus (covalently closed circular DNA with or without pregenomic RNA) in the pancreatic tumor tissue samples. Hepatitis B virus X antigen expression and active cell proliferation was revealed by immunohistochemistry in 4 patients with PDAC in the pancreatic tumor tissue samples.CONCLUSIONWe found significantly higher risks of PDAC in anti-HBc-positive patients. Detection of viral replication and hepatitis B virus X protein expression in the tumor tissue prove involvement of HBV infection in pancreatic cancer development.

Machine learning-featured Secretogranin V is a circulating diagnostic biomarker for pancreatic adenocarcinomas associated with adipopenia.

BackgroundPancreatic cancer is one of the most fatal malignancies of the gastrointestinal cancer, with a challenging early diagnosis due to lack of distinctive symptoms and specific biomarkers. The exact etiology of pancreatic cancer is unknown, making the development of reliable biomarkers difficult. The accumulation of patient-derived omics data along with technological advances in artificial intelligence is giving way to a new era in the discovery of suitable biomarkers.MethodsWe performed machine learning (ML)-based modeling using four independent transcriptomic datasets, including GSE16515, GSE62165, GSE71729, and the pancreatic adenocarcinoma (PAC) dataset of the Cancer Genome Atlas. To find candidates for circulating biomarkers, we exported expression profiles of 1,703 genes encoding secretory proteins. Integrating three transcriptomic datasets into either a training or test set, ML-based modeling distinguishing PAC from normal was carried out. Another ML-model classifying long-lived and short-lived patients with PAC was also built to select prognosis-associated features. Finally, circulating level of SCG5 in the plasma was determined from the independent cohort (non-tumor = 25 and pancreatic cancer = 25). We also investigated the impact of SCG5 on adipocyte biology using recombinant protein.ResultsThree distinctive ML-classifiers selected 29-, 64- and 18-featured genes, recognizing the only common gene, SCG5. As per the prediction of ML-models, the SCG5 transcripts was significantly reduced in PAC and decreased further with the progression of the tumor, indicating its potential as a diagnostic as well as prognostic marker for PAC. External validation of SCG5 using plasma samples from patients with PAC confirmed that SCG5 was reduced significantly in patients with PAC when compared to controls. Interestingly, plasma SCG5 levels were correlated with the body mass index and age of donors, implying pancreas-originated SCG5 could regulate energy metabolism systemically. Additionally, analyses using publicly available Genotype-Tissue Expression datasets, including adipose tissue histology and pancreatic SCG5 expression, further validated the association between pancreatic SCG5 expression and the size of subcutaneous adipocytes in humans. However, we could not observe any definite effect of rSCG5 on the cultured adipocyte, in 2D in vitro culture.ConclusionCirculating SCG5, which may be associated with adipopenia, is a promising diagnostic biomarker for PAC.

Exocrine pancreatic cancer and living near to waste sites containing hazardous organic chemicals, New York State, USA - an 18-year population-based study.

The etiology of exocrine pancreatic cancer (EPC) remains unknown except for family history and smoking. Despite recent medical advances, rates of pancreatic cancer incidence and mortality are increasing. Although existing evidence suggests a potentially causal relationship between environmental chemical exposures and pancreatic cancer, whether residential exposure impacts pancreatic cancer rates remains unknown. The authors identified 28 941 patients diagnosed with exocrine pancreatic cancer in New York State exclusive of New York City for the years 1996-2013. Descriptive statistics and negative binomial regression were used in this ecological study to compare pancreatic cancer hospitalization rates among patients who lived in zip codes with hazardous waste sites (HWSs) containing persistent organic pollutants (POPs) and volatile organic pollutants (VOCs) compared with clean zip codes with no identified hazardous waste sites. The authors assessed the effect of selected known and suspected human carcinogens on the EPC hospitalization rates by subgroup analyses. Compared with the clean sites, the pancreatic cancer hospital discharge rate in the "VOCs without POPs" and "VOCs and POPs" sites, after adjustment for potential confounders were 1.06 (95% CI: 1.03-1.09) and 1.05 (95% CI: 1.01-1.08), respectively. In the analysis by specific chemicals, rate ratios (RR) for the benzene (RR = 1.12) and ethylbenzene (RR = 1.34) in the non-chlorinated VOCs group, trichloroethylene (RR = 1.07) and tetrachloroethylene (RR = 1.11) in the chlorinated VOCs group, chlorinated pesticides (RR = 1.11) and PCBs (RR = 1.05) in the POPs groups were statistically significant (p-values <0.05) compared with clean sites. Compared with the clean sites, the pancreatic cancer hospital discharge rate in the "VOCs without POPs" and "VOCs and POPs" sites, after adjustment for potential confounders were 1.06 (95% CI: 1.03-1.09) and 1.05 (95% CI: 1.01-1.08), respectively. In the analysis by specific chemicals, rate ratios (RR) for the benzene (RR = 1.12) and ethylbenzene (RR = 1.34) in the non-chlorinated VOCs group, trichloroethylene (RR = 1.07) and tetrachloroethylene (RR = 1.11) in the chlorinated VOCs group, chlorinated pesticides (RR = 1.11) and PCBs (RR = 1.05) in the POPs groups were statistically significant (p-values <0.05) compared with clean sites. Int J Occup Med Environ Health. 2022;35(4):459-71.

Descriptive, analytical and molecular epidemiology of pancreatic cancer

The purpose of the study was to present current data on the role of lifestyle and heredity factors in the etiology of pancreatic cancer (PC). Material and Methods. A systemic literature search was conducted using Medline and Elibrary databases. Results. Pancreatic cancer is the 9th leading cause of cancer-related deaths worldwide. PC has an extremely poor prognosis. The 5-year survival rate of patients with PC does not exceed 9 %. The highest incidence and mortality rates from PC are found in Eastern Europe, including Russia. The incidence of PC in 2019 was 9.3 per 100,000 males and 5.7 per 100,000 females. In Russia, PC incidence and mortality rates in both males and females show a steady increase. Risk factors associated with PC include smoking, heavy alcohol drinking, overweight and obesity, diabetes and chronic pancreatitis. The microbiome of the oral cavity and colon infuence the risk of PС. Approximately 10 % of PC is estimated to have familial inheritance. The risk of PC in patients with inherited syndromes ranges from 2 (hereditary breast and ovarian cancer syndrome) to 132 (Peutz-Jeghers syndrome). Regions of the genome containing variants of single nucleotide polymorphism (SNPs), which are more common in patients with PC than in healthy people, were identifed. The most common somatic mutations include mutations in the driver genes of prostate cancer, which include the KRAS oncogene and tumor suppressor genes TP53, CDKN2A, and SMAD4.The less common mutations of genes include AIB1/NCOA, ERBB2/HER2/EGFR2, AKT2, BRAF, CCND1, RB1, etc. They are identifed as “passenger” mutations although the combined effect of polymorphism of these genes can be signifcant and comparable to the infuence of the driver gene. Conclusion. A signifcant disadvantage of our understanding of the process of carcinogenesis is the lack of information about carcinogenic factors that cause specifc mutations, i.e. the formation of mutational signatures. To solve this problem, in 2017, the international scientifc project GRAND CHALLENGE “Mutograph” was launched. The scientists of the Department of Cancer Epidemiology of N. N. Blokhin National Medical Research Center of Oncology are members of the international team working on this project.

Smoking and Pancreatic Cancer: Smoking Patterns, Tobacco Type, and Dose-Response Relationship.

Pancreatic cancer (PC) is the primary cause of cancer death in the United States and Europe. Despite remarkable advances in the molecular understanding of PC and advances in new therapeutic approaches, PC remains a disease with a poor prognosis. Although evidence indicates that long-term smoking is a major cause of PC, the molecular pathways behind smoking-induced PC pathogenesis are not fully understood. Smoking cessation can significantly reduce the occurrence of PC.This review explores the processes underpinning the influence of smoking-related chemicals on fibrosis and inflammation and provides insight into the etiology of PC. In the future, a thorough exploration of the effects of smoking chemicals on the activity of pancreatic stem cells and then on the essential mediators of the association with cancer cells would likely yield new diagnostic targets.

Abstract 5870: Diet quality and pancreatic cancer incidence in the Multiethnic Cohort

Abstract Background: Pancreatic cancer is one of the deadliest cancers, and its incidence has been increasing steadily in the past decade. While some dietary components have been implicated as risk factors for pancreatic cancer, epidemiological data on the role of overall diet quality in pancreatic cancer etiology are limited, especially from population-based prospective studies. This study examined the relationship between diet quality and pancreatic cancer incidence in the Multiethnic Cohort Study (MEC). Methods: Data were analyzed from 177,313 African American, Native Hawaiian, Japanese American, Latino, and White men and women aged 45-75 years who completed a quantitative food frequency questionnaire at cohort entry. Diet quality was assessed by a priori diet quality indices (DQIs), the Healthy Eating Index-2015 (HEI-2015), the Alternative Healthy Eating Index-2010 (AHEI-2010), the alternate Mediterranean Diet (aMED) score, the Dietary Approaches to Stop Hypertension (DASH) score, and the Dietary Inflammatory Index (DII®). These five DQIs were investigated because of their potential to capture differences in various nutritional patterns across different racial/ethnic groups. Multivariate Cox models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the DQIs and pancreatic cancer incidence adjusted for age, sex, race/ethnicity, education, diabetes status, family history of pancreatic cancer, vigorous physical activity, smoking status with pack years, total energy intake, body mass index (BMI), and alcohol consumption. Stratified analyses were done by sex, race/ethnicity, smoking status and BMI. Results: During an average follow up of 19.3 years, 1,782 incident pancreatic cancer cases were identified. Overall, we did not observe statistically significant associations between the DQIs and pancreatic cancer risk. In subgroup analyses comparing the highest vs. lowest quintiles of the scores, a protective association was observed with the DASH for ever smokers (HR = 0.75, 95% CI: 0.60-0.92) and individuals with BMI ≥ 25 kg/m2 (HR = 0.77, 95% CI: 0.63-0.94), but not for never smokers (HR = 1.04, 95% CI: 0.82-1.31, P for heterogeneity = 0.004) or those with BMI &amp;lt; 25 kg/m2 (HR = 1.21, 95% CI: 0.94-1.56, P for heterogeneity = 0.097). There were no differences in associations by sex or race/ethnicity (P for heterogeneity ≥ 0.43). Conclusion: In this large prospective study, we did not find reduction in pancreatic cancer risk associated with healthier diet as assessed by the 5 DQIs. There is some indication that adherence to the DASH diet may potentially be protective against pancreatic cancer among ever smokers or individuals classified as overweight or obese. Further investigations are needed to confirm these findings. Citation Format: Heather Steel, Song-Yi Park, Tiffany Lim, Daniel Stram, Loic Le Marchand, Anna H. Wu, V. Wendy Setiawan. Diet quality and pancreatic cancer incidence in the Multiethnic Cohort [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 5870.

Serum trace element levels of liver cirrhosis and pancreatic cancer patients

The incidence of liver cirrhosis and pancreatic cancer varies between countries and stands out as an important health problem worldwide. Liver cirrhosis is the most advanced stage of chronic liver disease and is a widespread result of chronic liver damage. The etiology of liver cirrhosis and pancreatic cancer, which are major causes of cancer fatalities in developed countries, is poorly understood. Many metabolic and physiological processes in the human body utilize trace elements. The creation and development of many diseases like cancer, cardiovascular, and diabetes mellitus occur with the disruption of trace element metabolism in the body as a result of improper nutrition, environmental, and occupational exposure, and impaired digestion and absorption. Methods and materials: In this study, copper (Cu), cadmium (Cd), iron (Fe), cobalt (Co), manganese (Mn), magnesium (Mg), nickel (Ni), zinc (Zn), and lead (Pb) concentrations were researched in the serum of liver cirrhosis and Pancreatic Cancer (PC) patients and healthy controls. Analysis of the elements was carried out by flame atomic absorption spectrophotometer. Results: Fe and Zn serum levels were considerably lower in individuals with liver cirrhosis and pancreatic cancer than in controls (p &lt;0.001). Furthermore, mean serum levels of Cd and Mn in patients with liver cirrhosis and pancreatic Ca were considerably lower than in controls (p &lt;0.01). In addition, when compared to pancreatic cancer, mean serum Cu and Ni levels in liver cirrhosis patients and controls were considerably lower (p &lt;0.05). Mean serum levels of Pb in pancreatic Ca patients were significantly lower compared to liver cirrhosis patients and controls (p &lt;0.05). When comparing all cancer patients to controls, mean serum Co and Mg levels were not substantially different. Conclusion: Deficiency in four trace elements (Cd, Mn, Fe, and Zn) was determined in patients with liver cirrhosis and pancreatic cancer. In addition, we have determined the deficiency of Cu and Ni trace elements (TEs) in pancreatic cancer patients. TE insufficiencies in cancer patients may be due to excessive consumption of foods and undernourishment. Epidemiological and physiological causes of trace element changes should be investigated further.

A whole-exome case-control association study to characterize the contribution of rare coding variation to pancreatic cancer risk.

SummaryPancreatic cancer is a deadly disease that accounts for approximately 5% of cancer deaths worldwide, with a dismal 5-year survival rate of 10%. Known genetic risk factors explain only a modest proportion of the heritable risk of pancreatic cancer. We conducted a whole-exome case-control sequencing study in 1,591 pancreatic cancer cases and 2,134 cancer-free controls of European ancestry. In our gene-based analysis, ATM ranked first, with a genome-wide significant p value of 1 × 10−8. The odds ratio for protein-truncating variants in ATM was 24, which is substantially higher than prior estimates, although ours includes a broad 95% confidence interval (4.0–1000). SIK3 was the second highest ranking gene (p = 3.84 × 10−6, false discovery rate or FDR = 0.032). We observed nominally significant association signals in several genes of a priori interest, including BRCA2 (p = 4.3 × 10−4), STK11 (p = 0.003), PALB2 (p = 0.019), and TP53 (p = 0.037), and reported risk estimates for known pathogenic variants and variants of uncertain significance (VUS) in these genes. The rare variants in established susceptibility genes explain approximately 24% of log familial relative risk, which is comparable to the contribution from established common susceptibility variants (17%). In conclusion, this study provides new insights into the genetic susceptibility of pancreatic cancer, refining rare variant risk estimates in known pancreatic cancer susceptibility genes and identifying SIK3 as a novel candidate susceptibility gene. This study highlights the prominent importance of ATM truncating variants and the underappreciated role of VUS in pancreatic cancer etiology.

Are Circulating Immune Cells a Determinant of Pancreatic Cancer Risk? A Prospective Study Using Epigenetic Cell Count Measures.

Evidence is accumulating that immune cells play a prominent role in pancreatic cancer etiology but prospective investigations are missing. We conducted a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) study with 502 pairs of incident pancreatic cancer cases and matched controls. Relative counts of circulating immune cells (neutrophils and lymphocyte sublineages: total CD3+, CD8+, CD4+, and FOXP3+ regulatory T cells (Tregs) relative to nucleated cells, (white blood cells) were measured by qRT-PCR. ORs with 95% confidence intervals were estimated using logistic regressions, modeling relative counts of immune cells on a continuous scale. Neither relative counts of immune cell types taken individually, nor mutually adjusted for each other were associated with pancreatic cancer risks. However, in subgroup analyses by strata of lag-time, higher relative counts of Tregs and lower relative counts of CD8+ were significantly associated with an increased pancreatic cancer risks in participants diagnosed within the first 5 years of follow-up. These results might reflect reverse causation, due to higher relative counts of Tregs and lower counts of CD8+ cells among individuals with more advanced stages of latent pancreatic cancer, who are closer to the point of developing clinical manifest disease. We have shown, for the first time, that increased relative counts of regulatory T cells and lower relative counts of CD8+, cytotoxic T cells may be associated with pancreatic cancer risk or relatively late-stage tumor development.See related commentary by Michaud and Kelsey, p. 2176.

Abstract 2740: Effect of pancreatic cancer cell derived extracellularvesicles on the tumor microenvironment

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is one amongst the most lethal malignancies, with a 5 year survival rate of &amp;lt;10%.While the tumor microenvironment in PDAC is highly immunosuppressive, little is known about the mechanisms of immune invasion leading to rapid tumor progression. Hence, in-depth exploration of early cellular and molecular drivers of PDAC is desirable for early and precise diagnosis and to identify new biological targets for developing new therapies. Extracellular vesicles (EVs) are nanometer sized particles that are shed by most tissues/organs and are known to be important mediators of intercellular signaling and molecular transfer. We hypothesized that pancreatic cancer derived EVs may play an important role in mediating the interactions among the tumor and surrounding microenvironment (TME). Given that tumor-associated macrophages (TAMs) are integral components of the TME that can promote tumor progression, tumor invasion, and intravasation to other parts of the body, this study is focused on investigating the role of PDAC derived EVs in macrophages polarization, which in turn would impact tumor cell proliferation and invasion. Results: EVs were isolated from 6 pancreatic cancer (PaCa) and 2 normal established pancreatic epithelial cell lines. EVs were characterized using nanoparticle tracking (NTA) and immunoblot analysis. LC-MS/MS based shotgun proteomics analyses of EVs revealed that PaCa cell line derived EVs were significantly enriched in potentially immunomodulatory proteins such as S100 calcium-binding protein A4 (S100A4) and human leukocyte antigen-B (HLA-B). However, PaCa cell EVs had significantly less MHC-class-I-related chain A (MICA), a protein important for proper human leukocyte antigen (HLA) function, as compared to normal pancreatic epithelial cell derived EVs. These data suggest that PaCa derived EVs may influence immunomodulation and macrophage function within the tumor microenvironment thereby strengthening our hypothesis. Further experimental studies aimed at delineating the precise mechanism of action of EVs in macrophage polarization is ongoing. Conclusions: Our finding suggests significant difference among the molecular composition of PaCa derived cargos as compared to and normal cells derived EVs that could be useful in furthering our understanding about pancreatic cancer etiology. Furthermore, the novel insights obtained from these studies may augment the development of biomarkers that can be used for early detection of the disease and improved therapeutics to improve clinical outcomes. Citation Format: Baldev Singh, Charles Hinzman, Edina Wang, Anton Iliuk, Jose Trevino, Keith Unger, Partha Banerjee, Amrita K. Cheema. Effect of pancreatic cancer cell derived extracellularvesicles on the tumor microenvironment [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 2740.

Reproductive Factors, Use of Exogenous Hormones, and Pancreatic Cancer Incidence: The Norwegian Women and Cancer Study.

IntroductionThe incidence of pancreatic cancer is increasing worldwide and characterized by a particularly low survival rate. Studies have reported weak and inconsistent evidence for associations among reproductive factors, use of exogenous hormones, and pancreatic cancer incidence in women.PurposeTo investigate relationships between reproductive factors, exogenous hormones, and the rate of pancreatic cancer incidence in a large population-based prospective cohort of women in Norway.MethodsWe used data from the Norwegian Women and Cancer study on 588 incident cases of pancreatic cancer diagnosed among 165,419 women, with mean follow-up of 18.7 years. Cox proportional-hazard models were used to estimate HRs and 95% CIs for associations of interest.ResultsCumulative breastfeeding duration >24 months was associated with 63% decreased incidence of pancreatic cancer compared to no breastfeeding. We observed an inverse linear dose–response trend between cumulative breastfeeding duration and pancreatic cancer incidence, which was confirmed in parous women and ever-smokers. Higher age at first birth and menopause were inversely associated with pancreatic cancer incidence, though with less precise effect estimates. Current use of oral contraceptives was associated with a doubling of pancreatic cancer incidence, but the analysis was hampered by a small number of cases. There was no evidence of any associations between age at menarche, parity or use of menopausal hormone therapy, and incidence of pancreatic cancer.ConclusionOur results suggest a potential protective effect of breastfeeding duration against pancreatic cancer incidence. Inconsistent results for the other reproductive factors suggested no important role of estrogens in pancreatic cancer etiology.