Risk Of Pancreatic Adenocarcinoma Research Articles

Pesticides and risk of pancreatic adenocarcinoma in France: a nationwide spatiotemporal ecological study between 2011 and 2021.

While pancreatic adenocarcinoma (PA) incidence is increasing, especially in France, the association between pesticides and PA remains unclear. The aims of this study were to assess the spatiotemporal distribution of the incidence of PA in France between 2011 and 2021 and to determine whether pesticide exposure was associated with higher risk of PA. We employed a disease-mapping and ecological regression approach with medicoadministrative data covering 99% of the French population. Exposure data were drawn from an open purchase database. A pesticide exposure intensity index (PEXI), defined as the logged and scaled median of the ratio quantity of substance over agricultural surface per spatial unit was used for total quantity (total PEXI) and 9 specific substances. The analyses were adjusted for tobacco-induced diseases, deprivation, community medicine accessibility, alcohol-related disease and morbid obesity. A Bayesian hierarchical spatiotemporal model was used to both model the incidence over time and space, and to estimate the risk of PA for pesticide use. We identified 134102 incident cases of PA between 2011 and 2021. The relative risk of PA was heterogeneous across space with greater risk around Paris, central France and the Mediterranean coast. We observed an association, albeit small, between the total PEXI and PA incidence over the study period (RR: 1.0130; CI95% [1.0057;1.0204]). Sulphur for spraying, mancozeb, and glyphosate showedevidence of an association of the same magnitude. These findings show that new cases of PA occur heterogeneously in space, raising questions about our understanding of PA environmental risk factors. The association with pesticide exposure should be confirmed and underlying mechanisms understood using individual-level studies.

Causal associations of tea consumption on risk of pancreatic adenocarcinoma and the mediating role of vascular endothelial growth factor D levels.

Tea is one of the most widely consumed beverages in the world. However, the association between tea and risk of pancreatic adenocarcinoma remains controversial. This study aimed to investigate the causal relationship between tea consumption and risk of pancreatic adenocarcinoma and to explore their mediating effects. The two-sample Mendelian randomisation (MR) analysis showed an inverse causal relationship between tea intake and pancreatic adenocarcinoma (OR: 0·111 (0·02, 0·85), P < 0·04). To examine the mediating effects, we explored the potential mechanisms by which tea intake reduces the risk of pancreatic adenocarcinoma. Based on the oral bioavailability and drug-like properties in Traditional Chinese Medicine Systems Pharmacology database, we selected the main active ingredients of tea. We screened out the fifteen representative targeted genes by Pharmmapper database, and the gene ontology enrichment analysis showed that these targeted genes were related to vascular endothelial growth factor (VEGF) pathway. The two-step MR analysis of results showed that only VEGF-D played a mediating role, with a mediation ratio of 0·230 (0·066, 0·394). In conclusion, the findings suggest that VEGF-D mediates the effect of tea intake on the risk of pancreatic adenocarcinoma.

Association of Smoking with progression from low-risk to high-risk intraductal papillary mucinous neoplasms and pancreatic cancer

BackgroundFactors associated with the risk of pancreatic adenocarcinoma (PDAC) may play a role in the development and progression of Intraductal Papillary Mucinous Neoplasms (IPMNs). However, data are limited. AimTo compare exposome factors in three groups of patients with “high or low-risk” IPMNs, as assessed at diagnosis and during a 24-months follow-up, and with PDAC. MethodsPatients were matched (same sex, age ±5) 1:1. Exposure variables were compared across groups using Kruskal-Wallis, ANOVA, or Chi-square tests with Bonferroni correction. ResultsA total of 151 patients were enrolled in each of the three groups (453 overall). The proportion of current smokers was progressively higher in “low-risk”, “high-risk” IPMNs and PDAC patients (8.1 %, 11.2 %, 23.3 %; p = 0.0002). The three groups did not differ in terms of ever or heavy smoking, BMI, history of diabetes, cancer, cholecystectomy or chronic pancreatitis, use of statins or aspirin, and family history of cancer. A history of peptic ulcer was more common in PDAC (7.2 %) than in either “low-risk” (2.0 %) or “high-risk” (2.6%) IPMNs (p = 0.02, not significant after Bonferroni correction). ConclusionActive smoking seems associated with the progression of IPMNs to malignancy, and cessation of active smoking might be advised in patients with IPMN.

Tumor microbiome differences in early-onset versus average-onset pancreatic adenocarcinoma.

4016 Background: The rise in early-onset gastrointestinal cancers includes an increased risk of pancreatic adenocarcinoma (PDAC), but the underlying pathogenesis is incompletely understood. The tumor microbiome is an increasing focus of research given its impact on tumor pathogenesis and outcomes. We evaluated microbiome profiles in resected specimens from early-onset PDAC (eoPDAC) and average-onset PDAC (aoPDAC). Methods: PDAC specimens were selected consecutively from Cleveland Clinic and Roswell Park Cancer Institute biorepositories and categorized on age at diagnosis ( &lt; 50 years defined as eoPDAC, and &gt; 50 years as aoPDAC). The tissue microbiome was characterized using shotgun metagenomic sequencing. Alpha diversity, denoting the richness and evenness of microbial species within a specific sample, was compared using the Wilcoxon rank-sum test. The differential test of Beta-diversity distances (Bray Curtis distance), representing microbial taxonomic differences between the specimens was performed using Permutational MANOVA. All p-values were adjusted for multiple testing. Results: The study comprised 44 individuals with resected PDAC (24 eoPDAC and 20 aoPDAC). After quality checks, 63 tissue specimens were selected for analysis (13 tumor and 10 adjacent normal specimens for eoPDAC, 20 each of tumor and adjacent normal specimens for aoPDAC). eoPDAC tumor demonstrated significantly higher alpha diversity compared to adjacent normal tissue (P = 0.02) and aoPDAC (P = 0.0062) while aoPDAC did not (tumor vs normal alpha diversity P = 0.31). Beta diversity analysis demonstrated significantly different diversity of genera between all the groups (P &lt; 0.05). Consistent with this finding, the majority of the species - 259/302 (85.8%) in eo vs aoPDAC comparison and 262/366 (71.6%) for eoPDAC vs normal comparison did not overlap. Differential abundance analysis revealed a significant variation of tumor microbiome in eoPDAC vs aoPDAC (P &lt; 0.05). Prevalent bacterial genera (tumor specimens) are listed in the Table. eoPDAC tumor tissues were enriched in Enterobacter, Neisseria,and Escherichia genera, while aoPDAC tumor tissues were enriched in Klebsiella and Bacillus genera. Conclusions: eoPDAC has a distinct microbiome profile compared to aoPDAC. The correlation with several microbial genera associated with pancreatic diseases is a significant finding and warrants further exploration. This is relevant considering the rising incidence of eoPDAC of unknown etiology, and ongoing efforts to develop microbiome-based biomarkers for screening and treatment. [Table: see text]

Childhood and adulthood passive and active smoking, and the ABO group as risk factors for pancreatic cancer in women.

Active smoking and the A blood group are associated with pancreatic adenocarcinoma (PC) risk. However, potential interactions between those risk factors and the role of passive smoking have been little investigated. We aimed to explore specific and joint associations of passive and active smoking, and effect modification by the ABO blood group in French women. The study included 96,594 women from the E3N prospective cohort, mean age: 49years (SD 6.7). Information on active and passive smoking was reported at inclusion and throughout follow-up. Cases were classified according to the International Classification of Diseases 10. Associations with passive and active smoking and effect modification by the ABO blood group were investigated with multivariable Cox regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI). During a 24-year median follow-up, 346 incident PC cases were identified. Current smoking compared with never and former smoking (HR 1.51 [95% CI 1.08-2.10]), and passive smoking in childhood compared with no childhood exposure (HR 1.47 [95% CI 1.08-2.00]) were associated with increased PC risk, but not passive exposure in adulthood (HR 1.16 [95% CI 0.91-1.47]). Exposure to both passive smoking in childhood and current smoking was associated with a stronger risk (HR 2.80 [95% CI 1.42-5.52]) than exposure to both current smoking and passive smoking only in adulthood (HR 1.68 [95% CI 1.10-2.57]) compared with neither passive nor active smoking. Associations between active smoking and PC risk were strongest in the O or B groups, while associations with passive smoking were strongest in the A or AB blood groups, but the interaction terms were not statistically significant. Both current smoking and passive smoking in childhood were associated with PC risk, with a maximal risk of current smokers exposed to passive smoking during childhood. Possible interactions between blood groups and active or passive smoking must be investigated in a larger series.

S90 New-Onset Diabetes Mellitus and the Risk of Pancreatic Adenocarcinoma: A Propensity Matched Population-Level Study Using Hemoglobin A1c

S90 New-Onset Diabetes Mellitus and the Risk of Pancreatic Adenocarcinoma: A Propensity Matched Population-Level Study Using Hemoglobin A1c

S91 Risk of Pancreatic Adenocarcinoma in Patients on Oral Hypoglycemic Agents for Type 2 Diabetes Mellitus

S91 Risk of Pancreatic Adenocarcinoma in Patients on Oral Hypoglycemic Agents for Type 2 Diabetes Mellitus

Construction of a novel signature based on immune-related lncRNA to identify high and low risk pancreatic adenocarcinoma patients

BackgroundPancreatic adenocarcinoma is one of the most lethal tumors in the world with a poor prognosis. Thus, an accurate prediction model, which identify patients within high risk of pancreatic adenocarcinoma is needed to adjust the treatment and elevate the prognosis of these patients.MethodsWe obtained RNAseq data of The Cancer Genome Atlas (TCGA) pancreatic adenocarcinoma (PAAD) from UCSC Xena database, identified immune-related lncRNAs (irlncRNAs) by correlation analysis, and identified differential expressed irlncRNAs (DEirlncRNAs) between pancreatic adenocarcinoma tissues from TCGA and normal pancreatic tissues from TCGA and Genotype-Tissue Expression (GTEx). Further univariate and lasso regression analysis were performed to construct prognostic signature model. Then, we calculated the areas under curve and identified the best cut-off value to identify high- and low-risk patients with pancreatic adenocarcinoma. The clinical characteristics, immune cell infiltration, immunosuppressive microenvironment, and chemoresistance were compared between high- and low-risk patients with pancreatic adenocarcinoma.ResultsWe identified 20 DEirlncRNA pairs and grouped the patients by the best cut-off value. We proved that our prognostic signature model possesses a remarkable efficiency to predict prognosis of PAAD patients. The AUC for ROC curve was 0.905 for 1-year prediction, 0.942 for 2-year prediction, and 0.966 for 3-year prediction. Patients in high-risk group have poor survival rate and worse clinical characteristics. We also proved that patients in high-risk groups were in immunosuppressive status and may be resistant to immunotherapy. Anti-cancer drug evaluation was performed based on in-silico predated tool, such as paclitaxel, sorafenib, and erlotinib, may be suitable for PAAD patients in high-risk group.ConclusionsOverall, our study constructed a novel prognostic risk model based on pairing irlncRNAs, exhibited a promising prediction value in patients with pancreatic adenocarcinoma. Our prognostic risk model may help distinguish PAAD patients suitable for medical treatments.

Identification of a costimulatory molecule-based signature to predict prognostic risk of pancreatic adenocarcinoma

We aimed to investigate the prognostic value of costimulatory molecules in PAAD by generating a CMS. Gene expression data and clinical factors of PAAD patients were obtained from TCGA. The signature was constructed using the survival package progressive Cox risk proportional regression model. Analyses of CMS-related genes, pathways, immune cell infiltration, and somatic mutations were conducted. A five-gene-based CMS was developed, and the risk score for CMS could be an independent risk factor for PAAD patients. Patients were divided into high- and low-risk groups based on the median Y of the CMS model. Differential analysis revealed 341 DEGs between the groups, and KEGG analysis demonstrated that these positively related genes in the high-risk group were mainly involved in chemical synaptic transmission pathway modulation and trans-synaptic signaling pathway regulation. Immune cell infiltration analysis revealed that the high-risk patients had higher proportions of M1 macrophages and T+ CD4 cells, but a lower proportion of M2 macrophages than that of the low-risk group. Mutational analysis revealed that the high-risk group showed a higher proportion of somatic mutations compared with that of the low-risk group. A CMS was developed, and the risk score could be an independent risk factor for PAAD patients.

Abstract 1318: Interleukin-1 promotes enhanced functional expression of dual oxidase 2 in human pancreatic cancer cells

Abstract Pancreatic inflammation contributes to increased risk of pancreatic adenocarcinoma (PDAC) development through the release of pro-inflammatory cytokines and generation of reactive oxygen species (ROS). Interleukin-1 (IL-1) is a major upstream pro-inflammatory cytokine secreted by malignant or microenvironmental cells that supports pancreatic tumorigenesis, invasiveness, and tumor heterogeneity. Previously, our laboratory has established that dual oxidase 2 (DUOX2), one of seven NADPH oxidase (NOX) family members, plays a critical role in H2O2-mediated host defense and chronic inflammation in the gastrointestinal tract. DUOX2 is upregulated and expressed along with its maturation factor, DUOXA2, in several human pancreatic cancer cell lines following exposure to various pro-inflammatory cytokines, including IFN-γ, IL-4, and IL-17A. Using a panel of PDAC cells lines, we report the induction of DUOX2/DUOXA2 mRNA and protein expression by both IL-1α and IL-1ß, two major agonists of IL-1. In BxPC-3, CFPAC-1 and Hs 766T (HTB-134) cells, prolonged treatment with IL-1α or IL-1ß results in transient activation of STAT1 and NF-kB signaling followed by prolonged induction of DUOX2/DUOXA2 mRNA and protein expression. Stimulation by IL-1α or IL-1ß results in a specific increase in the expression of DUOX2/DUOXA2; increased expression of other NOX family members was not observed. Activation of canonical IL-1 signaling in our PDAC cell lines was supported by the observation of IL-1-related upregulation of IL-8 (CXCL8) mRNA, a chemokine essential for neutrophil recruitment and a potent promoter of angiogenesis, in IL-1-treated PDAC cells. Moreover, when the anti-inflammatory compound anakinra (an IL-1R antagonist) was co-administered in vitro with IL-1, cytokine-induced DUOX2/DUOXA2 and CXCL8 induction was significantly suppressed. Finally, xenografts established with BxPC-3 cells demonstrated slower growth and significant downregulation of IL-1ß and DUOX2 when the immunosuppressive corticosteroid dexamethasone was administered. Given our previous findings that DUOX2 is highly expressed in the pancreas during episodes of chronic pancreatitis or pancreatic cancer, and contributes significantly to extracellular ROS formation, these studies suggest that IL-1 may play a role in promoting inflammation and tumorigenesis in pancreatic malignancies through upregulation of DUOX2. Citation Format: David J. Mallick, Yongzhong Wu, Mariam M. Konaté, Becky A. Diebold, Smitha Antony, Jennifer L. Meitzler, Guojian Jiang, Jiamo Lu, Krishnendu Roy, James H. Doroshow. Interleukin-1 promotes enhanced functional expression of dual oxidase 2 in human pancreatic cancer cells [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 1318.

IDF21-0114 Comparative Study of the Clinical Profile of FCPD and T2DM patients and Assess the Link of inflammatory markers and IR

Background: In progression of type 2 diabetes mellitus, inflammation plays an extremely vital and critical role along with insulin resistance (IR) and in long term results in further worsening of complications specially in fibrocalculous pancreatic diabetic patients (FCPD). FCPD is an uncommon form of diabetes that occurs as a result of chronic calcific pancreatitis, in the absence of alcohol abuse. Diabetes in FCPD is often brittle and difficult to control and most patients require multiple doses of insulin for control of glycemia. Aim: To assess the link between bio-inflammatory markers and IR in fibrocalculous pancreatic diabetic patients. Method: It is a cross sectional observational study. hsCRP was considered for assessing bio-inflammatory factor and HOMA index for IR among 70 FCPD subjects and 100 type 2 diabetes (T2DM). FCPD was diagnosed by evidence of ductal dilation measured by ultrasonography or by presence of pancreatic calculi on abdominal X-ray and absence of alcoholism, or other known causes of chronic pancreatitis in existing T2DM subjects. Results: 59.6±4.8 years was the mean age of the FCPD group whereas 37.4±5.1 years were for T2DM groups. FCPD patients had an earlier age at onset of diabetes (36.3 ± 15.1 years vs. 46.0±10.0 years; P = 0.031). BMI (20.7±2.1 vs 25.6±3.2 kg/m2), serum total cholesterol (147±34 vs 174±41 mg/dl), triglyceride (142±43 vs 217±94 mg/dl), and LDL cholesterol levels (91±24 vs 109±36 mg/dl) were significantly lower among FCPD patients than the T2DM patients (P<0.001). 22 subjects in FCPD group and 39 subjects in T2DM group were also diagnosed with retinopathy after initial fundoscopy. Glycated hemoglobin levels (HbA1C) were significantly higher in patients with FCPD as compare to T2DM group (9.4±2.2 vs 8.5±1.2 %, p<0.001). HOMA index among the FCPD group was 4.21 ± 1.1where as it was 5.37 ± 1.8 in T2DM group with significant P value (<0.05). A statistically significant difference (p < 0.001) was observed between the FCPD and T2DM in hsCRP (3.7±1.1 vs 1.6± 0.8). Discussion: Insulin resistance as measured by HOMA IR and inflammatory markers measured by hsCRP were found to be higher in pancreatic patients to that of type 2 DM. Despite the fact that the prevalence of FCPD being low, considering its impact of the condition on the quality of life (QOL) of the patients periodic screening is required specially for T2DM patients who complains of weight loss, back pain, abdominal pain, steatorrhoea or jaundice. Longer survival of FCPD patients also mandates periodic screening for possible risk of pancreatic adenocarcinoma.

The risk of pancreatic adenocarcinoma following SARS-CoV family infection

COVID 19 disease has become a global catastrophe over the past year that has claimed the lives of over two million people around the world. Despite the introduction of vaccines against the disease, there is still a long way to completely eradicate it. There are concerns about the complications following infection with SARS-CoV-2. This research aimed to evaluate the possible correlation between infection with SARS-CoV viruses and cancer in an in-silico study model. To do this, the relevent dataset was selected from GEO database. Identification of differentially expressed genes among defined groups including SARS-CoV, SARS-dORF6, SARS-BatSRBD, and H1N1 were screened where the |Log FC| ≥ 1and p < 0.05 were considered statistically significant. Later, the pathway enrichment analysis and gene ontology (GO) were used by Enrichr and Shiny GO databases. Evaluation with STRING online was applied to predict the functional interactions of proteins, followed by Cytoscape analysis to identify the master genes. Finally, analysis with GEPIA2 server was carried out to reveal the possible correlation between candidate genes and cancer development. The results showed that the main molecular function of up- and down-regulated genes was “double-stranded RNA binding” and actin-binding, respectively. STRING and Cytoscape analysis presented four genes, PTEN, CREB1, CASP3, and SMAD3 as the key genes involved in cancer development. According to TCGA database results, these four genes were up-regulated notably in pancreatic adenocarcinoma. Our findings suggest that pancreatic adenocarcinoma is the most probably malignancy happening after infection with SARS-CoV family.

A PAncreatic cancer screening study in individuals with New-onset or DeteriOrating diabetes MEllitus (PANDOME study).

TPS10607 Background: Pancreatic adenocarcinoma (PC) has a persistently high mortality as it presents in the advanced stages and has largely not benefited from the genomic and immunotherapeutic revolutions in oncology. Improvements in screening to detect early stage cancers are therefore urgently needed. Screening studies such as those from the International CAPS Consortium have demonstrated improved survivals in hereditary high risk individuals. In the sporadic population, individuals with new-onset diabetes (NOD) or long-standing deteriorating diabetes (DD) are at substantially increased risk of PC in the 12 months following these diagnoses and have been proposed as target populations for screening efforts. This trial will study the benefits of PC screening in the latter populations in a community setting. Methods: Individuals ≥ 50 years of age with either NOD or DD will be eligible. Criteria for NOD (within the past 12 months) include: fasting blood glucose ≥ 126 mg/dL, random blood glucose ≥ 200 mg/dL, or HbA1c ≥ 6.5%, with confirmed prior normal values. For those without prior glycemic values, a HbA1c ≥ 7.0% is required. Transition from pre-diabetes requires an increase in HgA1c of ≥ 0.5%. DD is defined by an increase in HbA1c of ≥ 2% within the past six months that is not associated with medication non-compliance or weight gain. Study participants will undergo every 6 months: evaluation by an APRN, testing for anxiety and depression and blood donation for biobanking purposes. High resolution MRI/MRCP with gadolinium will be performed at study entry and annually for 2 years. Images will be reviewed at a multi-disciplinary tumor board consisting of body-image certified radiologists, interventional gastroenterologists, hepatobiliary surgeons and medical oncologists. MRI results will be classified according to a novel PANC-RADS system. High-risk pancreatic findings will be further interrogated by endoscopic ultrasound (EUS). Study endpoints include detection rate of high-risk lesions, referrals for EUS and surgery and detection of incidental findings leading to unnecessary procedures. Adverse psychological impacts will be assessed through HADS testing. Target accrual: 500 patients within 3 years. Clinical trial information: NCT03937453 .

Susceptibility loci for pancreatic cancer in the Brazilian population

BackgroundPancreatic adenocarcinoma (PA) is a very aggressive cancer and has one of the poorest prognoses. Usually, the diagnosis is late and resistant to conventional treatment. Environmental and genetic factors contribute to the etiology, such as tobacco and alcohol consumption, chronic pancreatitis, diabetes and obesity. Somatic mutation in pancreatic cancer cells are known and SNP profile by GWAS could access novel genetic risk factors for this disease in different population context. Here we describe a SNP panel for Brazilian pancreatic cancer, together with clinical and epidemiological data.Methods78 pancreatic adenocarcinoma and 256 non-pancreatic cancer subjects had 25 SNPs genotyped by real-time PCR. Unconditional logistic regression methods were used to assess the main effects on PA risk, using allelic, co-dominant and dominant inheritance models.Results9 SNPs were nominally associated with pancreatic adenocarcinoma risk, with 5 of the minor alleles conferring protective effect while 4 related as risk factor. In epidemiological and clinical data, tobacco smoking, diabetes and pancreatitis history were significantly related to pancreatic adenocarcinoma risk. Polygenic risk scores computed using the SNPs in the study showed strong associations with PA risk.ConclusionWe could assess for the first time some SNPs related with PA in Brazilian populations, a result that could be used for genetic screening in risk population such as familial pancreatic cancer, smokers, alcohol users and diabetes patients.

Cancer surveillance awareness and practice among families at increased risk for pancreatic adenocarcinoma.

Early detection of pancreatic ductal adenocarcinoma (PDAC) is an important goal for improving survival. Individuals who meet published guidelines for surveillance may be underidentified, and family communication about risk represents a pathway to increasing participation in surveillance. We investigated the uptake of and barriers to surveillance in at-risk relatives of clinic patients. We conducted a retrospective record review of patients with personal or family history of PDAC evaluated over 12 months. The first relative presenting to clinic (proband) reported surveillance status and reasons for nonparticipation for at-risk relatives. Descriptive analyses and Fisher's exact tests were conducted to evaluate differences in surveillance participation. Among 193 at-risk relatives, 21% were in surveillance. The primary reasons for nonparticipation were lack of awareness (36%) and lack of interest (24%). Neither the sex nor the cancer status of probands impacted surveillance. At-risk relatives with familial pancreatic cancer (FPC) who also carried relevant pathogenic germline variants (PGVs) were more likely to undergo surveillance than those with FPC or PGVs alone (P = .003). Among families with PGVs, 59% of relatives potentially eligible for surveillance had not completed genetic testing. PDAC surveillance is underutilized in high-risk families. Communication interventions to address informational needs and decisional support could improve outcomes.

A 3-Decade Analysis of Pancreatic Adenocarcinoma After Solid Organ Transplant.

Solid organ transplant (SOT) recipients have moderately increased risk of pancreatic adenocarcinoma (PAC). We evaluated the incidence and survival of PAC in 2 cohorts and aimed to identify potential risk factors. This study performed a retrospective cohort analysis. Cohort A was extracted from the United Network of Organ Sharing data set and cohort B from SOT recipients evaluated at 3 Mayo Clinic transplant centers. The primary outcome was age-adjusted annual incidence of PAC. Descriptive statistics, hazard ratios, and survival rates were compared. Cohort A and cohort B included 617,042 and 29,472 SOT recipients, respectively. In cohort A, the annual incidence rate was 12.78 per 100,000 in kidney-pancreas, 13.34 in liver, and 21.87 in heart-lung transplant recipients. Receiving heart-lung transplant, 50 years or older, and history of cancer (in either recipient or donor) were independent factors associated with PAC. Fifty-two patients developed PAC in cohort B. Despite earlier diagnosis (21.15% with stage I-II), survival rates were similar to those reported for sporadic (non-SOT) patients. We report demographic and clinical risk factors for PAC after SOT, many of which were present before transplant and are common to sporadic pancreatic cancer. Despite the diagnosis at earlier stages, PAC in SOT portends a very poor survival.

Leukocyte Telomere Length and Its Interaction with Germline Variation in Telomere-Related Genes in Relation to Pancreatic Adenocarcinoma Risk.

Leukocyte telomere length (LTL) has been associated with risk of multiple cancers, but its association with pancreatic ductal adenocarcinoma (PDAC) is unclear. We therefore investigated the association between peripheral blood LTL and PDAC risk, and examined effect modification by candidate SNPs previously reported to be associated with variation in LTL. A case-control study of 1,460 PDAC cases and 1,459 frequency-matched controls was performed using biospecimens and data from the Mayo Clinic Biospecimen Resource for Pancreas Research. Quantitative PCR was used to measure LTL and categorized into tertiles based on sex-specific control distribution. Eleven telomere-related SNPs also were genotyped. Logistic regression was used to calculate ORs and 95% confidence intervals (CI). Shorter peripheral blood LTL was associated with a higher risk of PDAC (ORT1vsT3 = 1.26, 95% CI = 1.03-1.54, P trend = 0.02; ORcontinuous = 1.14, 95% CI = 1.02-1.28), but the association was restricted to cases with treatment-naïve blood samples (ORT1vsT3 = 1.51, 95% CI = 1.16-1.96, P trend = 0.002; ORcontinuous = 1.25, 95% CI = 1.08-1.45) and not cases whose blood samples were collected after initiation of cancer therapy (ORT1vsT3 = 1.10, 95% CI = 0.87-1.39, P trend = 0.42; ORcontinuous = 1.08, 95% CI = 0.94-1.23). Three SNPs (TERC-rs10936599, ACYP2-rs11125529, and TERC-rs1317082) were each associated with interindividual variation in LTL among controls, but there was no evidence of effect modification by these SNPs. Treatment-naïve short LTL is associated with a higher risk of PDAC, and the association does not differ by germline variation in the candidate telomere-related SNPs examined. Peripheral blood LTL might serve as a molecular marker for risk modeling to identify persons at high risk of PDAC.

Association of fatty pancreas with increased risk of pancreatic adenocarcinoma.

e16729 Background: Pancreatic adenocarcinoma (PADC) remains one of the most fatal malignancies with poor outcomes and prognosis. Several risk factors have been associated with its development such as smoking, age, obesity, chronic pancreatitis, diabetes mellitus and a family history of PADC. Furthermore, recent pathologic studies demonstrated that fatty infiltration of the pancreas (FP) is positively correlated with PADC development. We sought to systematically review the literature and perform the first meta-analysis to study the risk of PADC among patients with FP. Methods: We conducted a systematic search of the Pubmed, EMBASE, and Cochrane databases from inception through November-2019 for studies correlating FP with PADC. Relevant data was extracted and analyzed using comprehensive meta-analysis software. Random-effects model was used for all variables. Heterogeneity was assessed using the I2 measure and Cochrane Q-statistic. Publication bias was assessed using Egger’s test. Meta regression models accounting for independent variables such as age, sex, smoking, family history of PADC, chronic pancreatitis and method of FP diagnosis were constructed to explain heterogeneity. Results: Five observational case-control studies published between 2014 and 2019 including a total of 761 patients (320 PADC patients and 441 controls) were included. FP was associated with increased PADC with an OR 4.6 (CI 2.4-8.9) compared to controls with a considerable heterogeneity (I2= 69%). Meta regression analysis accounting for modality used to diagnose FP was able to explain 100% of the noted heterogeneity. Conclusions: While we noted FP to be significantly associated with increased PADC, heterogeneity in FP diagnostic approach resulted in significant inter-study variation. A consensus on a clear definition of FP with a standardized diagnostic approach is needed to better appraise literature on this emerging disease entity. Further prospective studies are needed to validate our results and explore the possible role for PADC screening in FP in addition to known factors such as family history and new-onset diabetes mellitus.

Patients with deleterious germline mutations: a heterogeneous population for pancreatic cancer screening?

Presenter: Alexandra M. Roch MD, MS | Indiana University Background: Many germline mutations are associated with an increased risk of pancreatic adenocarcinoma (PDAC). Screening at our institution is currently offered for mutation carriers or patients with at least one first-degree relative or two family members with PDAC. High-risk screening protocol includes complete history and physical examination, tumor markers (CA19-9 and CEA), and cross-sectional imaging (CT or MRI/MRCP with Gadolinium and Secretin enhancement), followed by semi-annual to annual clinic visits. Little data exists on the benefits of screening and surveillance for high-risk individuals with inherited genetic syndromes. Intraductal papillary mucinous neoplasm (IPMN) are well-established cystic precursors of PDAC. We hypothesized that patients with deleterious germline mutations in a pancreatic cancer susceptibility gene have a higher prevalence of IPMN. Methods: All consecutive patients undergoing going surveillance at our Pancreatic Cyst and Cancer Early Detection Center from 2013 to 2019 were included in the present study. We analyzed the prevalence and risk factors for IPMN in this high-risk population. Prevalence was compared to historical data from extensive literature review. Results: Of the 1166 patients in the surveillance program, 358 (31%) had a germline mutation and/or a strong family history of PDAC without a known mutation. Gender ratio was 3.5 in favor of women with a median age of 58 years, and a median follow-up of 2.7 years [range 1month-6years]. 201 patients (56%) were known to harbor a deleterious germline mutation, the most common being BRCA2 in 89 patients (25%). A total of 250 patients (70%) had a family history of pancreatic cancer. 132 patients had an IPMN (37%) and 8 had a PDAC (2%). The prevalence of IPMN was higher in the mutation carriers than in the general population (18% vs. 1%, p<0.0001). In multivariate analysis, germline mutation (RR=3.2; 95% CI 1.6-6.4, p=0.001), age, and symptoms were independent predictors of presence of IPMN, with no influence of family history of pancreatic cancer (p=0.22). Interestingly, the prevalence of IPMN was not distributed equally between all mutation types, ranging from 67% in patients with Peutz-Jeghers to 43% in HNPCC patients, 24% in BRCA2 patients, 14% in patients with ATM mutation, and 0% in CDKN2A, PALB2 or FAMM/p16 mutation patients. Conclusion: In this series, 18% of mutation carriers harbored IPMN. A strong family history of PDAC was not an independent risk factor for developing IPMN. The prevalence of IPMN was highly variable depending on the mutation subtype. This series suggests that not all mutation carriers may develop precancerous lesions, and relying on cross-sectional imaging alone for screening and follow-up may be suboptimal. Genetic testing for patients with positive family history may help better tailor surveillance modalities for this high-risk population.

A region-based gene association study combined with a leave-one-out sensitivity analysis identifies SMG1 as a pancreatic cancer susceptibility gene.

Pancreatic adenocarcinoma (PC) is a lethal malignancy that is familial or associated with genetic syndromes in 10% of cases. Gene-based surveillance strategies for at-risk individuals may improve clinical outcomes. However, familial PC (FPC) is plagued by genetic heterogeneity and the genetic basis for the majority of FPC remains elusive, hampering the development of gene-based surveillance programs. The study was powered to identify genes with a cumulative pathogenic variant prevalence of at least 3%, which includes the most prevalent PC susceptibility gene, BRCA2. Since the majority of known PC susceptibility genes are involved in DNA repair, we focused on genes implicated in these pathways. We performed a region-based association study using the Mixed-Effects Score Test, followed by leave-one-out characterization of PC-associated gene regions and variants to identify the genes and variants driving risk associations. We evaluated 398 cases from two case series and 987 controls without a personal history of cancer. The first case series consisted of 109 patients with either FPC (n = 101) or PC at ≤50 years of age (n = 8). The second case series was composed of 289 unselected PC cases. We validated this discovery strategy by identifying known pathogenic BRCA2 variants, and also identified SMG1, encoding a serine/threonine protein kinase, to be significantly associated with PC following correction for multiple testing (p = 3.22x10-7). The SMG1 association was validated in a second independent series of 532 FPC cases and 753 controls (p<0.0062, OR = 1.88, 95%CI 1.17–3.03). We showed segregation of the c.4249A>G SMG1 variant in 3 affected relatives in a FPC kindred, and we found c.103G>A to be a recurrent SMG1 variant associating with PC in both the discovery and validation series. These results suggest that SMG1 is a novel PC susceptibility gene, and we identified specific SMG1 gene variants associated with PC risk.