Increased Risk Of Pancreatic Cancer Research Articles

Abstract A015: Impact of healthy lifestyles and polygenic risk scores on pancreatic cancer risk: The Multiethnic Cohort Study

Abstract Background: Healthy lifestyles have been observed to reduce the risk of pancreatic cancer. However, it is unknown whether this protective impact varies among individuals with different levels of genetic susceptibility for pancreatic cancer. Methods: We investigated the association between healthy lifestyles, genetic risk, and pancreatic cancer incidence in 70,780 participants (32,783 males, 37,907 females) from the Multiethnic Cohort Study (MEC), a prospective cohort of White, African American, Native Hawaiian, Japanese American, and Latino men and women. We calculated a healthy lifestyle factor score (HLFS) based on smoking status, alcohol intake, body mass index and physical activity. We also estimated genetic risk using an established polygenic risk score (PRS) of 49 pancreatic cancer risk variants. Cox regression was used to assess the independent and joint associations of the HLFS (analyzed as quintiles) and PRS (analyzed as quintiles and high/low categories) with pancreatic cancer risk. Models were adjusted for age at blood draw, sex, race, family history of pancreatic cancer, and in the genetic analyses, the first ten principal components to account for population stratification. Results: The analytical cohort was comprised of 23,643 (33.4%) Japanese Americans, 16,816 (23.8%) Latinos, 14,305 (20.2%) Whites, 10,645 (15.0%) African Americans, and 5,371 (7.6%) Native Hawaiians. There were 721 incident cases of pancreatic cancer from an average follow-up period of 13.7 (SD 4.8) years. Higher levels of the PRS were associated with a 25-62% increase in pancreatic cancer risk, compared to the first PRS quintile. These elevated risks were borderline significant for quintile 2 (HR 1.25, 95% CI 0.97-1.61) and statistically significant for quintile 3 (HR 1.35, 95% CI 1.05-1.73), quintile 4 (HR 1.46, 95% CI 1.15-1.87), and quintile 5 (HR 1.62, 95% CI 1.27-2.06). For the HLFS, higher quintiles were associated with a 10-27% decreased risk of pancreatic cancer, compared to the lowest quintile, but this was only statistically significant for the highest quintile (HR 0.73, 95% CI 0.56-0.94). When evaluating the HLFS by levels of the PRS (low 0-50% vs. high 50-100%), the association between the highest HLFS quintile and pancreatic cancer was more pronounced among those in the high PRS group (HR 0.64, 95% CI 0.45-0.91), compared to those in the low PRS group (HR 0.80, 95% CI 0.55-1.18). However, this difference in effect by PRS levels was not statistically significant (p-interaction=0.43). Conclusions: Our study demonstrates that including information on healthy lifestyles and genetic risk may improve the risk stratification of pancreatic cancer for multiethnic populations. In addition, it is possible that healthy lifestyles could provide more benefit to individuals at higher genetic risk. Citation Format: Brian Huang, Adelynn Paik, David Bogumil, Fei Chen, Peggy Wan, Lynne Wilkens, Loic Le Marchand, David Conti, Christopher Haiman, Veronica Wendy Setiawan. Impact of healthy lifestyles and polygenic risk scores on pancreatic cancer risk: The Multiethnic Cohort Study [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A015.

Smoking and pancreatic cancer: a sex-specific analysis in the Multiethnic Cohort study

PurposeTo examine whether the detrimental smoking-related association with pancreatic cancer (PC) is the same for women as for men.MethodsWe analyzed data from 192,035 participants aged 45–75 years, enrolled in the Multiethnic Cohort study (MEC) in 1993–1996. We identified PC cases via linkage to the Hawaii and California Surveillance, Epidemiology, and End Results Program cancer registries through December 2017.ResultsDuring a mean follow-up of 19.2 years, we identified 1,936 incident PC cases. Women smokers smoked on average less than men smokers. In multivariate Cox regression models, as compared with sex-specific never smokers, current smokers had a similar elevated risk of PC for women, hazard ratio (HR) 1.49 (95% CI 1.24, 1.79) and as for men, HR 1.48 (95% CI 1.22, 1.79) (pheterogeneity: 0.79). Former smokers showed a decrease in risk of PC for men within 5 years, HR 0.74 (95% CI 0.57, 0.97) and for women within 10 years after quitting, HR 0.70 (95% CI 0.50, 0.96), compared with their sex-specific current smokers. Both sexes showed a consistent, strong, positive dose–response association with PC for the four measures (age at initiation, duration, number of cigarettes per day, number of pack-years) of smoking exposure among current smokers and an inverse association for years of quitting and age at smoking cessation among former smokers (all ptrend’s < 0.001).ConclusionAlthough MEC women smoke on average less than their men counterparts, the smoking-related increase in PC risk and the benefits of cessation seem to be of similar magnitudes for women as for men.

The association between diabetes mellitus of different durations and risk of pancreatic cancer: an Australian national data-linkage study in women

AimsThe bidirectional association between diabetes mellitus (DM) and pancreatic cancer (PC) is established; however, the strength of association between duration of DM and risk of PC needs further investigation. MethodsWe conducted a case-control study nested within a population-based cohort of Australian women established using record linkage. Women diagnosed with PC from July 2007 to December 2013, were matched to five controls based on age and state of residence. DM was defined according to prescription of anti-diabetic medication from administrative prescription data. We used conditional logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI), adjusted for area-level socioeconomic status, rurality of residence, weighted comorbidity score, and predicted probability of obesity. ResultsThe analyses included 7,267 cases and 35,978 controls. The mean age at the time of DM diagnosis was 71 years whereas the mean age at the time of diagnosis of PC was 76 years. A history of DM of any duration was associated with a 2-fold increase in risk of PC (OR=2.12; 95%CI:1.96–2.29) compared to having no history of DM. The risk decreased with increasing duration of DM. The highest risk was in those who had recent-onset DM (OR=8.08; 95%CI:6.88–9.50 for <12 months of DM), but the risk remained elevated with ≥5 years of DM (OR=1.40; 95%CI:1.27–1.55). ConclusionThe markedly increased risk of PC in those with recent-onset DM emphasises the need for further research to distinguish patients for whom new-onset DM is a manifestation of PC from those with type-2 DM. The elevated risk associated with long-standing DM suggests that preventing DM may contribute to a reduction in the incidence of PC.

Dietary inflammatory index and pancreatic cancer risk: a systematic review and dose-response meta-analysis.

The meta-analysis was conducted to test the link between pancreatic cancer (PC) risk and dietary inflammatory index (DII®) score. Systematic review and meta-analysis. We searched PubMed, Embase, Web of Science and the Cochrane Library up to 22 November 2020 to identify the relevant studies. Studies that reported the risk estimates and the corresponding 95 % CI for the DII category and PC risk were included. The effect sizes were pooled using the random-effects model. Dose-response analysis was conducted where possible. Two prospective cohort studies of 634 705 participants (3152 incident cases), and four case-control studies of 2737 cases and 4861 controls. Overall, the pooled risk ratio (RR) indicated that individuals in the highest category compared with the lowest category had an increased PC risk (RR = 1·45; 95 % CI 1·11, 1·90; P = 0·006). Meanwhile, significant heterogeneity was also revealed. The dose-response meta-analysis indicated that a 1-unit increase in the DII score was associated with the PC risk (RR = 1·08; 95 % CI 1·002, 1·166; P = 0·045; I2 = 94·1 %, P < 0·001). Nonlinear result showed an increased risk of moving from fewer to more inflammatory borders with increasing DII score (Pnonlinearity = 0·003; I2 = 76·5 %, P < 0·001). Subgroup analyses found that significant positive association between PC risk and DII score appeared to be in case-control studies (RR = 1·70; 95 % CI 1·16, 2·50; P = 0·007) and studies with ≤ 31 DII components (RR = 1·76; 95 % CI 1·14, 2·72; P = 0·011). These findings suggested dietary habits with high inflammatory features (high DII score) might increase PC risk.

Deciphering the complex interplay between pancreatic cancer, diabetes mellitus subtypes and obesity/BMI through causal inference and mediation analyses

ObjectivesTo characterise the association between type 2 diabetes mellitus (T2DM) subtypes (new-onset T2DM (NODM) or long-standing T2DM (LSDM)) and pancreatic cancer (PC) risk, to explore the direction of causation through...

Evaluation of polymorphisms in microRNA-binding sites and pancreatic cancer risk in Chinese population.

As promising biomarkers and therapy targets, microRNAs (miRNAs) are involved in various physiological and tumorigenic processes. Genetic variants in miRNA‐binding sites can lead to dysfunction of miRNAs and contribute to disease. However, systematic investigation of the miRNA‐related single nucleotide polymorphisms (SNPs) for pancreatic cancer (PC) risk remains elusive. We performed integrative bioinformatics analyses to select 31 SNPs located in miRNA‐target binding sites using the miRNASNP v2.0, a solid database providing miRNA‐related SNPs for genetic research, and investigated their associations with risk of PC in two large case‐control studies totally including 1847 cases and 5713 controls. We observed that the SNP rs3802266 is significantly associated with increased risk of PC (odds ratio (OR) = 1.21, 95% confidence intervals (CI) = 1.11‐1.31, P = 1.29E‐05). Following luciferase reporter gene assays show that rs3802266‐G creates a stronger binding site for miR‐181a‐2‐3p in 3′ untranslated region (3′UTR) of the gene ZHX2. Expression quantitative trait loci (eQTL) analysis suggests that ZHX2 expression is lower in individuals carrying rs3802266‐G with increased PC risk. In conclusion, our findings highlight the involvement of miRNA‐binding SNPs in PC susceptibility and provide new clues for PC carcinogenesis.

Radiation and Risk of Liver, Biliary Tract, and Pancreatic Cancers among Atomic Bomb Survivors in Hiroshima and Nagasaki: 1958-2009.

The Life Span Study (LSS) of atomic bomb survivors has consistently demonstrated significant excess radiation-related risks of liver cancer since the first cancer incidence report. Here, we present updated information on radiation risks of liver, biliary tract and pancreatic cancers based on 11 additional years of follow-up since the last report, from 1958 to 2009. The current analyses used improved individual radiation doses and accounted for the effects of alcohol consumption, smoking and body mass index. The study participants included 105,444 LSS participants with known individual radiation dose and no known history of cancer at the start of follow-up. Cases were the first primary incident cancers of the liver (including intrahepatic bile duct), biliary tract (gallbladder and other and unspecified parts of biliary tract) or pancreas identified through linkage with population-based cancer registries in Hiroshima and Nagasaki. Poisson regression methods were used to estimate excess relative risks (ERRs) and excess absolute risks (EARs) associated with DS02R1 doses for liver (liver and biliary tract cancers) or pancreas (pancreatic cancer). We identified 2,016 incident liver cancer cases during the follow-up period. Radiation dose was significantly associated with liver cancer risk (ERR per Gy: 0.53, 95% CI: 0.23 to 0.89; EAR per 10,000 person-year Gy: 5.32, 95% CI: 2.49 to 8.51). There was no evidence for curvature in the radiation dose response (P=0.344). ERRs by age-at-exposure categories were significantly increased among those who were exposed at 0-9, 10-19 and 20-29 years, but not significantly increased after age 30 years, although there was no statistical evidence of heterogeneity in these ERRs (P = 0.378). The radiation ERRs were not affected by adjustment for smoking, alcohol consumption or body mass index. As in previously reported studies, radiation dose was not associated with risk of biliary tract cancer (ERR per Gy: -0.02, 95% CI: -0.25 to 0.30). Radiation dose was associated with a nonsignificant increase in pancreatic cancer risk (ERR per Gy: 0.38, 95% CI: <0 to 0.83). The increased risk was statistically significant among women (ERR per Gy: 0.70, 95% CI: 0.12 to 1.45), but not among men.

Abstract 639: Dietary polyunsaturated fatty acids intake and pancreatic cancer risk in understudied populations

Abstract Background: Pancreatic cancer (PC) is one of the deadliest malignancies. Lab based research suggests that two types of polyunsaturated fatty acids (PUFA), n-3 and n-6 PUFA, may have opposing effects on PC carcinogenesis. However, human evidence on the role of dietary PUFA intake in PC risk is inconsistent. Previous epidemiological studies on this topic were conducted primarily among Whites and included few individuals from low socioeconomic status (SES). The exposure patterns of n-3 and n-6 PUFA differ across racial groups, with African Americans (AAs) in the high end and Asians in the low end of range. To better characterize the associations of PUFA with PC risk, we conducted a nested case-control study focusing on understudied Asians and low SES AAs and Whites. Methods: We performed a nested case-control study within three population-based prospective cohort studies: the Shanghai Women’s Health Study (SWHS), Shanghai Men’s Health Study (SMHS), and Southern Community Cohort Study (SCCS). Dietary PUFA intakes and other variables were collected from the baseline dietary and other questionnaires. Participants were followed up through annual linkage to cancer registries. Controls were matched to cases on age, sex, and blood sample availability in SWHS/SMHS, and age, sex, race, and enrollment location in SCCS, using incidence density sampling (case-to-control ratio:1:4). Included in the study are 244 cases and 973 controls of Asian females in SWHS, 189 cases and 755 controls of Asian males in SMHS, and 307 cases and 1,228 controls in SCCS (including 219 cases and 876 controls of AAs). The PUFA intake was adjusted for total energy intake using the residual method. Conditional logistic regression analyses were performed to estimate the association of PC risk with dietary PUFA consumption after adjusting for potential covariates. Results: The average dietary intake (mean ± SD; g/day) of n-3 and n-6 PUFA were 1.0 ± 0.5 and 6.3 ± 3.1, 1.1 ± 0.5 and 7.2 ± 3.0, and 2.0 ± 1.2 and 19.3 ± 11.7 in the controls of SWHS, SMHS and SCCS, respectively. We observed that in Chinese men, high intakes of certain n-3 PUFA were significantly associated with increased PC risk. The adjusted odds ratio (OR) (95% confidence interval (CI)) comparing the highest versus lowest quartile of docosapentaenoic acid (DPA) was 1.79 (1.10-2.93), with a p for trend across quartiles of 0.02. For docosahexaenoic acid (DHA), the OR 4th vs. 1st quartile (95% CI) = 1.71 (1.06-2.78) (p for trend = 0.04). For marine n-3 PUFA, the OR 4th vs. 1st quartile (95% CI) = 1.69 (1.03-2.76) (p for trend = 0.04). There was no significant association for n-6 PUFA. No significant association was observed for n-3 or n-6 PUFA with PC risk in SWHS or SCCS. Conclusions: In a nested case-control study, we observed that in Chinese men, the dietary intake of overall marine n-3 PUFA, DPA, and DHA were positively associated with PC risk. Such associations were not observed in Chinese women or low SES AAs/Whites. Citation Format: Lang Wu, Wei Zheng, William J. Blot, Mark D. Steinwandel, Wanqing Wen, Yong-Bing Xiang, Yu-Tang Gao, Hong-Lan Li, Rachael Stolzenberg-Solomon, Harvey J. Murff, Xiao-Ou Shu. Dietary polyunsaturated fatty acids intake and pancreatic cancer risk in understudied populations [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 639.

Proton pump inhibitor (PPI) exposure and risk of pancreatic cancer (PC): Meta-analysis.

e15755 Background: PPIs are widely used in the treatment of various acid related disorders. Observational studies have raised concern about an association of PPI use and PC but findings have been inconsistent. This meta-analysis aimed to estimate from published studies the pooled PC risk among subjects exposed and not exposed to PPIs. Methods: We searched PubMed, EMBASE, Scopus, Cochrane Library and clinicaltrials.gov to identify relevant studies on the association of PPI exposure and PC risk. Three reviewers independently screened search results for eligibility and extracted data from retained studies. Our primary analysis quantified PC risk among subjects exposed vs not exposed to PPI, expressed as the pooled (adjusted) odds ratio (OR/aOR) and 95% confidence interval (95%CI) as estimated in a random effect model. We performed similar secondary analyses in selected subgroups. Results: Of the 2683 reports yielded by the search 1 randomized trial, 2 cohort, and 9 case-control studies with 1,093,766 subjects (123,214 cases; 970,552 controls) were retained. Our main analysis (exposed vs non exposed) revealed a significant overall association between PPI exposure and PC risk (OR 1.77, 95%CI 1.14-2.74). Secondary analyses showed higher risk estimates from high quality (NOS &gt; 7) studies (OR 2.04, 95%CI 1.03-4.02), observational studies (aOR, 1.70 95%CI 1.08-2.68), and studies with PPI use and PC risk as main outcome (aOR 2.01, 95%CI 1.06-3.83). Subgroup analyses by comorbidities showed an association with diabetes (aOR 1.98, 95%CI 1.02-3.82) but not pancreatitis (aOR 1.77, 95%CI 0.93-3.35). PC risk was not associated with duration of PPI use longer 1 (aOR 1.36 95%CI 0.81-2.28 and &gt; 3 yrs (aOR 1.21 95%CI 0.73-2.02). In addition to the overall PPI class effect in the primary analysis, rabeprazole was singularly associated with PC risk (aOR 5.40 95%CI 1.98-14.70). Conclusions: Pooled risk estimates suggest that the class of PPIs is associated with a general 1.77 fold increase in PC risk, independent of duration of PPI exposure. Diabetic patients are at a significant incremental risk over the base risk.

Interaction of polymorphisms in xeroderma pigmentosum group C with cigarette smoking and pancreatic cancer risk.

The aim of the present study was to evaluate the association between xeroderma pigmentosum group C (XPC) polymorphisms and pancreatic cancer (PC) risk. A total of 7 XPC tagging SNPs (tag-SNPs) were selected from the International HapMap Project Databases (rs2228001A/C, rs2470353G/C, rs2228000C/T, rs3731114C/G, rs3729587G/C, rs2607775C/G and rs3731055G/A) and were genotyped in 205 patients with PC and 230 non-cancer control subjects using a SNaPshot assay. The C allelic gene frequency of rs2470353 was higher in patients with PC compared with that in the control group (P=0.003). Compared with the GG gene type, PC risk was increased in subjects with GC and GC+CC gene types (P=0.012 and P=0.006, respectively). PC risk increased 3.505-fold for the subjects who were heavy smokers (tobacco, ≥25 packets/year) with the GC+CC gene type (P=0.008). The G allelic gene frequency of rs2607775 was higher in PC patients compared with that in the control group (P=0.003). Compared with the CC gene type, PC risk increased in subjects with CG and CG+GG gene types (P=0.013 and P=0.005, respectively). Furthermore, PC risk increased 3.950-fold in subjects who were heavy smokers (tobacco, ≥25 packets/year) with the CG+GG gene type (P=0.001). Haplotype analysis further revealed that the CCC haplotype of rs2228000, rs3731114 and rs3729587 increased PC risk (odds ratio, 1.610; 95% confidence interval, 1.035–2.481; P=0.034). The present study revealed that XPC gene polymorphisms could increase the risk of PC in the study population, particularly among heavy smokers.

Abstract 1239: Risk of pancreatic cancer is increased among first-degree relatives of pancreatic cancer probands who have non-O ABO blood type

Abstract Background: Pancreatic cancer (PC) ranks among the top causes of cancer mortality. Risk stratification is an important step toward prevention and early detection. Prior work has shown that ABO blood type (non-O) and first-degree family history of PC are associated with increased PC risk. Individuals with first-degree family history of PC have a 2- to 3-fold increased risk, but it is unclear if ABO blood type plays a role in the familial aggregation of PC. We investigated PC risk among first-degree relatives (FDRs) of PC probands based on the probands' serologic blood type (O vs non-O). Methods: A total of 702 probands sequentially enrolled in the Mayo Clinic Pancreas Research Registry from 2000-2016 with serologic ABO blood type provided information on family history of cancer for 5,178 FDRs. FDRs were grouped based on their related probands' blood type as type O (n=242; 1,768 FDRs) vs non-O (n=460; 3,410 FDRs). Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated by comparing the number of PC cases observed among FDRs to those expected using data from the Surveillance, Epidemiology and End Results (SEER) Program as the reference population. SIRs for PC risk were calculated separately for FDRs of probands with type O vs FDRs of probands with non-O blood, and stratified by sex of FDRs and relationship to proband (parent, sibling, or offspring). Results: Compared to the SEER reference, PC risk was nearly 2-fold higher among FDRs of PC probands (SIR=1.76; 95%CI: 1.35-2.26). When stratified by probands' ABO type, risk for PC was higher among FDRs of probands with non-O blood (SIR=1.94; 95%CI: 1.41-2.60), compared to FDRs of probands with O blood (SIR=1.42; 95%CI: 0.83-2.28). Parents of probands with non-O blood had increased PC risk (SIR=3.28; 95%CI: 2.18-4.74, n=920), but not parents of probands with O blood (SIR=1.75; 95%CI: 0.75-3.45, n=484), p-value for between-group difference=0.10. Among FDRs of probands with O blood, female FDRs had increased PC risk (SIR=2.12; 95%CI: 1.06-3.79), but male FDRs did not (SIR=0.86; 95%CI: 0.31-1.88). Higher PC risk was observed among female FDRs of probands with non-O blood (SIR=2.28; 95%CI: 1.44-3.41) than male FDRs of probands with non-O blood (SIR=1.62; 95%CI: 1.00-2.48). Mothers of probands with O blood had increased PC risk (SIR=2.89; 95%CI: 1.05-6.28) compared to fathers (SIR=0.79; 95%CI: 0.09-2.84). Both mothers (SIR=3.60; 95%CI: 1.96-6.03) and fathers (SIR=2.95; 95%CI: 1.61-4.95) of probands with non-O blood had increased PC risk. No major findings were observed among probands' siblings or offspring. Conclusions: PC risk is greater among FDRs of PC probands with non-O blood than among FDRs of probands with type O. PC risk is higher among parents of probands with non-O blood, and female FDRs and mothers of probands with non-O blood. Possible clustering of non-O blood type in families may contribute to increased PC risk. Citation Format: Aarti Kolluri, Samuel O. Antwi, Sarah E. Fagan, Kari G. Chaffee, Brendan T. Broderick, William R. Bamlet, Ann L. Oberg, Robert R. McWilliams, Gloria M. Petersen. Risk of pancreatic cancer is increased among first-degree relatives of pancreatic cancer probands who have non-O ABO blood type [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1239.

Pancreatic Cancer Following Incident Diabetes in African Americans and Latinos: The Multiethnic Cohort.

Diabetes has been proposed to be a risk factor for and a consequence of pancreatic cancer (PC). The relationship between recent-onset diabetes and PC is not well understood, and data in minorities are sparse. We examined the relationships between recent-onset diabetes and PC incidence in African Americans and Latinos in the Multiethnic Cohort. A total of 48 995 African Americans and Latinos without prior diabetes and cancer at baseline (1993-1996) were included in the study. Questionnaires, Medicare data, and California hospital discharge files were used to identify new diabetes diagnoses. Cox regressions were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for cancer associated with diabetes and with diabetes duration. A total of 15 833 (32.3%) participants developed diabetes between baseline and 2013. A total of 408 incident PC cases were identified during follow-up. Diabetes was associated with PC (HRage75 = 2.39, 95% CI = 1.91 to 2.98). Individuals with recent-onset diabetes (within three or fewer years of PC diagnosis) had a greater risk compared with those with long-term diabetes across all ages. The HRage75 for recent-onset diabetes was 4.08 (95% CI = 2.76 to 6.03) in Latinos and 3.38 (95% CI = 2.30 to 4.98) in African Americans. Diabetes was associated with a more than twofold higher risk of PC in African Americans and Latinos, but recent-onset diabetes was associated with a 2.3-fold greater increase in risk of PC than long-standing diabetes. Our findings support the hypothesis that recent-onset diabetes is a manifestation of PC and that long-standing diabetes is a risk factor for this malignancy.

Pancreatic cancer risk is modulated by inflammatory potential of diet and ABO genotype: a consortia-based evaluation and replication study.

Diets with high inflammatory potential are suspected to increase risk for pancreatic cancer (PC). Using pooled analyses, we examined whether this association applies to populations from different geographic regions and population subgroups with varying risks for PC, including variation in ABO blood type. Data from six case-control studies (cases, n = 2414; controls, n = 4528) in the Pancreatic Cancer Case-Control Consortium (PanC4) were analyzed, followed by replication in five nested case-control studies (cases, n = 1268; controls, n = 4215) from the Pancreatic Cancer Cohort Consortium (PanScan). Two polymorphisms in the ABO locus (rs505922 and rs8176746) were used to infer participants' blood types. Dietary questionnaire-derived nutrient/food intake was used to compute energy-adjusted dietary inflammatory index (E-DII®) scores to assess inflammatory potential of diet. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariable-adjusted logistic regression. Higher E-DII scores, reflecting greater inflammatory potential of diet, were associated with increased PC risk in PanC4 [ORQ5 versus Q1=2.20, 95% confidence interval (CI) = 1.85-2.61, Ptrend < 0.0001; ORcontinuous = 1.20, 95% CI = 1.17-1.24], and PanScan (ORQ5 versus Q1 = 1.23, 95% CI = 0.92-1.66, Ptrend = 0.008; ORcontinuous = 1.09, 95% CI = 1.02-1.15). As expected, genotype-derived non-O blood type was associated with increased PC risk in both the PanC4 and PanScan studies. Stratified analyses of associations between E-DII quintiles and PC by genotype-derived ABO blood type did not show interaction by blood type (Pinteraction = 0.10 in PanC4 and Pinteraction=0.13 in PanScan). The results show that consuming a pro-inflammatory diet and carrying non-O blood type are each individually, but not interactively, associated with increased PC risk.

Risk of pancreatic cancer associated with family history of cancer and other medical conditions by accounting for smoking among relatives.

Family history (FH) of pancreatic cancer (PC) has been associated with an increased risk of PC, but little is known regarding the role of inherited/environmental factors or that of FH of other comorbidities in PC risk. We aimed to address these issues using multiple methodological approaches. Case-control study including 1431 PC cases and 1090 controls and a reconstructed-cohort study (N = 16 747) made up of their first-degree relatives (FDR). Logistic regression was used to evaluate PC risk associated with FH of cancer, diabetes, allergies, asthma, cystic fibrosis and chronic pancreatitis by relative type and number of affected relatives, by smoking status and other potential effect modifiers, and by tumour stage and location. Familial aggregation of cancer was assessed within the cohort using Cox proportional hazard regression. FH of PC was associated with an increased PC risk [odds ratio (OR) = 2.68; 95% confidence interval (CI): 2.27-4.06] when compared with cancer-free FH, the risk being greater when ≥ 2 FDRs suffered PC (OR = 3.88; 95% CI: 2.96-9.73) and among current smokers (OR = 3.16; 95% CI: 2.56-5.78, interaction FHPC*smoking P-value = 0.04). PC cumulative risk by age 75 was 2.2% among FDRs of cases and 0.7% in those of controls [hazard ratio (HR) = 2.42; 95% CI: 2.16-2.71]. PC risk was significantly associated with FH of cancer (OR = 1.30; 95% CI: 1.13-1.54) and diabetes (OR = 1.24; 95% CI: 1.01-1.52), but not with FH of other diseases. The concordant findings using both approaches strengthen the notion that FH of cancer, PC or diabetes confers a higher PC risk. Smoking notably increases PC risk associated with FH of PC. Further evaluation of these associations should be undertaken to guide PC prevention strategies.

Contribution of DNA repair xeroderma pigmentosum group D genotypes to pancreatic cancer risk in the Chinese Han population.

This study aimed to determine the association between the polymorphisms and haplotypes in the xeroderma pigmentosum group D (XPD) gene and the risk of pancreatic cancer in the Chinese Han population. SNaPshot was used for genotyping six SNP sites of the XPD gene. Comparisons of the correlations between different genotypes in combination with smoking and the susceptibility to pancreatic cancer were performed. Individual pancreatic cancer risk in patients who carry mutant C alleles (AC, CC, and AC+CC) at rs13181 increased (p < 0.05). Taking non-smoking individuals who carry the AA genotype as a reference, and non-smoking individuals who carry mutant allele C (AC+CC), the risk of pancreatic cancer increased by 3.343 times in individuals who smoked ≥ 20 cigarettes daily, 3.309 times in individuals who smoked ≥ 14 packs per year, 5.011 times in individuals who smoked ≥ 24 packs per year, and 4.013 times in the individuals who smoked ≥ 37 packs per year (P < 0.05). In addition, haplotype analysis revealed that haplotype AGG, which comprised rs13181, rs3916874 and rs238415, was associated with a 1.401-fold increase in pancreatic cancer risk (p < 0.05). We conclude that the polymorphism of XPD Lys751Gln (rs13181) in combination with smoking contributes to increased risk of pancreatic cancer in the Chinese Han population. Haplotype AGG might be a susceptibility haplotype for pancreatic cancer.

Development of a high risk pancreatic screening clinic using 3.0T MRI.

Selective screening for pancreatic cancer (PC) has been proposed. We describe the establishment of a comprehensive multidisciplinary screening program using 3.0T MRI. Criteria for screening included the presence of PC in: ≥ 2 first degree relatives (FDR), 1 FDR and 1s degree relative (SDR), ≥ 3 any degree relatives (ADR), or any known hereditary cancer syndrome with increased PC risk. Imaging with 3.0T MRI was performed routinely and endoscopic ultrasound was used selectively. Screening was completed in 75 patients (pts). Hereditary cancer syndromes were present in 42 (56%) of the 75 pts: BRCA2 (18), ATM (8), BRCA1 (6), CDKN2A (4), PALB2 (3), Lynch (2), and Peutz-Jeghers (1). A family history of PC was present in ≥ 2 FDR in 12 (16%) pts, 1 FDR and 1 SDR in 5 (7) pts, and ≥ 3 ADR in 16 (21%) pts. Of the 65 pts who received screening MRI, 28 (43%) pts had pancreatic cystic lesions identified, including 1 (1%) patient in whom a cholangiocarcinoma was diagnosed as well. No patient underwent surgical resection. Using a 3.0T MRI to screen patients at high risk for developing PC identified radiographic abnormalities in 43% of patients, which were stable on subsequent surveillance. Specific guidelines for the frequency of surveillance and indications for surgery remain areas of active investigation as the global experience with high risk screening continues to mature.

Pancreatic Dose in Seminoma Radiation Therapy: Impact of Reduced Treatment Fields

Hypotesis: The adoption of reduced treatment fields significantly decreases the pancreatic dose in adjuvant treatment of seminoma. Reduced fields and lower radiation doses decrease the risk of secondary pancreatic cancer. Adjuvant radiotherapy (RT) of seminoma (SM) is associated to a dose-dependent increase in pancreatic cancer risk, with an excess odds ratio (EOR) of 0,12 per Gy. The upper border of standard paraaortic radiation fields (SPRF) is placed at the T10-T11 interspace. Recently, it has been suggested that the upper paraaortic field may be placed at 1 cm superior to the right renal artery or 1.5 cm above the left one, whichever point is more inferior. A randomized trial established equivalent survival rates with 20 or 30 Gy total dose. We reviewed planning CTs of a retrospective cohort to evaluate the pancreatic dose of a reduced field approach (RFA). The risk of secondary pancreatic cancer is estimated for SPRF versus RFA, and for doses of 20 and 30 Gy. The anonymized planning data for patients receiving adjuvant radiotherapy was reviewed. RT treatment plans were analyzed with Eclipse 8.4. All pancreases were contoured and the irradiated volume was calculated from the intersection of the pancreas and the 50 % isodose line. A corresponding RFA was planned for each case. Pancreatic dose were estimated by comparing the irradiated volumes for SPRF and RFA. Odds rates for pancreatic cancer were calculated using an EOR of 0.12 per Gy. Of 77 evaluated patients, imaging, and treatment planning data were available for 34 cases. The average pancreatic volume was 91.1 cc (range 52.2 - 133.5). For SPRF, the average irradiated volume was 68 cc (range 40.4 - 101.1), or 74.7 % of the pancreas. For RFA, the average irradiated volume was 25.0 cc (range 6.9 - 71), or 27,4 %. Thus, the RFA results in approximately a two-third reduction in irradiated pancreatic volume. The odds rates of pancreatic cancer treated with SPRF were estimated from published data at 0,12 excess risk per Gray [OR = 1+(Dose x 0.12)]. With RFA, the calculated risk was corrected multiplying it by the proportion of irradiated pancreas, and are summarized in table 1. Two prescription (PX) levels, 20 and 30 Gy, were used for calculation.Abstract 2649; Table 1Irradiated Pancreas %Pancreatic cancer Risk (OR)PX 30 GyPX 20 GySPRT74.74.63.4RFA27.42.31.9 Open table in a new tab Reducing the treatment fields significantly decreases the pancreatic irradiated volume, from 74.7 to 27.4 %. We estimated that at the 30 Gy dose level, this results in an OR of 2,3 for pancreatic cancer. A 20 Gy dose for the SPRT yields a calculated OR of 3.4. The lowest risk of pancreatic cancer (OR 1.9) is obtained by combining a field and radiation dose reduction. As cancer cure rates increase, greater emphasis is placed in long-term complications of treatment. Second malignancies have long been recognized as a side effect of radiotherapy, in a dose and volume-dependent manner. Strategies aimed to decrease the secondary cancer rate should incorporate both dose and volume reduction.

Elevation of β-galactoside α2,6-sialyltransferase 1 in a fructoseresponsive manner promotes pancreatic cancer metastasis.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive type of pancreatic cancer with clinical characteristics of local invasion and early metastasis. Recent cohort studies indicate high fructose intake is associated with an increase in pancreatic cancer risk. However, the mechanisms by which fructose promotes pancreatic tumorigenesis remain unclear. Herein, Kras+/LSLG12D mice were crossed with Elas-CreER transgenic mice to determine whether fructose intake directly contributes to tumor formation. Orthotopic tumor-xenograft experiments were performed to determine whether fructose substitution enhances the metastatic potential of PDAC cells. The mechanisms underlying the effects of fructose were explored by RNAseq analysis in combination with high-performance anion exchange chromatography. Dietary fructose was initially found to promote the development of aggressive pancreatic cancer in mice conditionally expressing KrasG12D in the adult pancreas. We further revealed that fructose substitution enhanced the metastatic potential of human PDAC cell via selective outgrowth of aggressive ABCG2-positive subpopulations and elevating N-acetylmannosamine levels that upregulated β-galactoside α2,6-sialyltransferase 1 (ST6Gal1), thereby promoting distant metastasis. Finally, we observed that PDAC patients expressing higher levels of ST6Gal1 and GLUT5 presented poorer prognosis compared to other groups. In conclusion, our findings have elucidated a crucial role of ST6Gal1 in regulating the invasiveness of PDACs in a fructose-responsive manner.

Statewide Retrospective Review of Familial Pancreatic Cancer in Delaware, and Frequency of Genetic Mutations in Pancreatic Cancer Kindreds.

Considering the typical rapid progression and high mortality of pancreatic cancer (PC), early detection may lead to an improved outcome. To date, there is no safe, sensitive, and cost-effective screening strategy to detect PC. Currently, screening is focused on individuals at the highest risk of developing PC based on family history. A high-risk individual is defined as having two or more first-degree relatives with PC, or one first- or second-degree relative with PC with a confirmed mutation in a gene associated with PC. The BRCA2 gene is one of the most common genes linked to pancreatic-only cancer families; however, other hereditary cancer syndromes have also been associated with an increased risk for PC. We conducted a retrospective review of pedigrees of families with a pancreatic adenocarcinoma cancer diagnosis held in the statewide Ruth Ann Minner High Risk Family Cancer Registry at the Helen F. Graham Cancer Center and Research Institute, Christiana Care Health System, Newark, DE, USA, from 2002 to 2013. The registry was queried based on how many first-, second-, or third-degree relatives of the proband were affected with PC, genetic testing status, and (if applicable) the results. These data were then categorized into families that meet familial PC (FPC) criteria, defined as two first-degree relatives with PC (FPC families), families that did not meet the FPC definition but had one first-degree relative affected with PC (first-degree families), and probands with PC (probands). Each family was counted only once in the analysis, even if multiple family members were tested. Our analysis revealed that 175 of 597 families fitting any of the above criteria completed genetic testing. Of this cohort, 52 had pathogenic alterations with nine different genes implicated. Overall, 164 of the 175 families that fitted into any of the three categories previously identified had BRCA1 or BRCA2 testing, either by DNA sequencing or next-generation sequencing via a panel test that included BRCA1/2. BRCA1 pathogenic alterations were noted in 17/164 (10.4%) and BRCA2 pathogenic alterations were noted in 23/164 (14.0%). FPC families (n=46) 42/46 of the FPC families underwent BRCA1/2 testing, and 11/42 (26% [95% CI 12.89-39.49]) had pathogenic alterations. Specifically, 4/42=BRCA1 (9.5%) and 7/42=BRCA2 (16.7%). Additionally, 16/46 of the FPC families underwent exclusively Lynch syndrome (LS) testing, and pathogenic mutations in a mismatch repair protein were identified in 2/16. Specifically, 1/16=MLH1 (6.3%) and 1/16=MSH2 (3.6%). Overall, a genetic mutation within any gene associated with an increased PC risk was found in 28% of FPC families. First-degree families (n=106) 99/106 of the families with one first-degree relative underwent BRCA1/2 testing, and 21/99 (21.2% [95% CI 13.16-29.27]) had pathogenic alterations. Specifically, 11/99=BRCA1 (11.1%) and 10/99=BRCA2 (10.1%). 32/99 first-degree families underwent exclusively LS testing, and pathogenic mutations were identified in 4/32. Specifically, 3/32=MLH1 (9%) and 1/32=MSH6 (3%). 25/99 of the families pursued panel testing, and pathogenic alterations in any gene were identified in 3/25. Specifically, the mutations were found in 1/25=ATM (4%), 1/25=CHEK2 (4%), and 1/25=RAD51D (4%). Affected probands (n=23) Lastly, all 23 probands affected with PC pursued genetic testing. Of these, 11/23 were found to have pathogenic alterations. All 23 underwent BRCA1/2 testing, and pathogenic alterations were identified in 8/23 (35% [95% CI 15.32-54.25]), specifically 2/23=BRCA1 (9%), and 6/23=BRCA2 (26%). 10/23 patients underwent panel testing and pathogenic alterations were found in 3/10 (30%) patients, of whom 1/10=MSH6 (10%), 1/10=ATM (10%), and 1/10=TP53 (10%). This study demonstrates that a statewide high-risk family cancer registry is an important instrument in studying the risk of PC in families. Our analysis revealed 14 mutations associated with FPC, among which hereditary breast and ovarian cancer and LS were most prevalent. BRCA1 was found to have the same association with PC as BRCA2, which appears unique to our population. We plan to use our knowledge of these mutations in developing a PC screening program.

Abstract B16: Activated glucocorticoid signaling in pancreatitis contributes to acinar-to-ductal metaplasia and KrasG12D-driven tumorigenesis

Abstract Patients with chronic pancreatitis are at increased risk of developing pancreatic cancer. However, the key inflammatory action mediating pancreatic tumorigenesis has not been clearly determined. Here, we initially identified evaluated levels of activated glucocorticoid receptors (GR) were observed in patients of chronic pancreatitis and pancreatic ductal adenocarcinomas (PDAC). Utilizing mice that conditionally expressed KrasG12D in acinar cell compartment with or without loss of GR, we demonstrated that activation of GR was required for generation of metaplastic ductal lesion and development of pancreatic intraepithelial neoplasia (PanIN) in mice with experimental pancreatitis. Administration of dexamethason, a potent synthetic glucocoticoid, was sufficient to induce development of advanced PanINs and metastatic PDACs in KrasG12D mice that harbour single-allele deletion of p53. We further revealed that nongenomic activation of GR was a key action that led to evaluating c-Src signaling and triggering a pathological threshold of Ras activity necessary for neoplastic transformation. In contrast, treatment of dasatinib, a Src kinase inhibitor, could suppressed development of PanIN and PDAC induced by dexamethasone. Importantly, cre-lox based lineage-tracing mice was applied and identified that GR activation directly transformed GFP-tagged KrasG12D-expressing acinar cells to tumorigenic cells that posse features of cancer initiating cells. The findings explained why chronic inflammation increase pancreatic cancer risk and raised concerns on the use of glucocorticoids on patients of chronic pancreatitis Citation Format: Chia-Ning Shen, Chien-Chang Su, Chi-Chih Hsieh, Wen-Ying Liao, Wan-Yu Mao, Chia-Rui Shen, Michael Hsiao. Activated glucocorticoid signaling in pancreatitis contributes to acinar-to-ductal metaplasia and KrasG12D-driven tumorigenesis. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr B16. doi: 10.1158/1557-3125.RASONC14-B16