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Pancreatic Neoplasms: HELP
Articles by William R. Bamlet
Based on 61 articles published since 2010
(Why 61 articles?)
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Between 2010 and 2020, W. Bamlet wrote the following 61 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Clinical Trial The vitamin D receptor gene as a determinant of survival in pancreatic cancer patients: Genomic analysis and experimental validation. 2018

Innocenti, Federico / Owzar, Kouros / Jiang, Chen / Etheridge, Amy S / Gordân, Raluca / Sibley, Alexander B / Mulkey, Flora / Niedzwiecki, Donna / Glubb, Dylan / Neel, Nicole / Talamonti, Mark S / Bentrem, David J / Seiser, Eric / Yeh, Jen Jen / Van Loon, Katherine / McLeod, Howard / Ratain, Mark J / Kindler, Hedy L / Venook, Alan P / Nakamura, Yusuke / Kubo, Michiaki / Petersen, Gloria M / Bamlet, William R / McWilliams, Robert R. ·UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, United States of America. · Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina, United States of America. · Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, United States of America. · North Shore University Health System, Evanston, IL, United States of America. · Northwestern University, Chicago, IL, United States of America. · University of California at San Francisco, San Francisco, CA, United States of America. · Moffitt Cancer Center, Tampa, FL, United States of America. · University of Chicago, Chicago, IL, United States of America. · Center for Genomic Medicine, RIKEN, Yokohama, Japan. · Mayo Clinic, Rochester, MN, United States of America. ·PLoS One · Pubmed #30107003.

ABSTRACT: PURPOSE: Advanced pancreatic cancer is a highly refractory disease almost always associated with survival of little more than a year. New interventions based on novel targets are needed. We aim to identify new genetic determinants of overall survival (OS) in patients after treatment with gemcitabine using genome-wide screens of germline DNA. We aim also to support these findings with in vitro functional analysis. PATIENTS AND METHODS: Genome-wide screens of germline DNA in two independent cohorts of pancreatic cancer patients (from the Cancer and Leukemia Group B (CALGB) 80303 and the Mayo Clinic) were used to select new genes associated with OS. The vitamin D receptor gene (VDR) was selected, and the interactions of genetic variation in VDR with circulating vitamin D levels and gemcitabine treatment were evaluated. Functional effects of common VDR variants were also evaluated in experimental assays in human cell lines. RESULTS: The rs2853564 variant in VDR was associated with OS in patients from both the Mayo Clinic (HR 0.81, 95% CI 0.70-0.94, p = 0.0059) and CALGB 80303 (HR 0.74, 0.63-0.87, p = 0.0002). rs2853564 interacted with high pre-treatment levels of 25-hydroxyvitamin D (25(OH)D, a measure of endogenous vitamin D) (p = 0.0079 for interaction) and with gemcitabine treatment (p = 0.024 for interaction) to confer increased OS. rs2853564 increased transcriptional activity in luciferase assays and reduced the binding of the IRF4 transcription factor. CONCLUSION: Our findings propose VDR as a novel determinant of survival in advanced pancreatic cancer patients. Common functional variation in this gene might interact with endogenous vitamin D and gemcitabine treatment to determine improved patient survival. These results support evidence for a modulatory role of the vitamin D pathway for the survival of advanced pancreatic cancer patients.

2 Article Agnostic Pathway/Gene Set Analysis of Genome-Wide Association Data Identifies Associations for Pancreatic Cancer. 2019

Walsh, Naomi / Zhang, Han / Hyland, Paula L / Yang, Qi / Mocci, Evelina / Zhang, Mingfeng / Childs, Erica J / Collins, Irene / Wang, Zhaoming / Arslan, Alan A / Beane-Freeman, Laura / Bracci, Paige M / Brennan, Paul / Canzian, Federico / Duell, Eric J / Gallinger, Steven / Giles, Graham G / Goggins, Michael / Goodman, Gary E / Goodman, Phyllis J / Hung, Rayjean J / Kooperberg, Charles / Kurtz, Robert C / Malats, Núria / LeMarchand, Loic / Neale, Rachel E / Olson, Sara H / Scelo, Ghislaine / Shu, Xiao O / Van Den Eeden, Stephen K / Visvanathan, Kala / White, Emily / Zheng, Wei / Anonymous2461116 / Albanes, Demetrius / Andreotti, Gabriella / Babic, Ana / Bamlet, William R / Berndt, Sonja I / Borgida, Ayelet / Boutron-Ruault, Marie-Christine / Brais, Lauren / Brennan, Paul / Bueno-de-Mesquita, Bas / Buring, Julie / Chaffee, Kari G / Chanock, Stephen / Cleary, Sean / Cotterchio, Michelle / Foretova, Lenka / Fuchs, Charles / M Gaziano, J Michael / Giovannucci, Edward / Goggins, Michael / Hackert, Thilo / Haiman, Christopher / Hartge, Patricia / Hasan, Manal / Helzlsouer, Kathy J / Herman, Joseph / Holcatova, Ivana / Holly, Elizabeth A / Hoover, Robert / Hung, Rayjean J / Janout, Vladimir / Klein, Eric A / Kurtz, Robert C / Laheru, Daniel / Lee, I-Min / Lu, Lingeng / Malats, Núria / Mannisto, Satu / Milne, Roger L / Oberg, Ann L / Orlow, Irene / Patel, Alpa V / Peters, Ulrike / Porta, Miquel / Real, Francisco X / Rothman, Nathaniel / Sesso, Howard D / Severi, Gianluca / Silverman, Debra / Strobel, Oliver / Sund, Malin / Thornquist, Mark D / Tobias, Geoffrey S / Wactawski-Wende, Jean / Wareham, Nick / Weiderpass, Elisabete / Wentzensen, Nicolas / Wheeler, William / Yu, Herbert / Zeleniuch-Jacquotte, Anne / Kraft, Peter / Li, Donghui / Jacobs, Eric J / Petersen, Gloria M / Wolpin, Brian M / Risch, Harvey A / Amundadottir, Laufey T / Yu, Kai / Klein, Alison P / Stolzenberg-Solomon, Rachael Z. ·National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin, Ireland. · Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD. · Division of Applied Regulatory Science, Office of Translational Science, Center for Drug Evaluation & Research, U.S. Food and Drug Administration, Silver Spring, MD. · Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD. · Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD. · Division of Epidemiology II, Office of Surveillance and Epidemiology, Center for Drug Evaluation & Research, U.S. Food and Drug Administration, Silver Spring, MD. · Department of Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee. · Department of Obstetrics and Gynecology, New York University School of Medicine, New York, NY. · Department of Environmental Medicine, New York University School of Medicine, New York, NY. · Department of Population Health, New York University School of Medicine, New York, NY. · Department of Epidemiology and Biostatistics, University of California, San Francisco, CA. · International Agency for Research on Cancer (IARC), Lyon, France. · Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Bellvitge Biomedical Research Institute (IDIBELL), Catalan Institute of Oncology (ICO), Barcelona, Spain. · Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada. · Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, Victoria, Australia. · Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia. · Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, MD. · Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA. · SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA. · Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY. · Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain. · CIBERONC, Madrid, Spain. · Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI. · Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. · Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY. · Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN. · Division of Research, Kaiser Permanente Northern California, Oakland, CA. · Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD. · Department of Epidemiology, University of Washington, Seattle, WA. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA. · Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN. · Centre de Recherche en Épidémiologie et Santé des Populations (CESP, Inserm U1018), Facultés de Medicine, Université Paris-Saclay, UPS, UVSQ, Gustave Roussy, Villejuif, France. · Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands. · Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK. · Department of Social & Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia. · Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA. · Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA. · Division of Hepatobiliary and Pancreas Surgery, Mayo Clinic, Rochester, MN. · Cancer Care Ontario, University of Toronto, Toronto, ON, Canada. · Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada. · Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic. · Yale Cancer Center, New Haven, CT. · Division of Aging, Brigham and Women's Hospital, Boston, MA. · Boston VA Healthcare System, Boston, MA. · Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany. · Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA. · Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX. · Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD. · Department of Radiation Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD. · Institute of Public Health and Preventive Medicine, Charles University, 2nd Faculty of Medicine, Prague, Czech Republic. · Department of Epidemiology and Public Health, Faculty of Medicine, University of Ostrava, Czech Republic. · Faculty of Medicine, University of Olomouc, Olomouc, Czech Republic. · Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH. · Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT. · Department of Public Health Solutions, National Institute for Health and Welfare, Helsinki, Finland. · Epidemiology Research Program, American Cancer Society, Atlanta, GA. · CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain. · Hospital del Mar Institute of Medical Research (IMIM), Universitat Autònoma de Barcelona, Barcelona, Spain. · Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre-CNIO, Madrid, Spain. · Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain. · Department of Surgical and Perioperative Sciences, Umeå University, Umeå, Sweden. · Department of Epidemiology and Environmental Health, University at Buffalo, Buffalo, NY. · MRC Epidemiology Unit, University of Cambridge, Cambridge, UK. · Department of Research, Cancer Registry of Norway, Institute of Population-Based Cancer Research, Oslo, Norway. · Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. · Genetic Epidemiology Group, Folkhälsan Research Center and Faculty of Medicine, University of Helsinki, Helsinki, Finland. · Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway. · Information Management Systems, Silver Spring, MD. · Perlmutter Cancer Center, New York University School of Medicine, New York, NY. · Department of Biostatistics, Harvard School of Public Health, Boston, MA. · Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX. ·J Natl Cancer Inst · Pubmed #30541042.

ABSTRACT: BACKGROUND: Genome-wide association studies (GWAS) identify associations of individual single-nucleotide polymorphisms (SNPs) with cancer risk but usually only explain a fraction of the inherited variability. Pathway analysis of genetic variants is a powerful tool to identify networks of susceptibility genes. METHODS: We conducted a large agnostic pathway-based meta-analysis of GWAS data using the summary-based adaptive rank truncated product method to identify gene sets and pathways associated with pancreatic ductal adenocarcinoma (PDAC) in 9040 cases and 12 496 controls. We performed expression quantitative trait loci (eQTL) analysis and functional annotation of the top SNPs in genes contributing to the top associated pathways and gene sets. All statistical tests were two-sided. RESULTS: We identified 14 pathways and gene sets associated with PDAC at a false discovery rate of less than 0.05. After Bonferroni correction (P ≤ 1.3 × 10-5), the strongest associations were detected in five pathways and gene sets, including maturity-onset diabetes of the young, regulation of beta-cell development, role of epidermal growth factor (EGF) receptor transactivation by G protein-coupled receptors in cardiac hypertrophy pathways, and the Nikolsky breast cancer chr17q11-q21 amplicon and Pujana ATM Pearson correlation coefficient (PCC) network gene sets. We identified and validated rs876493 and three correlating SNPs (PGAP3) and rs3124737 (CASP7) from the Pujana ATM PCC gene set as eQTLs in two normal derived pancreas tissue datasets. CONCLUSION: Our agnostic pathway and gene set analysis integrated with functional annotation and eQTL analysis provides insight into genes and pathways that may be biologically relevant for risk of PDAC, including those not previously identified.

3 Article Risk of Different Cancers Among First-degree Relatives of Pancreatic Cancer Patients: Influence of Probands' Susceptibility Gene Mutation Status. 2019

Antwi, Samuel O / Fagan, Sarah E / Chaffee, Kari G / Bamlet, William R / Hu, Chunling / Polley, Eric C / Hart, Steven N / Shimelis, Hermela / Lilyquist, Jenna / Gnanaolivu, Rohan D / McWilliams, Robert R / Oberg, Ann L / Couch, Fergus J / Petersen, Gloria M. ·Department of Health Sciences Research, Mayo Clinic, Rochester, MN. · Department of Epidemiology, Tulane University, New Orleans, LA. · Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN. · Department of Medical Oncology, Mayo Clinic, Rochester, MN. ·J Natl Cancer Inst · Pubmed #29982661.

ABSTRACT: BACKGROUND: Increased risk of malignancies other than pancreatic cancer (PC) has been reported among first-degree relatives (FDRs) of PC patients; however, the roles of susceptibility gene mutations are unclear. We assessed risk for 15 cancers among FDRs of unselected PC probands. METHODS: Data on 17 162 FDRs, with more than 336 000 person-years at risk, identified through 2305 sequential PC probands enrolled at Mayo Clinic (2000-2016) were analyzed. Family history data were provided by the probands. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated, comparing malignancies observed among the FDRs with that expected using Surveillance, Epidemiology, and End Results (SEER) data. Genetic testing was performed among a subset of probands (n = 2094), enabling stratified analyses among FDRs based on whether the related proband tested positive or negative for inherited mutation in 22 sequenced cancer susceptibility genes. All statistical tests were two-sided. RESULTS: Compared with SEER, PC risk was twofold higher among FDRs of PC probands (SIR = 2.04, 95% CI = 1.78 to 2.31, P < .001). Primary liver cancer risk was elevated among female FDRs (SIR = 2.10, 95% CI = 1.34 to 3.12, P < .001). PC risk was more elevated among FDRs of mutation-positive probands (SIR = 4.32, 95% CI = 3.10 to 5.86) than FDRs of mutation-negative probands (SIR = 1.77, 95% CI = 1.51 to 2.05, between-group P < .001). FDR PC risk was higher when the related proband was younger than age 60 years at diagnosis and mutation-positive (SIR = 5.24, 95% CI = 2.93 to 8.64) than when the proband was younger than age 60 years but mutation-negative (SIR = 1.76, 95% CI = 1.21 to 2.47, between-group P < .001). Breast (SIR = 1.29, 95% CI = 1.01 to 1.63) and ovarian (SIR = 2.38, 95% CI = 1.30 to 4.00) cancers were elevated among FDRs of mutation-positive probands. CONCLUSIONS: Our study substantiates twofold risk of PC among FDRs of PC patients and suggests increased risk for primary liver cancer among female FDRs. FDRs of susceptibility mutation carriers had substantially increased risk for PC and increased risk for breast and ovarian cancers.

4 Article Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer. 2018

Hu, Chunling / Hart, Steven N / Polley, Eric C / Gnanaolivu, Rohan / Shimelis, Hermela / Lee, Kun Y / Lilyquist, Jenna / Na, Jie / Moore, Raymond / Antwi, Samuel O / Bamlet, William R / Chaffee, Kari G / DiCarlo, John / Wu, Zhong / Samara, Raed / Kasi, Pashtoon M / McWilliams, Robert R / Petersen, Gloria M / Couch, Fergus J. ·Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota. · Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota. · Department of Health Sciences Research, Mayo Clinic, Jacksonville, Florida. · Qiagen Sciences Research and Development, Qiagen Inc, Hilden, Germany. · Department of Medicine, Mayo Clinic, Jacksonville, Florida. · Department of Medical Oncology, Mayo Clinic, Rochester, Minnesota. ·JAMA · Pubmed #29922827.

ABSTRACT: Importance: Individuals genetically predisposed to pancreatic cancer may benefit from early detection. Genes that predispose to pancreatic cancer and the risks of pancreatic cancer associated with mutations in these genes are not well defined. Objective: To determine whether inherited germline mutations in cancer predisposition genes are associated with increased risks of pancreatic cancer. Design, Setting, and Participants: Case-control analysis to identify pancreatic cancer predisposition genes; longitudinal analysis of patients with pancreatic cancer for prognosis. The study included 3030 adults diagnosed as having pancreatic cancer and enrolled in a Mayo Clinic registry between October 12, 2000, and March 31, 2016, with last follow-up on June 22, 2017. Reference controls were 123 136 individuals with exome sequence data in the public Genome Aggregation Database and 53 105 in the Exome Aggregation Consortium database. Exposures: Individuals were classified based on carrying a deleterious mutation in cancer predisposition genes and having a personal or family history of cancer. Main Outcomes and Measures: Germline mutations in coding regions of 21 cancer predisposition genes were identified by sequencing of products from a custom multiplex polymerase chain reaction-based panel; associations of genes with pancreatic cancer were assessed by comparing frequency of mutations in genes of pancreatic cancer patients with those of reference controls. Results: Comparing 3030 case patients with pancreatic cancer (43.2% female; 95.6% non-Hispanic white; mean age at diagnosis, 65.3 [SD, 10.7] years) with reference controls, significant associations were observed between pancreatic cancer and mutations in CDKN2A (0.3% of cases and 0.02% of controls; odds ratio [OR], 12.33; 95% CI, 5.43-25.61); TP53 (0.2% of cases and 0.02% of controls; OR, 6.70; 95% CI, 2.52-14.95); MLH1 (0.13% of cases and 0.02% of controls; OR, 6.66; 95% CI, 1.94-17.53); BRCA2 (1.9% of cases and 0.3% of controls; OR, 6.20; 95% CI, 4.62-8.17); ATM (2.3% of cases and 0.37% of controls; OR, 5.71; 95% CI, 4.38-7.33); and BRCA1 (0.6% of cases and 0.2% of controls; OR, 2.58; 95% CI, 1.54-4.05). Conclusions and Relevance: In this case-control study, mutations in 6 genes associated with pancreatic cancer were found in 5.5% of all pancreatic cancer patients, including 7.9% of patients with a family history of pancreatic cancer and 5.2% of patients without a family history of pancreatic cancer. Further research is needed for replication in other populations.

5 Article Pancreatic cancer risk is modulated by inflammatory potential of diet and ABO genotype: a consortia-based evaluation and replication study. 2018

Antwi, Samuel O / Bamlet, William R / Pedersen, Katrina S / Chaffee, Kari G / Risch, Harvey A / Shivappa, Nitin / Steck, Susan E / Anderson, Kristin E / Bracci, Paige M / Polesel, Jerry / Serraino, Diego / La Vecchia, Carlo / Bosetti, Cristina / Li, Donghui / Oberg, Ann L / Arslan, Alan A / Albanes, Demetrius / Duell, Eric J / Huybrechts, Inge / Amundadottir, Laufey T / Hoover, Robert / Mannisto, Satu / Chanock, Stephen J / Zheng, Wei / Shu, Xiao-Ou / Stepien, Magdalena / Canzian, Federico / Bueno-de-Mesquita, Bas / Quirós, José Ramon / Zeleniuch-Jacquotte, Anne / Bruinsma, Fiona / Milne, Roger L / Giles, Graham G / Hébert, James R / Stolzenberg-Solomon, Rachael Z / Petersen, Gloria M. ·Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA. · Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA. · Division of Oncology, Washington University, St. Louis, MO, USA. · Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA. · Cancer Prevention and Control Program, USA. · Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA. · Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA. · Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA. · Unit of Epidemiology and Biostatistics, Centro di Riferimento Oncologico, Aviano (PN), Italy. · Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy. · Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy. · Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA. · Department of Environmental Medicine, New York University School of Medicine, New York, NY, USA. · Department of Population Health, New York University School of Medicine, New York, NY, USA. · Department of Obstetrics and Gynecology, New York University School of Medicine, New York, NY, USA. · Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA. · Unit of Nutrition and Cancer, Bellvitge Biomedical Research Institute-IDIBELL, Catalan Institute of Oncology-ICO. L'Hospitalet de Llobregat, Barcelona, Spain. · International Agency for Research on Cancer, World Health Organization, France. · Department of Public Health Solutions, National Institute for Health and Welfare Helsinki, Finland. · Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, and Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA. · Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Campus, Norfolk Place, London, UK. · Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Pantai Valley, Kuala Lumpur, Malaysia. · Public Health Directorate, Asturias, Spain. · Perlmutter Cancer Center, New York University School of Medicine, New York, NY, USA. · Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, and Centre for Epidemiology and Biostatistics, Melbourne School of Global and Population Health, The University of Melbourne, Melbourne, Australia. ·Carcinogenesis · Pubmed #29800239.

ABSTRACT: 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.

6 Article Comparison of Fasting Human Pancreatic Polypeptide Levels Among Patients With Pancreatic Ductal Adenocarcinoma, Chronic Pancreatitis, and Type 2 Diabetes Mellitus. 2018

Nagpal, Sajan Jiv Singh / Bamlet, William R / Kudva, Yogish C / Chari, Suresh T. ·From the Divisions of Gastroenterology and Hepatology. · Biomedical Statistics and Informatics, and. · Endocrinology, Mayo Clinic, Rochester, MN. ·Pancreas · Pubmed #29771765.

ABSTRACT: OBJECTIVES: Human pancreatic polypeptide (HPP) is a hormone secreted by the ventral pancreas. While postprandial HPP levels have been studied in chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC), there are limited data on fasting HPP in these diseases. METHODS: Fasting serum HPP was measured in the following groups of patients: CP with diabetes mellitus (DM) (n = 16), CP without DM (n = 34), PDAC with new-onset DM (n = 50), PDAC without DM (n = 49), new-onset type 2 DM (n = 50), and controls without DM (n = 49). Sixty-six had type 3c DM (CP with DM, n = 16; PDAC with new-onset DM, n = 50). RESULTS: Median fasting HPP levels (in picograms per milliliter) were similar among all groups. Median (interquartile range) HPP levels in new-onset type 2 DM (n = 50; 288.3 [80.1-1072.1]) were similar to those in type 3c DM (n = 66; 242.3 [64.9-890.9]) (P = 0.71). In PDAC (n = 99), HPP values were similar in pancreatic head (n = 75) versus body/tail (n = 24) tumors (245.3 [64.3-1091.3] vs 334.7 [136.1-841.5]; P = 0.95), regardless of DM. CONCLUSIONS: Fasting HPP levels are similar in CP, PDAC, and controls regardless of glycemic status.

7 Article Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer. 2018

Klein, Alison P / Wolpin, Brian M / Risch, Harvey A / Stolzenberg-Solomon, Rachael Z / Mocci, Evelina / Zhang, Mingfeng / Canzian, Federico / Childs, Erica J / Hoskins, Jason W / Jermusyk, Ashley / Zhong, Jun / Chen, Fei / Albanes, Demetrius / Andreotti, Gabriella / Arslan, Alan A / Babic, Ana / Bamlet, William R / Beane-Freeman, Laura / Berndt, Sonja I / Blackford, Amanda / Borges, Michael / Borgida, Ayelet / Bracci, Paige M / Brais, Lauren / Brennan, Paul / Brenner, Hermann / Bueno-de-Mesquita, Bas / Buring, Julie / Campa, Daniele / Capurso, Gabriele / Cavestro, Giulia Martina / Chaffee, Kari G / Chung, Charles C / Cleary, Sean / Cotterchio, Michelle / Dijk, Frederike / Duell, Eric J / Foretova, Lenka / Fuchs, Charles / Funel, Niccola / Gallinger, Steven / M Gaziano, J Michael / Gazouli, Maria / Giles, Graham G / Giovannucci, Edward / Goggins, Michael / Goodman, Gary E / Goodman, Phyllis J / Hackert, Thilo / Haiman, Christopher / Hartge, Patricia / Hasan, Manal / Hegyi, Peter / Helzlsouer, Kathy J / Herman, Joseph / Holcatova, Ivana / Holly, Elizabeth A / Hoover, Robert / Hung, Rayjean J / Jacobs, Eric J / Jamroziak, Krzysztof / Janout, Vladimir / Kaaks, Rudolf / Khaw, Kay-Tee / Klein, Eric A / Kogevinas, Manolis / Kooperberg, Charles / Kulke, Matthew H / Kupcinskas, Juozas / Kurtz, Robert J / Laheru, Daniel / Landi, Stefano / Lawlor, Rita T / Lee, I-Min / LeMarchand, Loic / Lu, Lingeng / Malats, Núria / Mambrini, Andrea / Mannisto, Satu / Milne, Roger L / Mohelníková-Duchoňová, Beatrice / Neale, Rachel E / Neoptolemos, John P / Oberg, Ann L / Olson, Sara H / Orlow, Irene / Pasquali, Claudio / Patel, Alpa V / Peters, Ulrike / Pezzilli, Raffaele / Porta, Miquel / Real, Francisco X / Rothman, Nathaniel / Scelo, Ghislaine / Sesso, Howard D / Severi, Gianluca / Shu, Xiao-Ou / Silverman, Debra / Smith, Jill P / Soucek, Pavel / Sund, Malin / Talar-Wojnarowska, Renata / Tavano, Francesca / Thornquist, Mark D / Tobias, Geoffrey S / Van Den Eeden, Stephen K / Vashist, Yogesh / Visvanathan, Kala / Vodicka, Pavel / Wactawski-Wende, Jean / Wang, Zhaoming / Wentzensen, Nicolas / White, Emily / Yu, Herbert / Yu, Kai / Zeleniuch-Jacquotte, Anne / Zheng, Wei / Kraft, Peter / Li, Donghui / Chanock, Stephen / Obazee, Ofure / Petersen, Gloria M / Amundadottir, Laufey T. ·Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, 21231, USA. aklein1@jhmi.edu. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, MD, 21287, USA. aklein1@jhmi.edu. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. · Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, 06520, USA. · Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. · Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, 21231, USA. · Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. · Genomic Epidemiology Group, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. · Department of Obstetrics and Gynecology, New York University School of Medicine, New York, NY, 10016, USA. · Department of Population Health, New York University School of Medicine, New York, NY, 10016, USA. · Department of Environmental Medicine, New York University School of Medicine, New York, NY, 10016, USA. · Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, MD, 21287, USA. · Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, M5G 1×5, Canada. · Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, 94158, USA. · International Agency for Research on Cancer (IARC), 69372, Lyon, France. · Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. · Division of Preventive Oncology, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. · National Center for Tumor Diseases (NCT), 69120, Heidelberg, Germany. · Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), 3720 BA, Bilthoven, The Netherlands. · Department of Gastroenterology and Hepatology, University Medical Centre, 3584 CX, Utrecht, The Netherlands. · Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, SW7 2AZ, UK. · Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia. · Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, 02215, USA. · Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA. · Department of Biology, University of Pisa, 56126, Pisa, Italy. · Digestive and Liver Disease Unit, 'Sapienza' University of Rome, 00185, Rome, Italy. · Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy. · Cancer Genomics Research Laboratory, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA. · Cancer Care Ontario, University of Toronto, Toronto, Ontario, M5G 2L7, Canada. · Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, M5T 3M7, Canada. · Department of Pathology, Academic Medical Center, University of Amsterdam, 1007 MB, Amsterdam, The Netherlands. · Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Bellvitge Biomedical Research Institute (IDIBELL), Catalan Institute of Oncology (ICO), Barcelona, 08908, Spain. · Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, 65653, Brno, Czech Republic. · Yale Cancer Center, New Haven, CT, 06510, USA. · Department of Translational Research and The New Technologies in Medicine and Surgery, University of Pisa, 56126, Pisa, Italy. · Division of Aging, Brigham and Women's Hospital, Boston, MA, 02115, USA. · Boston VA Healthcare System, Boston, MA, 02132, USA. · Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, 106 79, Athens, Greece. · Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, VIC, 3004, Australia. · Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, 3010, Australia. · Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, 3004, Australia. · Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA. · SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA. · Department of General Surgery, University Hospital Heidelberg, 69120, Heidelberg, Germany. · Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90032, USA. · Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, 77230, USA. · First Department of Medicine, University of Szeged, 6725, Szeged, Hungary. · Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. · Department of Radiation Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, 21231, USA. · Institute of Public Health and Preventive Medicine, Charles University, 2nd Faculty of Medicine, 150 06, Prague 5, Czech Republic. · Epidemiology Research Program, American Cancer Society, Atlanta, GA, 30303, USA. · Department of Hematology, Institute of Hematology and Transfusion Medicine, 02-776, Warsaw, Poland. · Department of Epidemiology and Public Health, Faculty of Medicine, University of Ostrava, 701 03, Ostrava, Czech Republic. · Faculty of Medicine, University of Olomouc, 771 47, Olomouc, Czech Republic. · Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. · School of Clinical Medicine, University of Cambridge, Cambridge, CB2 0SP, UK. · Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, 44195, USA. · ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), 08003, Barcelona, Spain. · CIBER Epidemiología y Salud Pública (CIBERESP), 08003, Barcelona, Spain. · Hospital del Mar Institute of Medical Research (IMIM), Universitat Autònoma de Barcelona, 08003, Barcelona, Spain. · Universitat Pompeu Fabra (UPF), 08002, Barcelona, Spain. · Department of Gastroenterology, Lithuanian University of Health Sciences, 44307, Kaunas, Lithuania. · Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. · ARC-NET: Centre for Applied Research on Cancer, University and Hospital Trust of Verona, 37134, Verona, Italy. · Department of Epidemiology, Harvard School of Public Health, Boston, MA, 02115, USA. · Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, 96813, USA. · Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center (CNIO), 28029, Madrid, Spain. · CIBERONC, 28029, Madrid, Spain. · Oncology Department, ASL1 Massa Carrara, Carrara, 54033, Italy. · Department of Public Health Solutions, National Institute for Health and Welfare, 00271, Helsinki, Finland. · Department of Oncology, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital, 775 20, Olomouc, Czech Republic. · Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, 4029, Australia. · Department of General Surgery, University of Heidelburg, Heidelberg, Germany. · Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. · Department of Surgery, Oncology and Gastroenterology (DiSCOG), University of Padua, 35124, Padua, Italy. · Pancreas Unit, Department of Digestive Diseases and Internal Medicine, Sant'Orsola-Malpighi Hospital, 40138, Bologna, Italy. · Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre-CNIO, 28029, Madrid, Spain. · Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08002, Barcelona, Spain. · Centre de Recherche en Épidémiologie et Santé des Populations (CESP, Inserm U1018), Facultés de Medicine, Université Paris-Saclay, UPS, UVSQ, Gustave Roussy, 94800, Villejuif, France. · Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA. · Department of Medicine, Georgetown University, Washington, 20057, USA. · Laboratory for Pharmacogenomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, 323 00, Pilsen, Czech Republic. · Department of Surgical and Perioperative Sciences, Umeå University, 901 85, Umeå, Sweden. · Department of Digestive Tract Diseases, Medical University of Łodz, 90-647, Łodz, Poland. · Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", 71013, San Giovanni Rotondo, FG, Italy. · Division of Research, Kaiser Permanente Northern California, Oakland, CA, 94612, USA. · Department of General, Visceral and Thoracic Surgery, University Hamburg-Eppendorf, 20246, Hamburg, Germany. · Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA. · Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, 142 20, Prague 4, Czech Republic. · Department of Epidemiology and Environmental Health, University at Buffalo, Buffalo, NY, 14214, USA. · Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. · Department of Epidemiology, University of Washington, Seattle, WA, 98195, USA. · Perlmutter Cancer Center, New York University School of Medicine, New York, NY, 10016, USA. · Department of Biostatistics, Harvard School of Public Health, Boston, MA, 02115, USA. · Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. · Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. amundadottirl@mail.nih.gov. ·Nat Commun · Pubmed #29422604.

ABSTRACT: In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 × 10

8 Article Identification of a pyruvate-to-lactate signature in pancreatic intraductal papillary mucinous neoplasms. 2018

Penheiter, Alan R / Deelchand, Dinesh K / Kittelson, Emily / Damgard, Sibel Erdogan / Murphy, Stephen J / O'Brien, Daniel R / Bamlet, William R / Passow, Marie R / Smyrk, Thomas C / Couch, Fergus J / Vasmatzis, George / Port, John D / Marjańska, Małgorzata / Carlson, Stephanie K. ·Department of Molecular Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. · Center for Magnetic Resonance Research and Department of Radiology, University of Minnesota, 2021 6th Street SE, Minneapolis, MN 55455, USA. · Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. · Department of Health Science Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. · Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. · Department of Radiology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. · Department of Molecular Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA; Department of Radiology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Electronic address: scarlson@mayo.edu. ·Pancreatology · Pubmed #29170050.

ABSTRACT: OBJECTIVE: We used transcriptomic profiling and immunohistochemistry (IHC) to search for a functional imaging strategy to resolve common problems with morphological imaging of cystic neoplasms and benign cystic lesions of the pancreas. METHODS: Resected pancreatic cancer (n = 21) and normal pancreas were laser-capture micro-dissected, and transcripts were quantified by RNAseq. Functional imaging targets were validated at the protein level by IHC on a pancreatic adenocarcinoma tissue microarray and a newly created tissue microarray of resected intraductal papillary mucinous neoplasms (IPMNs) and IPMN-associated adenocarcinomas. RESULTS: Genes encoding proteins responsible for cellular import of pyruvate, export of lactate, and conversion of pyruvate to lactate were highly upregulated in pancreatic adenocarcinoma compared to normal pancreas. Strong expression of MCT4 and LDHA was observed by IHC in >90% of adenocarcinoma specimens. In IPMNs, the pyruvate-to-lactate signature was significantly elevated in high grade dysplasia (HGD) and IPMN-associated adenocarcinoma. Additionally, cores containing HGD and/or adenocarcinoma exhibited a higher number of peri-lesional stromal cells and a significant increase in peri-lesional stromal cell staining of LDHA and MCT4. Interestingly, the pyruvate-to-lactate signature was significantly upregulated in cores containing only low grade dysplasia (LGD) from patients with histologically confirmed IPMN-associated adenocarcinoma versus LGD cores from patients with non-invasive IPMNs. CONCLUSION: Our results suggest prospective studies with hyperpolarized [1-

9 Article Characterising 2018

Zhang, Mingfeng / Lykke-Andersen, Soren / Zhu, Bin / Xiao, Wenming / Hoskins, Jason W / Zhang, Xijun / Rost, Lauren M / Collins, Irene / Bunt, Martijn van de / Jia, Jinping / Parikh, Hemang / Zhang, Tongwu / Song, Lei / Jermusyk, Ashley / Chung, Charles C / Zhu, Bin / Zhou, Weiyin / Matters, Gail L / Kurtz, Robert C / Yeager, Meredith / Jensen, Torben Heick / Brown, Kevin M / Ongen, Halit / Bamlet, William R / Murray, Bradley A / McCarthy, Mark I / Chanock, Stephen J / Chatterjee, Nilanjan / Wolpin, Brian M / Smith, Jill P / Olson, Sara H / Petersen, Gloria M / Shi, Jianxin / Amundadottir, Laufey. ·Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, USA. · Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark. · Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, USA. · Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, USA. · Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, FDA, Jefferson, Missouri, USA. · Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, Maryland, USA. · Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. · Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, UK. · Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA. · Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA. · Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, New York, USA. · Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland. · Department of Health Sciences Research, Division of Epidemiology, Mayo Clinic, Rochester, Minnesota, USA. · The Eli and Edythe L Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, Cambridge, Massachusetts, USA. · Oxford NIHR Biomedical Research Centre, Churchill Hospital, Headington, Oxford, UK. · Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. · Division of Gastroenterology and Hepatology, Georgetown University Hospital, Washington, D.C., USA. · Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, New York, USA. ·Gut · Pubmed #28634199.

ABSTRACT: OBJECTIVE: To elucidate the genetic architecture of gene expression in pancreatic tissues. DESIGN: We performed expression quantitative trait locus (eQTL) analysis in histologically normal pancreatic tissue samples (n=95) using RNA sequencing and the corresponding 1000 genomes imputed germline genotypes. Data from pancreatic tumour-derived tissue samples (n=115) from The Cancer Genome Atlas were included for comparison. RESULTS: We identified 38 615 CONCLUSIONS: We have identified

10 Article Detection of early pancreatic ductal adenocarcinoma with thrombospondin-2 and CA19-9 blood markers. 2017

Kim, Jungsun / Bamlet, William R / Oberg, Ann L / Chaffee, Kari G / Donahue, Greg / Cao, Xing-Jun / Chari, Suresh / Garcia, Benjamin A / Petersen, Gloria M / Zaret, Kenneth S. ·Institute for Regenerative Medicine, Department of Cell and Developmental Biology, Abramson Cancer Center (Tumor Biology Program), Perelman School of Medicine, University of Pennsylvania, 9-131 Smilow Center for Translational Research, 3400 Civic Center Boulevard, Philadelphia, PA 19104-5157, USA. · Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA. · Epigenetics Program, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. · Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA. · Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA. · Institute for Regenerative Medicine, Department of Cell and Developmental Biology, Abramson Cancer Center (Tumor Biology Program), Perelman School of Medicine, University of Pennsylvania, 9-131 Smilow Center for Translational Research, 3400 Civic Center Boulevard, Philadelphia, PA 19104-5157, USA. zaret@upenn.edu. ·Sci Transl Med · Pubmed #28701476.

ABSTRACT: Markers are needed to facilitate early detection of pancreatic ductal adenocarcinoma (PDAC), which is often diagnosed too late for effective therapy. Starting with a PDAC cell reprogramming model that recapitulated the progression of human PDAC, we identified secreted proteins and tested a subset as potential markers of PDAC. We optimized an enzyme-linked immunosorbent assay (ELISA) using plasma samples from patients with various stages of PDAC, from individuals with benign pancreatic disease, and from healthy controls. A phase 1 discovery study (

11 Article Association between Alcohol Consumption, Folate Intake, and Risk of Pancreatic Cancer: A Case-Control Study. 2017

Yallew, Winta / Bamlet, William R / Oberg, Ann L / Anderson, Kristin E / Olson, Janet E / Sinha, Rashmi / Petersen, Gloria M / Stolzenberg-Solomon, Rachael Z / Jansen, Rick J. ·Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA. Bamlet.William4@mayo.edu. · Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA. Oberg.Ann@mayo.edu. · Department of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN 55455, USA. ander116@umn.edu. · Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA. Olson.Janet@mayo.edu. · Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20850, USA. sinhar@mail.nih.gov. · Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA. Petersen.Gloria@mayo.edu. · Department of Epidemiology, National Institutes of Health, Bethesda, MD 20850, USA. Rachael.Solomon@nih.gov. · Department of Public Health, North Dakota State University, Fargo, ND 58102, USA. rick.jansen@ndsu.edu. ·Nutrients · Pubmed #28468303.

ABSTRACT: Pancreatic cancer is one of the most fatal common cancers affecting both men and women, representing about 3% of all new cancer cases in the United States. In this study, we aimed to investigate the association of pancreatic cancer risk with alcohol consumption as well as folate intake. We performed a case-control study of 384 patients diagnosed with pancreatic cancer from May 2004 to December 2009 and 983 primary care healthy controls in a largely white population (>96%). Our findings showed no significant association between risk of pancreatic cancer and either overall alcohol consumption or type of alcohol consumed (drinks/day). Our study showed dietary folate intake had a modest effect size, but was significantly inversely associated with pancreatic cancer (odds ratio (OR) = 0.99, p < 0.0001). The current study supports the hypothesis that pancreatic cancer risk is reduced with higher food-based folate intake.

12 Article Genetically Predicted Telomere Length is not Associated with Pancreatic Cancer Risk. 2017

Antwi, Samuel O / Bamlet, William R / Broderick, Brendan T / Chaffee, Kari G / Oberg, Ann / Jatoi, Aminah / Boardman, Lisa A / Petersen, Gloria M. ·Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota. · Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota. · Department of Medical Oncology, Mayo Clinic, Rochester, Minnesota. · Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. · Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota. petersen.gloria@mayo.edu. ·Cancer Epidemiol Biomarkers Prev · Pubmed #28264873.

ABSTRACT:

13 Article Immunosuppressive CD14 2017

Javeed, Naureen / Gustafson, Michael P / Dutta, Shamit K / Lin, Yi / Bamlet, William R / Oberg, Ann L / Petersen, Gloria M / Chari, Suresh T / Dietz, Allan B / Mukhopadhyay, Debabrata. ·Department of Biochemistry and Molecular Biology, Mayo Clinic , Rochester, MN, USA. · Human Cellular Therapy Laboratory, Division of Transfusion Medicine, Department of Laboratory Medicine and Pathology, Mayo Clinic , Rochester, MN, USA. · Division of Hematology, Mayo Clinic , Rochester, MN, USA. · Department of Health Sciences Research, Mayo Clinic , Rochester, MN, USA. · Division of Gastroenterology and Hepatology, Mayo Clinic , Rochester, MN, USA. ·Oncoimmunology · Pubmed #28197368.

ABSTRACT: Immunological strategies to treat pancreatic cancer offer new therapeutic approaches to improve patient outcomes. Understanding alterations in the immune systems of pancreatic cancer patients will likely lead to advances in immunotherapy for the disease. We profiled peripheral blood leukocytes from pancreatic cancer patients (

14 Article EUS-guided fine-needle injection of gemcitabine for locally advanced and metastatic pancreatic cancer. 2017

Levy, Michael J / Alberts, Steven R / Bamlet, William R / Burch, Patrick A / Farnell, Michael B / Gleeson, Ferga C / Haddock, Michael G / Kendrick, Michael L / Oberg, Ann L / Petersen, Gloria M / Takahashi, Naoki / Chari, Suresh T. ·Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA. · Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA. · Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA. · Department of Surgery, Mayo Clinic, Rochester, Minnesota, USA. · Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA. · Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA. · Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA. ·Gastrointest Endosc · Pubmed #27889543.

ABSTRACT: BACKGROUND AND AIMS: Among the greatest hurdles to pancreatic cancer (PC) therapy is the limited tissue penetration of systemic chemotherapy because of tumor desmoplasia. The primary study aim was to determine the toxicity profile of EUS-guided fine-needle injection (EUS-FNI) with gemcitabine. Secondary endpoints included the ability to disease downstage leading to an R0 resection and overall survival (OS) at 6 months, 12 months, and 5 years after therapy. METHODS: In a prospective study from a tertiary referral center, gemcitabine (38 mg/mL) EUS-FNI was performed in patients with PC before conventional therapy. Initial and delayed adverse events (AEs) were assessed within 72 hours and 4 to 14 days after EUS-FNI, respectively. Patients were followed for ≥5 years or until death. RESULTS: Thirty-six patients with stage II (n = 3), stage III (n = 20), or stage IV (n = 13) disease underwent gemcitabine EUS-FNI with 2.5 mL (.7-7.0 mg) total volume of injectate per patient. There were no initial or delayed AEs reported. Thirty-five patients (97.2%) were deceased at the time of analysis with a median 10.3 months of follow-up (range, 3.1-63.9). OS at 6 months and 12 months was 78% and 44%, respectively. The median OS was 10.4 months (range, 2.7-68). Among patients with stage III unresectable disease, 4 (20%) were downstaged and underwent an R0 resection. CONCLUSIONS: Our study suggests the feasibility, safety, and potential efficacy of gemcitabine EUS-FNI for PC. Additional data are needed to verify these observations and to determine the potential role relative to conventional multimodality therapy.

15 Article Functional characterization of a chr13q22.1 pancreatic cancer risk locus reveals long-range interaction and allele-specific effects on DIS3 expression. 2016

Hoskins, Jason W / Ibrahim, Abdisamad / Emmanuel, Mickey A / Manmiller, Sarah M / Wu, Yinglun / O'Neill, Maura / Jia, Jinping / Collins, Irene / Zhang, Mingfeng / Thomas, Janelle V / Rost, Lauren M / Das, Sudipto / Parikh, Hemang / Haake, Jefferson M / Matters, Gail L / Kurtz, Robert C / Bamlet, William R / Klein, Alison / Stolzenberg-Solomon, Rachael / Wolpin, Brian M / Yarden, Ronit / Wang, Zhaoming / Smith, Jill / Olson, Sara H / Andresson, Thorkell / Petersen, Gloria M / Amundadottir, Laufey T. ·Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. · Protein Characterization Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, USA. · Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. · Department of Human Science, NHS, Georgetown University Medical Center, NW, Washington DC, USA. · Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA, USA. · Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. · Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA. · Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, Maryland, USA · Department of Epidemiology, the Bloomberg School of Public Health, Baltimore, Maryland, USA · Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. · Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA · Department of Medicine, Georgetown University Hospital, Washington, DC, and Department of Medicine, Penn State University College of Medicine, Hershey PA, USA. ·Hum Mol Genet · Pubmed #28172817.

ABSTRACT: Genome-wide association studies (GWAS) have identified multiple common susceptibility loci for pancreatic cancer. Here we report fine-mapping and functional analysis of one such locus residing in a 610 kb gene desert on chr13q22.1 (marked by rs9543325). The closest candidate genes, KLF5, KLF12, PIBF1, DIS3 and BORA, range in distance from 265-586 kb. Sequencing three sub-regions containing the top ranked SNPs by imputation P-value revealed a 30 bp insertion/deletion (indel) variant that was significantly associated with pancreatic cancer risk (rs386772267, P = 2.30 × 10

16 Article Genetic variations associated with gemcitabine treatment outcome in pancreatic cancer. 2016

Li, Liang / Zhang, Jian-Wei / Jenkins, Gregory / Xie, Fang / Carlson, Erin E / Fridley, Brooke L / Bamlet, William R / Petersen, Gloria M / McWilliams, Robert R / Wang, Liewei. ·aDepartment of Oncology bKey Laboratory of Biotechnology of Antibiotics, the National Health and Family Planning Commission (NHFPC), Institute of Medicinal Biotechnology cDepartment of Abdominal Surgery, Cancer Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China dDepartment of Molecular Pharmacology and Experimental Therapeutics, Division of Clinical Pharmacology eDepartment of Health Sciences Research, Division of Biomedical Statistics and Informatics fDepartment of Oncology, Mayo Clinic, Rochester, Minnesota gDepartment of Biostatistics, University of Kansas Medical Center, Kansas City, Kansas, USA. ·Pharmacogenet Genomics · Pubmed #27749787.

ABSTRACT: BACKGROUND: Pancreatic cancer is a rapidly fatal disease with gemcitabine remaining the first-line therapy. We performed a genotype-phenotype association study to identify biomarkers for predicting gemcitabine treatment outcome. MATERIALS AND METHODS: We selected the top 200 single nucleotide polymorphisms (SNPs) identified from our previous genome-wide association study to associate with overall survival using 400 patients treated with/or without gemcitabine, followed by imputation analysis for regions around the identified SNPs and a replication study using an additional 537 patients by the TaqMan genotyping assay. Functional validation was performed using quantitative reverse transcription-PCR for gemcitabine-induced expression in genotyped lymphoblastoid cell lines and siRNA knockdown for candidate genes in pancreatic cancer cell lines. RESULTS: Four SNPs in chromosome 1, 3, 9, and 20 showed an interaction with gemcitabine from the discovery cohort of 400 patients (P<0.01). Subsequently, we selected those four genotyped plus four imputed SNPs for SNP×gemcitabine interaction analysis using the secondary validation cohort. Two imputed SNPs in CDH4 and KRT8P35 showed a trend in interaction with gemcitabine treatment. The lymphoblastoid cell lines with the variant sequences showed increased CDH4 expression compared with the wild-type cells after gemcitabine exposure. Knockdown of CDH4 significantly desensitized pancreatic cancer cells to gemcitabine cytotoxicity. The CDH4 SNPs that interacted with treatment are more predictive than prognostic. CONCLUSION: We identified SNPs with gemcitabine-dependent effects on overall survival. CDH4 might contribute to variations in gemcitabine response. These results might help us to better predict gemcitabine response in pancreatic cancer.

17 Article Metformin Use and Survival of Patients With Pancreatic Cancer: A Cautionary Lesson. 2016

Chaiteerakij, Roongruedee / Petersen, Gloria M / Bamlet, William R / Chaffee, Kari G / Zhen, David B / Burch, Patrick A / Leof, Emma R / Roberts, Lewis R / Oberg, Ann L. ·Roongruedee Chaiteerakij and Lewis R. Roberts, Mayo Clinic College of Medicine and Mayo Clinic Cancer Center · Gloria M. Petersen, William R. Bamlet, Kari G. Chaffee, David B. Zhen, Patrick A. Burch, Emma R. Leof, and Ann L. Oberg, Mayo Clinic, Rochester, MN · Roongruedee Chaiteerakij, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand · and David B. Zhen, University of Michigan, Ann Arbor, MI. ·J Clin Oncol · Pubmed #27069086.

ABSTRACT: PURPOSE: The inclusion of metformin in the treatment arms of cancer clinical trials is based on improved survival that has been demonstrated in retrospective epidemiologic studies; however, unintended biases may exist when analysis is performed by using a conventional Cox proportional hazards regression model with dichotomous ever/never categorization. We examined the impact of metformin exposure definitions, analytical methods, and patient selection on the estimated effect size of metformin exposure on survival in a large cohort of patients with pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: Of newly diagnosed patients with PDAC with diabetes, 980 were retrospectively included, and exposure to metformin documented. Median survival was assessed by using Kaplan-Meier and log-rank methods. Hazard ratios (HR) and 95% CIs were computed to compare time-varying covariate analysis with conventional Cox proportional hazards regression analysis. RESULTS: Median survival of metformin users versus nonusers was 9.9 versus 8.9 months, respectively. By the time-varying covariate analysis, metformin use was not statistically significantly associated with improved survival (HR, 0.93; 95% CI, 0.81 to1.07; P = .28). There was no evidence of benefit in the subset of patients who were naïve to metformin at the time of PDAC diagnosis (most representative of patients enrolled in clinical trials; HR, 1.01; 95% CI, 0.80 to 1.30; P = .89); however, when the analysis was performed by using the conventional Cox model, an artificial survival benefit of metformin was detected (HR, 0.88; 95% CI, 0.77 to 1.01; P = .08), which suggested biased results from the conventional Cox analysis. CONCLUSION: Our findings did not suggest the benefit of metformin use after patients are diagnosed with PDAC. We highlight the importance of patient selection and appropriate statistical analytical methods when studying medication exposure and cancer survival.

18 Article Pancreatic cancer: associations of inflammatory potential of diet, cigarette smoking and long-standing diabetes. 2016

Antwi, Samuel O / Oberg, Ann L / Shivappa, Nitin / Bamlet, William R / Chaffee, Kari G / Steck, Susan E / Hébert, James R / Petersen, Gloria M. ·Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, 200 First Street SW, Charlton 6-243, Rochester, MN 55905, USA and. · Cancer Prevention and Control Program and Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA. ·Carcinogenesis · Pubmed #26905587.

ABSTRACT: Epidemiologic studies show strong associations between pancreatic cancer (PC) and inflammatory stimuli or conditions such as cigarette smoking and diabetes, suggesting that inflammation may play a key role in PC. Studies of dietary patterns and cancer outcomes also suggest that diet might influence an individual's risk of PC by modulating inflammation. We therefore examined independent and joint associations between inflammatory potential of diet, cigarette smoking and long-standing (≥5 years) type II diabetes in relation to risk of PC. Analyses included data from 817 cases and 1756 controls. Inflammatory potential of diet was measured using the dietary inflammatory index (DII), calculated from dietary intake assessed via a 144-item food frequency questionnaire, and adjusted for energy intake. Information on smoking and diabetes were obtained via risk factor questionnaires. Associations were examined using multivariable-adjusted logistic regression. Higher DII scores, reflecting a more proinflammatory diet, were associated with increased risk of PC [odds ratio (OR)Quintile 5 versus 1 = 2.54, 95% confidence interval (CI) = 1.87-3.46, P trend < 0.0001]. Excess risk of PC also was observed among former (OR = 1.29, 95% CI = 1.07-1.54) and current (OR = 3.40, 95% CI = 2.28-5.07) smokers compared with never smokers, and among participants with long-standing diabetes (OR = 3.09, 95% CI = 2.02-4.72) compared with nondiabetics. Joint associations were observed for the combined effects of having greater than median DII score, and being a current smoker (OR = 4.79, 95% CI = 3.00-7.65) or having long-standing diabetes (OR = 6.03, 95% CI = 3.41-10.85). These findings suggest that a proinflammatory diet may act as cofactor with cigarette smoking and diabetes to increase risk of PC beyond the risk of any of these factors alone.

19 Article GSK-3β Governs Inflammation-Induced NFATc2 Signaling Hubs to Promote Pancreatic Cancer Progression. 2016

Baumgart, Sandra / Chen, Nai-Ming / Zhang, Jin-San / Billadeau, Daniel D / Gaisina, Irina N / Kozikowski, Alan P / Singh, Shiv K / Fink, Daniel / Ströbel, Philipp / Klindt, Caroline / Zhang, Lizhi / Bamlet, William R / Koenig, Alexander / Hessmann, Elisabeth / Gress, Thomas M / Ellenrieder, Volker / Neesse, Albrecht. ·Department of Gastroenterology, Endocrinology, Infectiology and Metabolism, University of Marburg, Marburg, Germany. · Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Göttingen, Germany. · Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, Minnesota. · Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, Illinois. · Barrow Brain Tumor Research Center, St. Joseph's Hospital and Medical Center, Phoenix, Arizona. · Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany. · Division of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota. · Division of Biostatistics, College of Medicine, Mayo Clinic, Rochester, Minnesota. · Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Göttingen, Germany. albrecht.neesse@med.uni-goettingen.de. ·Mol Cancer Ther · Pubmed #26823495.

ABSTRACT: We aimed to investigate the mechanistic, functional, and therapeutic role of glycogen synthase kinase 3β (GSK-3β) in the regulation and activation of the proinflammatory oncogenic transcription factor nuclear factor of activated T cells (NFATc2) in pancreatic cancer. IHC, qPCR, immunoblotting, immunofluorescence microscopy, and proliferation assays were used to analyze mouse and human tissues and cell lines. Protein-protein interactions and promoter regulation were analyzed by coimmunoprecipitation, DNA pulldown, reporter, and ChIP assays. Preclinical assays were performed using a variety of pancreatic cancer cells lines, xenografts, and a genetically engineered mouse model (GEMM). GSK-3β-dependent SP2 phosphorylation mediates NFATc2 protein stability in the nucleus of pancreatic cancer cells stimulating pancreatic cancer growth. In addition to protein stabilization, GSK-3β also maintains NFATc2 activation through a distinct mechanism involving stabilization of NFATc2-STAT3 complexes independent of SP2 phosphorylation. For NFATc2-STAT3 complex formation, GSK-3β-mediated phosphorylation of STAT3 at Y705 is required to stimulate euchromatin formation of NFAT target promoters, such as cyclin-dependent kinase-6, which promotes tumor growth. Finally, preclinical experiments suggest that targeting the NFATc2-STAT3-GSK-3β module inhibits proliferation and tumor growth and interferes with inflammation-induced pancreatic cancer progression in Kras(G12D) mice. In conclusion, we describe a novel mechanism by which GSK-3β fine-tunes NFATc2 and STAT3 transcriptional networks to integrate upstream signaling events that govern pancreatic cancer progression and growth. Furthermore, the therapeutic potential of GSK-3β is demonstrated for the first time in a relevant Kras and inflammation-induced GEMM for pancreatic cancer.

20 Article Risk Factors for Early-Onset and Very-Early-Onset Pancreatic Adenocarcinoma: A Pancreatic Cancer Case-Control Consortium (PanC4) Analysis. 2016

McWilliams, Robert R / Maisonneuve, Patrick / Bamlet, William R / Petersen, Gloria M / Li, Donghui / Risch, Harvey A / Yu, Herbert / Fontham, Elizabeth T H / Luckett, Brian / Bosetti, Cristina / Negri, Eva / La Vecchia, Carlo / Talamini, Renato / Bueno de Mesquita, H Bas / Bracci, Paige / Gallinger, Steven / Neale, Rachel E / Lowenfels, Albert B. ·From the *Department of Oncology, Mayo Clinic, Rochester, MN; †Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy; ‡Division of Biostatistics, Mayo Clinic; §Department of Health Sciences Research, Mayo Clinic, Rochester, MN; ∥Department of Gastrointestinal Medical Oncology, UT MD Anderson Cancer Center, Houston, TX; ¶Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT; #Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI; **Louisiana State University School of Public Health, New Orleans, LA; ††Tulane School of Public Health, New Orleans, LA; ‡‡Department of Epidemiology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," and §§Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy; ∥∥S.O.C. Epidemiologia e Biostatistica, Centro di Riferimento Oncologico, IRCCS, Aviano (PN), Italy; ¶¶National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands; Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands; School of Public Health, Imperial College London, London, United Kingdom; ##Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA; ***Division of General Surgery, University of Toronto, Toronto, Ontario, Canada; †††Cancer and Population Studies Group, QIMR Berghofer Medical Research Institute, Brisbane, Australia; and ‡‡‡Department of Surgery, Department of Family Medicine, New York Medical College, Valhalla, NY. ·Pancreas · Pubmed #26646264.

ABSTRACT: OBJECTIVES: While pancreatic cancer (PC) most often affects older adults, to date, there has been no comprehensive assessment of risk factors among PC patients younger than 60 years. METHODS: We defined early-onset PC (EOPC) and very-early-onset PC (VEOPC) as diagnosis of PC in patients younger than 60 and 45 years, respectively. We pooled data from 8 case-control studies, including 1954 patients with EOPC and 3278 age- and sex-matched control subjects. Logistic regression analysis was performed to identify associations with EOPC and VEOPC. RESULTS: Family history of PC, diabetes mellitus, smoking, obesity, and pancreatitis were associated with EOPC. Alcohol use equal to or greater than 26 g daily also was associated with increased risk of EOPC (odds ratio, 1.49; 95% confidence interval, 1.21-1.84), and there appeared to be a dose- and age-dependent effect of alcohol on risk. The point estimate for risk of VEOPC was an odds ratio of 2.18 (95% confidence interval, 1.17-4.09). CONCLUSIONS: The established risk factors for PC, including smoking, diabetes, family history of PC, and obesity, also apply to EOPC. Alcohol intake appeared to have an age-dependent effect; the strongest association was with VEOPC.

21 Article Prevalence of Pathogenic Mutations in Cancer Predisposition Genes among Pancreatic Cancer Patients. 2016

Hu, Chunling / Hart, Steven N / Bamlet, William R / Moore, Raymond M / Nandakumar, Kannabiran / Eckloff, Bruce W / Lee, Yean K / Petersen, Gloria M / McWilliams, Robert R / Couch, Fergus J. ·Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota. · Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota. · Medical Genome Facility, Mayo Clinic, Rochester, Minnesota. · Department of Oncology, Mayo Clinic, Rochester, Minnesota. · Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota. Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota. couch.fergus@mayo.edu. ·Cancer Epidemiol Biomarkers Prev · Pubmed #26483394.

ABSTRACT: The prevalence of germline pathogenic mutations in a comprehensive panel of cancer predisposition genes is not well-defined for patients with pancreatic ductal adenocarcinoma (PDAC). To estimate the frequency of mutations in a panel of 22 cancer predisposition genes, 96 patients unselected for a family history of cancer who were recruited to the Mayo Clinic Pancreatic Cancer patient registry over a 12-month period were screened by next-generation sequencing. Fourteen pathogenic mutations in 13 patients (13.5%) were identified in eight genes: four in ATM, two in BRCA2, CHEK2, and MSH6, and one in BARD1, BRCA1, FANCM, and NBN. These included nine mutations (9.4%) in established pancreatic cancer genes. Three mutations were found in patients with a first-degree relative with PDAC, and 10 mutations were found in patients with first- or second-degree relatives with breast, pancreas, colorectal, ovarian, or endometrial cancers. These results suggest that a substantial proportion of patients with PDAC carry germline mutations in predisposition genes associated with other cancers and that a better understanding of pancreatic cancer risk will depend on evaluation of families with broad constellations of tumors. These findings highlight the need for recommendations governing germline gene-panel testing of patients with pancreatic cancer.

22 Article Impact of Intratumoral Inflammation on Survival After Pancreatic Cancer Resection. 2016

Hart, Phil A / Smyrk, Thomas C / Bamlet, William R / Chari, Suresh T. ·From the *Division of Gastroenterology and Hepatology, †Department of Pathology, ‡Health Sciences Research, Mayo Clinic Rochester, MN. ·Pancreas · Pubmed #26474423.

ABSTRACT: OBJECTIVES: Pancreatic cancer (PaC) frequently results in death despite surgical resection. We sought to evaluate whether inflammation in the primary tumor was associated with early death after surgical resection. METHODS: In this case-control study, we identified 21 individuals who died less than 12 months after surgery for PaC and 42 controls who survived more than 36 months after surgery. Differences in the composition of host inflammatory response between the groups were evaluated with univariate comparisons and odds ratios for early death were calculated using logistic regression modeling. RESULTS: Cases were more likely to have a high tumor grade (90.5% vs 26.2%; P < 0.01). The odds of early death were increased in those with a high-grade tumor (unadjusted odds ratio, 26.77; 95% confidence interval, 5.35-134.07; P < 0.01). Conversely, the density (high vs low) of inflammatory cells in tumors was similar between the groups, and odds of early death were not associated with any inflammatory marker. CONCLUSIONS: High tumor grade, but not altered density of inflammatory cells in the intratumoral compartment, is associated with increased odds of early death after PaC resection. Future studies evaluating the host response in multiple tumor compartments with advanced histologic techniques is needed to further elucidate the role of inflammation in PaC.

23 Article Tumor cell expression of MMP3 as a prognostic factor for poor survival in pancreatic, pulmonary, and mammary carcinoma. 2015

Mehner, Christine / Miller, Erin / Nassar, Aziza / Bamlet, William R / Radisky, Evette S / Radisky, Derek C. ·Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA. · Department of Pathology, Mayo Clinic, Jacksonville, FL, USA. · Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA. ·Genes Cancer · Pubmed #26807201.

ABSTRACT: Breast, lung, and pancreatic cancers collectively represent one third of all diagnosed tumors and are responsible for almost 40% of overall cancer mortality. Despite improvements in current treatments, efforts to develop more specific therapeutic options are warranted. Here we identify matrix metalloproteinase 3 (MMP3) as a potential target within all three of these tumor types. MMP3 has previously been shown to induce expression of Rac1b, a tumorigenic splice isoform of Rac1. In this study we find that MMP3 and Rac1b proteins are both strongly expressed by the tumor cells of all three tumor types and that expression of MMP3 protein is prognostic of poor survival in pancreatic cancer patients. We also find that MMP3 gene expression can serve as a prognostic marker for patient survival in breast and lung cancer. These results suggest an oncogenic MMP3-Rac1b signaling axis as a driver of tumor progression in three common poor prognosis tumor types, further suggesting that new therapies to target these pathways could have substantial therapeutic benefit.

24 Article Exposure to environmental chemicals and heavy metals, and risk of pancreatic cancer. 2015

Antwi, Samuel O / Eckert, Elizabeth C / Sabaque, Corinna V / Leof, Emma R / Hawthorne, Kieran M / Bamlet, William R / Chaffee, Kari G / Oberg, Ann L / Petersen, Gloria M. ·Division of Epidemiology, Health Sciences Research, Mayo Clinic, 200 First Street SW, Charlton 6-243, Rochester, MN, 55905, USA. · Department of Clinical and Translational Science, Mayo Clinic Graduate School, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA. · Division of Biomedical Statistics and Informatics, Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA. · Division of Epidemiology, Health Sciences Research, Mayo Clinic, 200 First Street SW, Charlton 6-243, Rochester, MN, 55905, USA. Petersen.Gloria@mayo.edu. ·Cancer Causes Control · Pubmed #26293241.

ABSTRACT: PURPOSE: Exposure to various chemicals and heavy metals has been associated with risk of different cancers; however, data on whether such exposures may increase the risk of pancreatic cancer (PC) are very limited and inconclusive. We examined PC risk with self-reported exposures to chemicals and heavy metals. METHODS: The design was a clinic-based, case-control study of data collected from 2000 to 2014 at Mayo Clinic in Rochester, Minnesota, USA. Cases were rapidly ascertained patients diagnosed with pancreatic ductal adenocarcinoma (n = 2,092). Controls were cancer-free patients in primary care clinics (n = 2,353), frequency-matched to cases on age, race, sex, and state/region of residence. Cases and controls completed identical risk factor questionnaires, which included yes/no questions about regular exposure to pesticides, asbestos, benzene, chlorinated hydrocarbons, chromium, and nickel. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) comparing those who affirmed exposure to each of the chemicals/heavy metals to those who reported no regular exposure, adjusting for potential confounders. RESULTS: Self-reported regular exposure to pesticides was associated with increased odds of PC (OR 1.21, 95% CI 1.02-1.44). Regular exposure to asbestos (OR 1.54, 95% CI 1.23-1.92), benzene (OR 1.70, 95% CI 1.23-2.35), and chlorinated hydrocarbons (OR 1.63, 95% CI 1.32-2.02) also was associated with higher odds of PC. Chromium and nickel exposures were not significantly associated with PC. CONCLUSIONS: These findings add to the limited data suggesting that exposure to pesticides, asbestos, benzene, and chlorinated hydrocarbons may increase PC risk. They further support the importance of implementing strategies that reduce exposure to these substances.

25 Article Transcriptomic and Immunohistochemical Profiling of SLC6A14 in Pancreatic Ductal Adenocarcinoma. 2015

Penheiter, Alan R / Erdogan, Sibel / Murphy, Stephen J / Hart, Steven N / Felipe Lima, Joema / Rakhshan Rohakhtar, Fariborz / O'Brien, Daniel R / Bamlet, William R / Wuertz, Ryan E / Smyrk, Thomas C / Couch, Fergus J / Vasmatzis, George / Bender, Claire E / Carlson, Stephanie K. ·Department of Molecular Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. · Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. · Biomedical Statistics and Informatics, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. · Medical Genome Facility, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. · Department of Epidemiology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. · Department of Anatomic Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. · Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. · Department of Radiology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. · Department of Molecular Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA ; Department of Radiology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. ·Biomed Res Int · Pubmed #26106611.

ABSTRACT: We used a target-centric strategy to identify transporter proteins upregulated in pancreatic ductal adenocarcinoma (PDAC) as potential targets for a functional imaging probe to complement existing anatomical imaging approaches. We performed transcriptomic profiling (microarray and RNASeq) on histologically confirmed primary PDAC tumors and normal pancreas tissue from 33 patients, including five patients whose tumors were not visible on computed tomography. Target expression was confirmed with immunohistochemistry on tissue microarrays from 94 PDAC patients. The best imaging target identified was SLC6A14 (a neutral and basic amino acid transporter). SLC6A14 was overexpressed at the transcriptional level in all patients and expressed at the protein level in 95% of PDAC tumors. Very little is known about the role of SLC6A14 in PDAC and our results demonstrate that this target merits further investigation as a candidate transporter for functional imaging of PDAC.

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