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Pancreatic Neoplasms: HELP
Articles by George Zogopoulos
Based on 11 articles published since 2009
(Why 11 articles?)
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Between 2009 and 2019, George Zogopoulos wrote the following 11 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Clinical Trial Mutations in the pancreatic secretory enzymes 2018

Tamura, Koji / Yu, Jun / Hata, Tatsuo / Suenaga, Masaya / Shindo, Koji / Abe, Toshiya / MacGregor-Das, Anne / Borges, Michael / Wolfgang, Christopher L / Weiss, Matthew J / He, Jin / Canto, Marcia Irene / Petersen, Gloria M / Gallinger, Steven / Syngal, Sapna / Brand, Randall E / Rustgi, Anil / Olson, Sara H / Stoffel, Elena / Cote, Michele L / Zogopoulos, George / Potash, James B / Goes, Fernando S / McCombie, Richard W / Zandi, Peter P / Pirooznia, Mehdi / Kramer, Melissa / Parla, Jennifer / Eshleman, James R / Roberts, Nicholas J / Hruban, Ralph H / Klein, Alison Patricia / Goggins, Michael. ·Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. · Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. · Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. · The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. · Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. · Health Sciences Research, Mayo Clinic, Rochester, MN 55905. · Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada M5G 1X5. · Population Sciences Division, Dana-Farber Cancer Institute, Boston, MA 02215. · Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213. · Division of Gastroenterology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104. · Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104. · Pancreatic Cancer Translational Center of Excellence, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104. · Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104. · Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10017. · Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109. · Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201. · The Research Institute of the McGill University Health Centre, McGill University, Montreal, QC, Canada H3H 2R9. · The Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada H3A 1A3. · Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Baltimore, MD 21287. · Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724. · InGenious Targeting Laboratory, Ronkonkoma, NY 11779. · Department of Epidemiology, Bloomberg School of Public Health, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. · Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; mgoggins@jhmi.edu. ·Proc Natl Acad Sci U S A · Pubmed #29669919.

ABSTRACT: To evaluate whether germline variants in genes encoding pancreatic secretory enzymes contribute to pancreatic cancer susceptibility, we sequenced the coding regions of

2 Article Exome-Wide Association Study of Pancreatic Cancer Risk. 2018

Grant, Robert C / Denroche, Robert E / Borgida, Ayelet / Virtanen, Carl / Cook, Natalie / Smith, Alyssa L / Connor, Ashton A / Wilson, Julie M / Peterson, Gloria / Roberts, Nicholas J / Klein, Alison P / Grimmond, Sean M / Biankin, Andrew / Cleary, Sean / Moore, Malcolm / Lemire, Mathieu / Zogopoulos, George / Stein, Lincoln / Gallinger, Steven. ·Ontario Institute for Cancer Research, Toronto, Canada. · Ontario Pancreas Cancer Study, Toronto, Canada. · Princess Margaret Genomics Centre, Toronto, Canada. · Research Institute of the McGill University Health Centre, Montreal, Canada. · Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota. · Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland; Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Melbourne, Australia. · Wohl Cancer Research Centre, Institute of, Cancer Sciences, University of Glasgow, Glasgow, United Kingdom; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom; South Western Sydney Clinical School, Faculty of Medicine, University of NSW, Liverpool, Australia. · Ontario Institute for Cancer Research, Toronto, Canada; Ontario Pancreas Cancer Study, Toronto, Canada. · Ontario Institute for Cancer Research, Toronto, Canada; Ontario Pancreas Cancer Study, Toronto, Canada. Electronic address: steven.gallinger@uhn.ca. ·Gastroenterology · Pubmed #29074453.

ABSTRACT: We conducted a case-control exome-wide association study to discover germline variants in coding regions that affect risk for pancreatic cancer, combining data from 5 studies. We analyzed exome and genome sequencing data from 437 patients with pancreatic cancer (cases) and 1922 individuals not known to have cancer (controls). In the primary analysis, BRCA2 had the strongest enrichment for rare inactivating variants (17/437 cases vs 3/1922 controls) (P = 3.27x10

3 Article Pancreatic adenocarcinoma: A simple CT score for predicting margin-positive resection in patients with resectable disease. 2017

Cassinotto, Christophe / Dohan, Anthony / Zogopoulos, George / Chiche, Laurence / Laurent, Christophe / Sa-Cunha, Antonio / Cuggia, Adeline / Reinhold, Caroline / Gallix, Benoît. ·Department of Radiology, Royal Victoria Hospital, McGill University Health Center, Montreal, Canada; Department of Diagnostic and Interventional Radiology, Hôpital Haut-Lévêque, University Hospital of Bordeaux, Pessac, France. Electronic address: Cassinotto@gmail.com. · Department of Radiology, Royal Victoria Hospital, McGill University Health Center, Montreal, Canada. Electronic address: Anthony.dohan@mcgill.ca. · Department of Visceral Surgery, Royal Victoria Hospital, McGill University Health Center, Montreal, Canada. Electronic address: George.zogopoulos@mcgill.ca. · Department of Visceral Surgery, Hôpital Haut-Lévêque, University Hospital of Bordeaux, Pessac, France. Electronic address: Laurence.chiche@chu-bordeaux.fr. · Department of Visceral Surgery, Hôpital Haut-Lévêque, University Hospital of Bordeaux, Pessac, France. Electronic address: Christophe.laurent@chu-bordeaux.fr. · Department of Visceral Surgery, Hôpital Paul Brousse, Assistance Publique des Hôpitaux de Paris, Villejuif, France. Electronic address: antonio.sacunha@aphp.fr. · Department of Visceral Surgery, Royal Victoria Hospital, McGill University Health Center, Montreal, Canada. Electronic address: adeline.cuggia@mcgill.ca. · Department of Radiology, Royal Victoria Hospital, McGill University Health Center, Montreal, Canada. Electronic address: caroline.reinhold@mcgill.ca. · Department of Radiology, Royal Victoria Hospital, McGill University Health Center, Montreal, Canada. Electronic address: benoit.gallix@mcgill.ca. ·Eur J Radiol · Pubmed #28987689.

ABSTRACT: BACKGROUND: Negative-margin status is a prognostic indicator for long-term survival following curative intent resection for pancreatic adenocarcinoma. Patients at increased risk for positive-margin resections may benefit from neoadjuvant chemotherapy prior to resection. METHODS: We retrospectively analyzed preoperative computed-tomography (CT) scans in 108 consecutive patients that underwent curative intent resection for a resectable pancreatic ductal adenocarcinoma from 2009 to 2016 in two academic hospitals. Two radiologists independently staged the tumor, including tumor location, size, and tumor-to-superior mesenteric/portal vein (SMV/PV) contact. Uni and multivariate analysis were performed to identify independent predictors of an R1 resection. RESULTS: Twenty-nine patients had an R1 resection (26.9%). Tumor size, location, and presence of tumor-to-SMV/PV contact were significantly associated with an R1 resection. In multivariate analysis, the independent parameters associated with resection status were: tumor size (R CONCLUSIONS: A simple score based on tumor location and size can accurately predict patients at high-risk of an R1 resection.

4 Article Resectable pancreatic adenocarcinoma: Role of CT quantitative imaging biomarkers for predicting pathology and patient outcomes. 2017

Cassinotto, Christophe / Chong, Jaron / Zogopoulos, George / Reinhold, Caroline / Chiche, Laurence / Lafourcade, Jean-Pierre / Cuggia, Adeline / Terrebonne, Eric / Dohan, Anthony / Gallix, Benoît. ·Department of Radiology, Royal Victoria Hospital, McGill University Health Center, 1001 Boulevard Decarie, Montreal, QC H4A 3J1, Canada. Electronic address: Cassinotto@gmail.com. · Department of Radiology, Royal Victoria Hospital, McGill University Health Center, 1001 Boulevard Decarie, Montreal, QC H4A 3J1, Canada. Electronic address: jaron.chong@mcgill.ca. · Department of Visceral Surgery, Royal Victoria Hospital, McGill University Health Center, 1001 Boulevard Decarie, Montreal, QC H4A 3J1, Canada. Electronic address: George.zogopoulos@mcgill.ca. · Department of Radiology, Royal Victoria Hospital, McGill University Health Center, 1001 Boulevard Decarie, Montreal, QC H4A 3J1, Canada. Electronic address: caroline.reinhold@mcgill.ca. · Department of Visceral Surgery, Hôpital Haut-Lévêque, University Hospital of Bordeaux, 1 Avenue de Magellan, 33604 Pessac, France. Electronic address: Laurence.chiche@chu-bordeaux.fr. · Department of Diagnostic and Interventional Radiology, Hôpital Haut-Lévêque, University Hospital of Bordeaux, 1 avenue de Magellan, 33604 Pessac, France. Electronic address: jean-pierre.lafourcade@chu-bordeaux.fr. · Department of Visceral Surgery, Royal Victoria Hospital, McGill University Health Center, 1001 Boulevard Decarie, Montreal, QC H4A 3J1, Canada. Electronic address: adeline.cuggia@mcgill.ca. · Department of Digestive Oncology, Hôpital Haut-Lévêque, University Hospital of Bordeaux, 1 Avenue de Magellan, 33604 Pessac, France. Electronic address: eric.terrebonne@mcgill.ca. · Department of Radiology, Royal Victoria Hospital, McGill University Health Center, 1001 Boulevard Decarie, Montreal, QC H4A 3J1, Canada. Electronic address: Anthony.dohan@mcgill.ca. · Department of Radiology, Royal Victoria Hospital, McGill University Health Center, 1001 Boulevard Decarie, Montreal, QC H4A 3J1, Canada. Electronic address: benoit.gallix@mcgill.ca. ·Eur J Radiol · Pubmed #28583627.

ABSTRACT: BACKGROUNDS: Patients with a pancreatic cancer amenable to surgery still have a poor prognosis and high risk of post-operative recurrence. We aimed to assess the value of quantitative imaging biomarkers using computed-tomography (CT) texture analysis to evaluate the pathologic tumor aggressiveness and predict disease-free survival (DFS) in patients with resectable pancreatic adenocarcinoma. METHODS: We retrospectively performed attenuation measurements and texture analysis on the portal-venous phase of the pre-operative CT scan of 99 patients that underwent resection of a pancreatic ductal adenocarcinoma in two university hospitals. Tumor attenuation parameters included: mean attenuation value of the whole tumor (WHOLE-AV), and of the most hypoattenuating area within the tumor (CENTRAL-AV). Tumor heterogeneity parameters included: standard deviation, entropy, skewness, and kurtosis. RESULTS: Tumor attenuation parameters showed significant association with the tumor differentiation grade (CENTRAL-AV, Odds ratio (OR) 0.968, 95% confidence interval (CI) 0.94-0.998) and lymph node invasion (WHOLE-AV, OR 0.886, CI 0.823-0.955). Variables associated with early-recurrence were: lymph node ratio (R CONCLUSION: Tumors that are more hypoattenuating on the portal-venous phase on CT scan are potentially more aggressive with higher tumor grade, greater lymph node invasion, and shorter DFS.

5 Article Reg proteins promote acinar-to-ductal metaplasia and act as novel diagnostic and prognostic markers in pancreatic ductal adenocarcinoma. 2016

Li, Qing / Wang, Hao / Zogopoulos, George / Shao, Qin / Dong, Kun / Lv, Fudong / Nwilati, Karam / Gui, Xian-Yong / Cuggia, Adeline / Liu, Jun-Li / Gao, Zu-Hua. ·Fraser Laboratories for Diabetes Research, Department of Medicine, McGill University Health Centre, Montreal, QC, Canada. · Department of Oncology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, China. · Department of Surgery, McGill University Health Centre, Montreal, QC, Canada. · Quebec Pancreas Cancer Study, McGill University Health Centre, Montreal, QC, Canada. · Department of Pathology, McGill University Health Centre, Montreal, QC, Canada. · Department of Pathology, You An Hospital, Capital Medical University, Beijing, China. · Department of Pathology, University of Calgary, Calgary, AB, Canada. ·Oncotarget · Pubmed #27788482.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignant tumor. Acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) are both precursor lesions that lead to the development of PDAC. Reg family proteins (Reg1A, 1B, 3A/G, 4) are a group of calcium-dependent lectins that promote islet growth in response to inflammation and/or injuries. The aim of this study was to establish a role for Reg proteins in the development of PDAC and their clinical value as biomarkers. We found that Reg1A and Reg3A/G were highly expressed in the ADM tissues by immunohistochemistry. In the 3-dimensional culture of mouse acinar cells, Reg3A promoted ADM formation with concurrent activation of mitogen-acitvated protein kinase. Upregulation of Reg1A and Reg1B levels was observed as benign ductal epithelium progresses from PanIN to invasive PDAC. Patients with PDAC showed significantly higher serum levels of Reg1A and Reg1B than matching healthy subjects. These results were further validated by the quantification of Reg 1A and 1B mRNA levels in the microdissected tissues (22- and 6-fold increases vs. non-tumor tissues). Interestingly, patients with higher levels of Reg1A and 1B exhibited improved survival rate than those with lower levels. Furthermore, tissue expressions of Reg1A, Reg1B, and Reg4 could differentiate metastatic PDAC in the liver from intrahepatic cholangiocarcinoma with 92% sensitivity and 95% specificity. Overall, our results demonstrate the upregulation of Reg proteins during PDAC development. If validated in larger scale, Reg1A and Reg1B could become clinical markers for detecting early stages of PDAC, monitoring therapeutic response, and/or predicting patient's prognosis.

6 Article A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns. 2016

Notta, Faiyaz / Chan-Seng-Yue, Michelle / Lemire, Mathieu / Li, Yilong / Wilson, Gavin W / Connor, Ashton A / Denroche, Robert E / Liang, Sheng-Ben / Brown, Andrew M K / Kim, Jaeseung C / Wang, Tao / Simpson, Jared T / Beck, Timothy / Borgida, Ayelet / Buchner, Nicholas / Chadwick, Dianne / Hafezi-Bakhtiari, Sara / Dick, John E / Heisler, Lawrence / Hollingsworth, Michael A / Ibrahimov, Emin / Jang, Gun Ho / Johns, Jeremy / Jorgensen, Lars G T / Law, Calvin / Ludkovski, Olga / Lungu, Ilinca / Ng, Karen / Pasternack, Danielle / Petersen, Gloria M / Shlush, Liran I / Timms, Lee / Tsao, Ming-Sound / Wilson, Julie M / Yung, Christina K / Zogopoulos, George / Bartlett, John M S / Alexandrov, Ludmil B / Real, Francisco X / Cleary, Sean P / Roehrl, Michael H / McPherson, John D / Stein, Lincoln D / Hudson, Thomas J / Campbell, Peter J / Gallinger, Steven. ·Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada. · Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK. · UHN Program in BioSpecimen Sciences, Department of Pathology, University Health Network, Toronto, Ontario M5G 2C4, Canada. · Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada. · Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada. · Department of Computer Science, University of Toronto, Toronto, Ontario M5S 3G4, Canada. · Eppley Institute for Research in Cancer, Nebraska Medical Center, Omaha, Nebraska 68198, USA. · Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada. · Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada. · Division of Surgical Oncology, Sunnybrook Health Sciences Centre, Odette Cancer Centre, Toronto, Ontario M4N 3M5, Canada. · Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55905, USA. · Research Institute of the McGill University Health Centre, Montreal, Québec, Canada, H3H 2L9. · Theoretical Biology and Biophysics (T-6) and Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico, USA, 87545. · Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada. · Department of Surgery, University Health Network, Toronto, Ontario M5G 2C4, Canada. · Department of Haematology, University of Cambridge, Cambridge CB2 0XY, UK. ·Nature · Pubmed #27732578.

ABSTRACT: Pancreatic cancer, a highly aggressive tumour type with uniformly poor prognosis, exemplifies the classically held view of stepwise cancer development. The current model of tumorigenesis, based on analyses of precursor lesions, termed pancreatic intraepithelial neoplasm (PanINs) lesions, makes two predictions: first, that pancreatic cancer develops through a particular sequence of genetic alterations (KRAS, followed by CDKN2A, then TP53 and SMAD4); and second, that the evolutionary trajectory of pancreatic cancer progression is gradual because each alteration is acquired independently. A shortcoming of this model is that clonally expanded precursor lesions do not always belong to the tumour lineage, indicating that the evolutionary trajectory of the tumour lineage and precursor lesions can be divergent. This prevailing model of tumorigenesis has contributed to the clinical notion that pancreatic cancer evolves slowly and presents at a late stage. However, the propensity for this disease to rapidly metastasize and the inability to improve patient outcomes, despite efforts aimed at early detection, suggest that pancreatic cancer progression is not gradual. Here, using newly developed informatics tools, we tracked changes in DNA copy number and their associated rearrangements in tumour-enriched genomes and found that pancreatic cancer tumorigenesis is neither gradual nor follows the accepted mutation order. Two-thirds of tumours harbour complex rearrangement patterns associated with mitotic errors, consistent with punctuated equilibrium as the principal evolutionary trajectory. In a subset of cases, the consequence of such errors is the simultaneous, rather than sequential, knockout of canonical preneoplastic genetic drivers that are likely to set-off invasive cancer growth. These findings challenge the current progression model of pancreatic cancer and provide insights into the mutational processes that give rise to these aggressive tumours.

7 Article Expression of DRD2 Is Increased in Human Pancreatic Ductal Adenocarcinoma and Inhibitors Slow Tumor Growth in Mice. 2016

Jandaghi, Pouria / Najafabadi, Hamed S / Bauer, Andrea S / Papadakis, Andreas I / Fassan, Matteo / Hall, Anita / Monast, Anie / von Knebel Doeberitz, Magnus / Neoptolemos, John P / Costello, Eithne / Greenhalf, William / Scarpa, Aldo / Sipos, Bence / Auld, Daniel / Lathrop, Mark / Park, Morag / Büchler, Markus W / Strobel, Oliver / Hackert, Thilo / Giese, Nathalia A / Zogopoulos, George / Sangwan, Veena / Huang, Sidong / Riazalhosseini, Yasser / Hoheisel, Jörg D. ·Functional Genome Analysis, Deutsches Krebsforschungszentrum, Heidelberg, Germany; Department of Human Genetics, McGill University, Montreal, Quebec, Canada; McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada. · Department of Human Genetics, McGill University, Montreal, Quebec, Canada; McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada. · Functional Genome Analysis, Deutsches Krebsforschungszentrum, Heidelberg, Germany. · Department of Biochemistry, McGill University, Montreal, Quebec, Canada; Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada. · ARC-NET Center for Applied Research on Cancer, University and Azienda Ospedaliera Universitaria Integrata, Verona, Italy. · Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada; The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada. · Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada. · Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. · National Institute for Health Research, Liverpool Pancreas Biomedical Research Unit, Liverpool, UK. · ARC-NET Center for Applied Research on Cancer, University and Azienda Ospedaliera Universitaria Integrata, Verona, Italy; Department of Pathology and Diagnostics, Università di Verona, Verona, Italy. · Institute for Pathology and Neuropathology, Universitätsklinikum Tübingen, Tübingen, Germany. · Department of Biochemistry, McGill University, Montreal, Quebec, Canada; Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada; Department of Pathology, McGill University, Montréal, Quebec, Canada; Department of Oncology, McGill University, Montréal, Quebec, Canada. · Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany. · Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada; Department of Oncology, McGill University, Montréal, Quebec, Canada. · Department of Human Genetics, McGill University, Montreal, Quebec, Canada; McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada. Electronic address: Yasser.riazalhosseini@mcgill.ca. ·Gastroenterology · Pubmed #27578530.

ABSTRACT: BACKGROUND & AIMS: Incidence of and mortality from pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, are almost equivalent, so better treatments are needed. We studied gene expression profiles of PDACs and the functions of genes with altered expression to identify new therapeutic targets. METHODS: We performed microarray analysis to analyze gene expression profiles of 195 PDAC and 41 non-tumor pancreatic tissue samples. We undertook an extensive analysis of the PDAC transcriptome by superimposing interaction networks of proteins encoded by aberrantly expressed genes over signaling pathways associated with PDAC development to identify factors that might alter regulation of these pathways during tumor progression. We performed tissue microarray analysis to verify changes in expression of candidate protein using an independent set of 152 samples (40 nontumor pancreatic tissues, 63 PDAC sections, and 49 chronic pancreatitis samples). We validated the functional relevance of the candidate molecule using RNA interference or pharmacologic inhibitors in pancreatic cancer cell lines and analyses of xenograft tumors in mice. RESULTS: In an analysis of 38,276 human genes and loci, we identified 1676 genes that were significantly up-regulated and 1166 genes that were significantly down-regulated in PDAC compared with nontumor pancreatic tissues. One gene that was up-regulated and associated with multiple signaling pathways that are dysregulated in PDAC was G protein subunit αi2, which has not been previously associated with PDAC. G protein subunit αi2 mediates the effects of dopamine receptor D2 (DRD2) on cyclic adenosine monophosphate signaling; PDAC tissues had a slight but significant increase in DRD2 messenger RNA. Levels of DRD2 protein were substantially increased in PDACs, compared with non-tumor tissues, in tissue microarray analyses. RNA interference knockdown of DRD2 or inhibition with pharmacologic antagonists (pimozide and haloperidol) reduced proliferation of pancreatic cancer cells, induced endoplasmic reticulum stress and apoptosis, and reduced cell migration. RNA interference knockdown of DRD2 in pancreatic tumor cells reduced growth of xenograft tumors in mice, and administration of the DRD2 inhibitor haloperidol to mice with orthotopic xenograft tumors reduced final tumor size and metastasis. CONCLUSIONS: In gene expression profile analysis of PDAC samples, we found the DRD2 signaling pathway to be activated. Inhibition of DRD2 in pancreatic cancer cells reduced proliferation and migration, and slowed growth of xenograft tumors in mice. DRD2 antagonists routinely used for management of schizophrenia might be tested in patients with pancreatic cancer.

8 Article Whole Genome Sequencing Defines the Genetic Heterogeneity of Familial Pancreatic Cancer. 2016

Roberts, Nicholas J / Norris, Alexis L / Petersen, Gloria M / Bondy, Melissa L / Brand, Randall / Gallinger, Steven / Kurtz, Robert C / Olson, Sara H / Rustgi, Anil K / Schwartz, Ann G / Stoffel, Elena / Syngal, Sapna / Zogopoulos, George / Ali, Syed Z / Axilbund, Jennifer / Chaffee, Kari G / Chen, Yun-Ching / Cote, Michele L / Childs, Erica J / Douville, Christopher / Goes, Fernando S / Herman, Joseph M / Iacobuzio-Donahue, Christine / Kramer, Melissa / Makohon-Moore, Alvin / McCombie, Richard W / McMahon, K Wyatt / Niknafs, Noushin / Parla, Jennifer / Pirooznia, Mehdi / Potash, James B / Rhim, Andrew D / Smith, Alyssa L / Wang, Yuxuan / Wolfgang, Christopher L / Wood, Laura D / Zandi, Peter P / Goggins, Michael / Karchin, Rachel / Eshleman, James R / Papadopoulos, Nickolas / Kinzler, Kenneth W / Vogelstein, Bert / Hruban, Ralph H / Klein, Alison P. ·Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. Ludwig Center and the Howard Hughes Medical Institute, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. vogelbe@jhmi.edu nrobert8@jhmi.edu kinzlke@jhmi.edu rhruban@jhmi.edu aklein1@jhmi.edu. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota. · Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas. · Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania. · Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. · Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. · Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York. · Division of Gastroenterology, Departments of Medicine and Genetics, Pancreatic Cancer Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. · Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan. · Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan. · Population Sciences Division, Dana-Farber Cancer Institute, and Gastroenterology Division, Brigham and Women's Hospital, Boston, Massachusetts. · The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada. Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada. · Department of Biomedical Engineering, Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland. · Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland. · Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Memorial Sloan Kettering Cancer Center, New York, New York. · Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. · Ludwig Center and the Howard Hughes Medical Institute, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. inGenious Targeting Laboratory, Ronkonkoma, New York. · Department of Psychiatry, University of Iowa, Iowa City, Iowa. · Division of Gastroenterology, Departments of Medicine and Genetics, Pancreatic Cancer Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Department of Medicine, University of Michigan, Ann Arbor, Michigan. · Department of Surgery, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Medicine, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Ludwig Center and the Howard Hughes Medical Institute, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. vogelbe@jhmi.edu nrobert8@jhmi.edu kinzlke@jhmi.edu rhruban@jhmi.edu aklein1@jhmi.edu. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. vogelbe@jhmi.edu nrobert8@jhmi.edu kinzlke@jhmi.edu rhruban@jhmi.edu aklein1@jhmi.edu. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland. Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. vogelbe@jhmi.edu nrobert8@jhmi.edu kinzlke@jhmi.edu rhruban@jhmi.edu aklein1@jhmi.edu. ·Cancer Discov · Pubmed #26658419.

ABSTRACT: SIGNIFICANCE: The genetic basis of disease susceptibility in the majority of patients with familial pancreatic cancer is unknown. We whole genome sequenced 638 patients with familial pancreatic cancer and demonstrate that the genetic underpinning of inherited pancreatic cancer is highly heterogeneous. This has significant implications for the management of patients with familial pancreatic cancer.

9 Article Candidate DNA repair susceptibility genes identified by exome sequencing in high-risk pancreatic cancer. 2016

Smith, Alyssa L / Alirezaie, Najmeh / Connor, Ashton / Chan-Seng-Yue, Michelle / Grant, Robert / Selander, Iris / Bascuñana, Claire / Borgida, Ayelet / Hall, Anita / Whelan, Thomas / Holter, Spring / McPherson, Treasa / Cleary, Sean / Petersen, Gloria M / Omeroglu, Atilla / Saloustros, Emmanouil / McPherson, John / Stein, Lincoln D / Foulkes, William D / Majewski, Jacek / Gallinger, Steven / Zogopoulos, George. ·Research Institute of the McGill University Health Centre, 1001 Décarie Boulevard, Montreal, QC, Canada H4A 3J1; Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue West, Montreal, QC, Canada H3A 1A3. · McGill University and Genome Quebec Innovation Centre, 740 Dr. Penfield Avenue, Montreal, QC, Canada H3A 0G1. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON, Canada M5G 1X5; MaRS Centre, Ontario Institute for Cancer Research, 661 University Avenue, Toronto, ON, Canada M5G 0A3. · MaRS Centre, Ontario Institute for Cancer Research, 661 University Avenue, Toronto, ON, Canada M5G 0A3. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON, Canada M5G 1X5. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON, Canada M5G 1X5; Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, 60 Murray Street, Toronto, ON, Canada M5T 3H7. · Department of Health Sciences Research, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA. · Department of Pathology, McGill University Health Centre, 1001 Décarie Boulevard, Montreal, QC, Canada H4A 3J1. · Department of Medical Oncology, Hereditary Cancer Clinic, University Hospital of Heraklion, Voutes, Heraklion 71110, Greece. · Program in Cancer Genetics, Departments of Oncology and Human Genetics, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, 3755 Côte-Ste-Catherine Road, Montreal, QC, Canada H3T 1E2. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON, Canada M5G 1X5; MaRS Centre, Ontario Institute for Cancer Research, 661 University Avenue, Toronto, ON, Canada M5G 0A3; Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, 60 Murray Street, Toronto, ON, Canada M5T 3H7. Electronic address: steven.gallinger@uhn.ca. · Research Institute of the McGill University Health Centre, 1001 Décarie Boulevard, Montreal, QC, Canada H4A 3J1; Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue West, Montreal, QC, Canada H3A 1A3; Program in Cancer Genetics, Departments of Oncology and Human Genetics, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, 3755 Côte-Ste-Catherine Road, Montreal, QC, Canada H3T 1E2. Electronic address: george.zogopoulos@mcgill.ca. ·Cancer Lett · Pubmed #26546047.

ABSTRACT: The genetic basis underlying the majority of hereditary pancreatic adenocarcinoma (PC) is unknown. Since DNA repair genes are widely implicated in gastrointestinal malignancies, including PC, we hypothesized that there are novel DNA repair PC susceptibility genes. As germline DNA repair gene mutations may lead to PC subtypes with selective therapeutic responses, we also hypothesized that there is an overall survival (OS) difference in mutation carriers versus non-carriers. We therefore interrogated the germline exomes of 109 high-risk PC cases for rare protein-truncating variants (PTVs) in 513 putative DNA repair genes. We identified PTVs in 41 novel genes among 36 kindred. Additional genetic evidence for causality was obtained for 17 genes, with FAN1, NEK1 and RHNO1 emerging as the strongest candidates. An OS difference was observed for carriers versus non-carriers of PTVs with early stage (≤IIB) disease. This adverse survival trend in carriers with early stage disease was also observed in an independent series of 130 PC cases. We identified candidate DNA repair PC susceptibility genes and suggest that carriers of a germline PTV in a DNA repair gene with early stage disease have worse survival.

10 Article Increased in vitro and in vivo sensitivity of BRCA2-associated pancreatic cancer to the poly(ADP-ribose) polymerase-1/2 inhibitor BMN 673. 2015

Andrei, Alexandra-Zoe / Hall, Anita / Smith, Alyssa L / Bascuñana, Claire / Malina, Abba / Connor, Ashton / Altinel-Omeroglu, Gulbeyaz / Huang, Sidong / Pelletier, Jerry / Huntsman, David / Gallinger, Steven / Omeroglu, Atilla / Metrakos, Peter / Zogopoulos, George. ·Rosalind and Morris Goodman Cancer Research Centre, McGill University, 1160 Pine Ave. West, Montreal, Quebec, Canada H3A 1A3; The Research Institute of the McGill University Health Centre, 1001 Decarie Boulevard, Montreal, Quebec, Canada H4A 3J1. · Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec, Canada H3G 1Y6. · The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, Canada M5G 1X5. · Department of Pathology, McGill University Health Centre, 1001 Decarie Boulevard, Montreal, Quebec, Canada H4A 3J1. · Rosalind and Morris Goodman Cancer Research Centre, McGill University, 1160 Pine Ave. West, Montreal, Quebec, Canada H3A 1A3; Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec, Canada H3G 1Y6. · Centre for the Translational and Applied Genomics, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 1L4. · The Research Institute of the McGill University Health Centre, 1001 Decarie Boulevard, Montreal, Quebec, Canada H4A 3J1. · Rosalind and Morris Goodman Cancer Research Centre, McGill University, 1160 Pine Ave. West, Montreal, Quebec, Canada H3A 1A3; The Research Institute of the McGill University Health Centre, 1001 Decarie Boulevard, Montreal, Quebec, Canada H4A 3J1. Electronic address: george.zogopoulos@mcgill.ca. ·Cancer Lett · Pubmed #25864590.

ABSTRACT: BRCA2-associated pancreatic ductal adenocarcinoma (PDAC) may be sensitive to agents that target homology-directed DNA repair, such as DNA crosslinking agents (DCLs) and PARP inhibitors (PARPis). Here, we assessed the sensitivities of BRCA2-deficient (Capan-1) and BRCA2-proficient (MIA PaCa-2) PDAC cell lines to a panel of DCLs and PARPis. Compared to MIA PaCa-2, Capan-1 was significantly more sensitive to all tested DCLs and PARPis, with similar increased sensitivities to cisplatin and the PARPi BMN 673 compared to other DCLs and the PARPi veliparib. We provide further support for this observation by showing that shRNA-mediated BRCA2 knockdown in PANC-1, a BRCA2-proficient cell line, induces sensitization to cisplatin and BMN 673 but not to veliparib. These findings were validated in a PDAC murine xenograft model derived from a patient with bi-allelic BRCA2 mutations. We found 64% and 61% tumor growth inhibition of this xenograft with cisplatin and BMN 673 treatments, respectively. Cisplatin and BMN 673 treatments reduced cellular proliferation and induced apoptosis. Our findings support a personalized treatment approach for BRCA2-associated PDAC.

11 Article Identification of germline genomic copy number variation in familial pancreatic cancer. 2012

Al-Sukhni, Wigdan / Joe, Sarah / Lionel, Anath C / Zwingerman, Nora / Zogopoulos, George / Marshall, Christian R / Borgida, Ayelet / Holter, Spring / Gropper, Aaron / Moore, Sara / Bondy, Melissa / Klein, Alison P / Petersen, Gloria M / Rabe, Kari G / Schwartz, Ann G / Syngal, Sapna / Scherer, Stephen W / Gallinger, Steven. ·Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada. wigdan.al.sukhni@utoronto.ca ·Hum Genet · Pubmed #22665139.

ABSTRACT: Adenocarcinoma of the pancreas is a significant cause of cancer mortality, and up to 10 % of cases appear to be familial. Heritable genomic copy number variants (CNVs) can modulate gene expression and predispose to disease. Here, we identify candidate predisposition genes for familial pancreatic cancer (FPC) by analyzing germline losses or gains present in one or more high-risk patients and absent in a large control group. A total of 120 FPC cases and 1,194 controls were genotyped on the Affymetrix 500K array, and 36 cases and 2,357 controls were genotyped on the Affymetrix 6.0 array. Detection of CNVs was performed by multiple computational algorithms and partially validated by quantitative PCR. We found no significant difference in the germline CNV profiles of cases and controls. A total of 93 non-redundant FPC-specific CNVs (53 losses and 40 gains) were identified in 50 cases, each CNV present in a single individual. FPC-specific CNVs overlapped the coding region of 88 RefSeq genes. Several of these genes have been reported to be differentially expressed and/or affected by copy number alterations in pancreatic adenocarcinoma. Further investigation in high-risk subjects may elucidate the role of one or more of these genes in genetic predisposition to pancreatic cancer.