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Pancreatic Neoplasms: HELP
Articles by Michael W. Borges
Based on 23 articles published since 2010
(Why 23 articles?)
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Between 2010 and 2020, Michael Borges wrote the following 23 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 Deleterious Germline Mutations Are a Risk Factor for Neoplastic Progression Among High-Risk Individuals Undergoing Pancreatic Surveillance. 2019

Abe, Toshiya / Blackford, Amanda L / Tamura, Koji / Ford, Madeline / McCormick, Patrick / Chuidian, Miguel / Almario, Jose Alejandro / Borges, Michael / Lennon, Anne Marie / Shin, Eun Ji / Klein, Alison P / Hruban, Ralph H / Canto, Marcia I / Goggins, Michael. ·1 Johns Hopkins Medical Institutions, Baltimore, MD. ·J Clin Oncol · Pubmed #30883245.

ABSTRACT: PURPOSE: To compare the risk of neoplastic progression by germline mutation status versus family history without a known germline mutation (familial risk) among individuals with an increased risk for pancreatic cancer who are undergoing surveillance. METHODS: Of 464 high-risk individuals in the Cancer of the Pancreas Screening program at Johns Hopkins Hospital who were undergoing pancreatic surveillance, 119 had a known deleterious germline mutation in a pancreatic cancer susceptibility gene; 345 met family history criteria for pancreatic surveillance but were not known to harbor a germline mutation. We used next-generation sequencing to identify previously unrecognized germline mutations among these 345 individuals. We compared the development of pancreatic cancer, high-grade dysplasia, or clinically worrisome features, adjusting for competing mortality, among all germline mutation carriers with the risk of progression in a cohort without a known germline mutation. RESULTS: Fifteen (4.3%) of 345 individuals classified as having familial risk had a previously unrecognized pancreatic cancer susceptibility gene mutation (nine that involved CONCLUSION: The cumulative incidence of pancreatic cancer is significantly higher among individuals with an identifiable deleterious germline mutation in a pancreatic cancer susceptibility gene than it is among individuals with a strong family history but no identified mutation. Gene testing of individuals who meet criteria for pancreatic surveillance on the basis of their family history may better define those most at risk for neoplastic progression.

3 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

4 Article Pancreatic Juice Mutation Concentrations Can Help Predict the Grade of Dysplasia in Patients Undergoing Pancreatic Surveillance. 2018

Suenaga, Masaya / Yu, Jun / Shindo, Koji / Tamura, Koji / Almario, Jose Alejandro / Zaykoski, Christopher / Witmer, P Dane / Fesharakizadeh, Shahriar / Borges, Michael / Lennon, Anne-Marie / Shin, Eun-Ji / Canto, Marcia Irene / Goggins, Michael. ·Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Center for Inherited Disease Research (CIDR), Baltimore, Maryland. · Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. mgoggins@jhmi.edu. ·Clin Cancer Res · Pubmed #29301828.

ABSTRACT:

5 Article The Effect of Pancreatic Juice Collection Time on the Detection of KRAS Mutations. 2018

Suenaga, Masaya / Dudley, Beth / Karloski, Eve / Borges, Michael / Irene Canto, Marcia / Brand, Randall E / Goggins, Michael. · ·Pancreas · Pubmed #29200129.

ABSTRACT: OBJECTIVE: Secretin-stimulated pancreatic juice is collected from the duodenum and analyzed to identify biomarkers of pancreatic neoplasia, but the optimal duration of pancreatic juice collection is not known. METHODS: We compared the yield of KRAS mutations detected in pancreatic juice samples aspirated from near the duodenal papilla at 1 to 5, 6 to 10, and 11 to 15 minutes after secretin infusion, and from the third part of the duodenum (at 15 minutes) from 45 patients undergoing endoscopic ultrasound pancreatic surveillance. KRAS mutation concentrations were measured by using droplet digital polymerase chain reaction. RESULTS: Forty of 45 patients had KRAS mutations detected in their pancreatic juice, and most patients' juice samples had more than 1 KRAS mutation. Of 106 KRAS mutations detected in 171 pancreatic juice samples, 58 were detected in the 5-minute samples, 70 mutations were detected in the 10-minute samples, and 65 were detected in the 15-minute samples. Nine patients who did not have KRAS mutations detected in their 5-minute sample had mutations detected in samples collected at later time points. Ninety-percent of all pancreatic juice mutations detected in any sample were detected in the 5- or 10-minute samples. CONCLUSIONS: Collecting pancreatic juice for 10 minutes after secretin infusion increases the likelihood of detecting pancreatic juice mutations over shorter collections.

6 Article IL2RG, identified as overexpressed by RNA-seq profiling of pancreatic intraepithelial neoplasia, mediates pancreatic cancer growth. 2017

Ayars, Michael / O'Sullivan, Eileen / Macgregor-Das, Anne / Shindo, Koji / Kim, Haeryoung / Borges, Michael / Yu, Jun / Hruban, Ralph H / Goggins, Michael. ·Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. ·Oncotarget · Pubmed #29137350.

ABSTRACT: Pancreatic ductal adenocarcinoma evolves from precursor lesions, the most common of which is pancreatic intraepithelial neoplasia (PanIN). We performed RNA-sequencing analysis of laser capture microdissected PanINs and normal pancreatic duct cells to identify differentially expressed genes between PanINs and normal pancreatic duct, and between low-grade and high-grade PanINs. One of the most highly overexpressed transcripts identified in PanIN is interleukin-2 receptor subunit gamma (

7 Article Lack of association between the pancreatitis risk allele CEL-HYB and pancreatic cancer. 2017

Shindo, Koji / Yu, Jun / Suenaga, Masaya / Fesharakizadeh, Shahriar / Tamura, Koji / Almario, Jose Alejandro Navarro / Brant, Aaron / Borges, Michael / Siddiqui, Abdulrehman / Datta, Lisa / Wolfgang, Christopher L / Hruban, Ralph H / Klein, Alison Patricia / Goggins, Michael. ·Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Epidemiology, Bloomberg School of Public Health, Baltimore, Maryland, USA. ·Oncotarget · Pubmed #28881607.

ABSTRACT: CEL-HYB is a hybrid allele that arose from a crossover between the 3' end of the Carboxyl ester lipase (

8 Article Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma. 2017

Shindo, Koji / Yu, Jun / Suenaga, Masaya / Fesharakizadeh, Shahriar / Cho, Christy / Macgregor-Das, Anne / Siddiqui, Abdulrehman / Witmer, P Dane / Tamura, Koji / Song, Tae Jun / Navarro Almario, Jose Alejandro / Brant, Aaron / Borges, Michael / Ford, Madeline / Barkley, Thomas / He, Jin / Weiss, Matthew J / Wolfgang, Christopher L / Roberts, Nicholas J / Hruban, Ralph H / Klein, Alison P / Goggins, Michael. ·All authors: The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD. ·J Clin Oncol · Pubmed #28767289.

ABSTRACT: Purpose Deleterious germline mutations contribute to pancreatic cancer susceptibility and are well documented in families in which multiple members have had pancreatic cancer. Methods To define the prevalence of these germline mutations in patients with apparently sporadic pancreatic cancer, we sequenced 32 genes, including known pancreatic cancer susceptibility genes, in DNA prepared from normal tissue obtained from 854 patients with pancreatic ductal adenocarcinoma, 288 patients with other pancreatic and periampullary neoplasms, and 51 patients with non-neoplastic diseases who underwent pancreatic resection at Johns Hopkins Hospital between 2000 and 2015. Results Thirty-three (3.9%; 95% CI, 3.0% to 5.8%) of 854 patients with pancreatic cancer had a deleterious germline mutation, 31 (3.5%) of which affected known familial pancreatic cancer susceptibility genes: BRCA2 (12 patients), ATM (10 patients), BRCA1 (3 patients), PALB2 (2 patients), MLH1 (2 patients), CDKN2A (1 patient), and TP53 (1 patient). Patients with these germline mutations were younger than those without (mean ± SD, 60.8 ± 10.6 v 65.1 ± 10.5 years; P = .03). Deleterious germline mutations were also found in BUB1B (1) and BUB3 (1). Only three of these 33 patients had reported a family history of pancreatic cancer, and most did not have a cancer family history to suggest an inherited cancer syndrome. Five (1.7%) of 288 patients with other periampullary neoplasms also had a deleterious germline mutation. Conclusion Germline mutations in pancreatic cancer susceptibility genes are commonly identified in patients with pancreatic cancer without a significant family history of cancer. These deleterious pancreatic cancer susceptibility gene mutations, some of which are therapeutically targetable, will be missed if current family history guidelines are the main criteria used to determine the appropriateness of gene testing.

9 Article Using an endoscopic distal cap to collect pancreatic fluid from the ampulla (with video). 2017

Suenaga, Masaya / Sadakari, Yoshihiko / Almario, Jose Alejandro / Borges, Michael / Lennon, Anne-Marie / Shin, Eun-Ji / Canto, Marcia Irene / Goggins, Michael. ·Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA. · Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA; Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA. · Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA. · Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA; Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA; Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA; Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA. ·Gastrointest Endosc · Pubmed #28259593.

ABSTRACT: BACKGROUND AND AIMS: Duodenal collections of pancreatic fluid can be used as a source of mutations and other markers of pancreatic ductal neoplasia, but admixing pancreatic juice with duodenal contents lowers the concentrations of mutations. Collecting pancreatic fluid directly from the ampulla could yield a purer sample of pancreatic fluid. METHODS: We used an endoscopic distal cap attachment to "cap" the ampulla and collect secretin-stimulated pancreatic fluid samples for 5 minutes from 81 patients undergoing pancreatic evaluation as part of the Cancer of the Pancreas Screening studies. We compared mutation concentrations (K-ras and GNAS) measured by droplet-digital PCR (ddPCR) in "cap-collected juice" samples to those found in juice samples obtained from 77 patients collected by aspiration from the duodenal lumen without capping the ampulla. RESULTS: Among all subjects, mutation concentrations were higher in pancreatic juice samples collected using the endoscopic cap method (median, .028%; IQR, 0-.077) compared with the noncap-collected (median, .019%; IQR, 0-.044; P = .055). Among pancreatic juice samples with detectable mutations, mutation concentrations were higher in the cap-collected juice samples than in those collected without the cap (.055%; IQR, .026-.092 vs .032%; IQR, .020-.066; P = .031). CONCLUSIONS: Collecting pancreatic juice directly from the ampulla using an endoscopic distal cap yields higher concentrations of pancreatic fluid mutations.

10 Article Digital next-generation sequencing identifies low-abundance mutations in pancreatic juice samples collected from the duodenum of patients with pancreatic cancer and intraductal papillary mucinous neoplasms. 2017

Yu, Jun / Sadakari, Yoshihiko / Shindo, Koji / Suenaga, Masaya / Brant, Aaron / Almario, Jose Alejandro Navarro / Borges, Michael / Barkley, Thomas / Fesharakizadeh, Shahriar / Ford, Madeline / Hruban, Ralph H / Shin, Eun Ji / Lennon, Anne Marie / Canto, Marcia Irene / Goggins, Michael. ·Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. ·Gut · Pubmed #27432539.

ABSTRACT: OBJECTIVE: Secretin-stimulated pancreatic juice contains DNA shed from cells lining the pancreatic ducts. Genetic analysis of this fluid may form a test to detect pancreatic ductal neoplasia. DESIGN: We employed digital next-generation sequencing ('digital NGS') to detect low-abundance mutations in secretin-stimulated juice samples collected from the duodenum of subjects enrolled in Cancer of the Pancreas Screening studies at Johns Hopkins Hospital. For each juice sample, digital NGS necessitated 96 NGS reactions sequencing nine genes. The study population included 115 subjects (53 discovery, 62 validation) (1) with pancreatic ductal adenocarcinoma (PDAC), (2) intraductal papillary mucinous neoplasm (IPMN), (3) controls with non-suspicious pancreata. RESULTS: Cases with PDAC and IPMN were more likely to have mutant DNA detected in pancreatic juice than controls (both p<0.0001); mutant DNA concentrations were higher in patients with PDAC than IPMN (p=0.003) or controls (p<0.001). CONCLUSIONS: The detection in pancreatic juice of mutations important for the progression of low-grade dysplasia to high-grade dysplasia and invasive pancreatic cancer may improve the management of patients undergoing pancreatic screening and surveillance.

11 Article Overexpression of ankyrin1 promotes pancreatic cancer cell growth. 2016

Omura, Noriyuki / Mizuma, Masamichi / MacGregor, Anne / Hong, Seung-Mo / Ayars, Michael / Almario, Jose Alejandro / Borges, Michael / Kanda, Mitsuro / Li, Ang / Vincent, Audrey / Maitra, Anirban / Goggins, Michael. ·Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Johns Hopkins University, Baltimore, MD, USA. · Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Johns Hopkins University, Baltimore, MD, USA. · Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Johns Hopkins University, Baltimore, MD, USA. ·Oncotarget · Pubmed #27144336.

ABSTRACT: The methylation status of a promoter influences gene expression and aberrant methylation during tumor development has important functional consequences for pancreatic and other cancers. Using methylated CpG island amplification and promoter microarrays, we identified ANK1 as hypomethylated in pancreatic cancers. Expression analysis determined ANK1 as commonly overexpressed in pancreatic cancers relative to normal pancreas. ANK1 was co-expressed with miR-486 in pancreatic cancer cells. Stable knockdown of ANK1 in the pancreatic cancer cell line AsPC1 led to changes in cell morphology, and decreases in colony formation. Stable knockdown of ANK1 also marked reduced the growth of tumors in athymic nude mice. Among patients undergoing pancreaticoduodenectomy, those with pancreatic cancers expressing ANK1 had a poorer prognosis than those without ANK1 expression. These findings indicate a role for ANK1 overexpression in mediating pancreatic cancer tumorigenicity.

12 Article Common variation at 2p13.3, 3q29, 7p13 and 17q25.1 associated with susceptibility to pancreatic cancer. 2015

Childs, Erica J / Mocci, Evelina / Campa, Daniele / Bracci, Paige M / Gallinger, Steven / Goggins, Michael / Li, Donghui / Neale, Rachel E / Olson, Sara H / Scelo, Ghislaine / Amundadottir, Laufey T / Bamlet, William R / Bijlsma, Maarten F / Blackford, Amanda / Borges, Michael / Brennan, Paul / Brenner, Hermann / Bueno-de-Mesquita, H Bas / Canzian, Federico / Capurso, Gabriele / Cavestro, Giulia M / Chaffee, Kari G / Chanock, Stephen J / Cleary, Sean P / Cotterchio, Michelle / Foretova, Lenka / Fuchs, Charles / Funel, Niccola / Gazouli, Maria / Hassan, Manal / Herman, Joseph M / Holcatova, Ivana / Holly, Elizabeth A / Hoover, Robert N / Hung, Rayjean J / Janout, Vladimir / Key, Timothy J / Kupcinskas, Juozas / Kurtz, Robert C / Landi, Stefano / Lu, Lingeng / Malecka-Panas, Ewa / Mambrini, Andrea / Mohelnikova-Duchonova, Beatrice / Neoptolemos, John P / Oberg, Ann L / Orlow, Irene / Pasquali, Claudio / Pezzilli, Raffaele / Rizzato, Cosmeri / Saldia, Amethyst / Scarpa, Aldo / Stolzenberg-Solomon, Rachael Z / Strobel, Oliver / Tavano, Francesca / Vashist, Yogesh K / Vodicka, Pavel / Wolpin, Brian M / Yu, Herbert / Petersen, Gloria M / Risch, Harvey A / Klein, Alison P. ·Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, Maryland, USA. · Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland, USA. · 1] Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. [2] Department of Biology, University of Pisa, Pisa, Italy. · Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA. · Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, Maryland, USA. · Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA. · Department of Population Health, QIMR Berghofer Medical Research Institute, Kelvin Grove,Queensland, Australia. · Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA. · International Agency for Research on Cancer (IARC), Lyon, France. · Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland, USA. · Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota, USA. · Laboratory for Experimental Oncology and Radiobiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. · Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany. · 1] Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands. [2] Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, the Netherlands. [3] Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK. [4] Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia. · Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Digestive and Liver Disease Unit, 'Sapienza' University of Rome, Rome, Italy. · Università Vita Salute San Raffaele and Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, Milan, Italy. · 1] Department of Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada. [2] Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. · 1] Cancer Care Ontario, University of Toronto, Toronto, Ontario, Canada. [2] Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada. · Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and Medical Faculty Masaryk University, Brno, Czech Republic. · 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. · Department of Surgery, Unit of Experimental Surgical Pathology, University Hospital of Pisa, Pisa, Italy. · Department of Medical Sciences, Laboratory of Biology, School of Medicine, University of Athens, Athens, Greece. · Department of Radiation Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Institute of Hygiene and Epidemiology, 1st Faculty of Medicine, Charles University in Prague, Prague, Czech Republic. · Department of Preventive Medicine, Faculty of Medicine, Palacky University, Olomouc, Czech Republic. · Cancer Epidemiology Unit, University of Oxford, Oxford, UK. · Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania. · Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA. · Department of Biology, Section of Genetics, University of Pisa, Pisa, Italy. · Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut, USA. · Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland. · Department of Oncology, Azienda USL 1 Massa Carrara, Massa Carrara, Italy. · Laboratory of Toxicogenomics, Institute of Public Health, Prague, Czech Republic. · National Institute for Health Research (NIHR) Pancreas Biomedical Research Unit, Liverpool Clinical Trials Unit and Cancer Research UK Clinical Trials Unit, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK. · Department of Surgery, Gastroenterology and Oncology, University of Padua, Padua, Italy. · Pancreas Unit, Department of Digestive Diseases, Sant'Orsola-Malpighi Hospital, Bologna, Italy. · ARC-NET-Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy. · Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Rockville, Maryland, USA. · Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany. · Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital 'Casa Sollievo della Sofferenza', San Giovanni Rotondo, Italy. · Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. · Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences, Prague, Czech Republic. · 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. · Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA. · 1] Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland, USA. [2] Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, Maryland, USA. ·Nat Genet · Pubmed #26098869.

ABSTRACT: Pancreatic cancer is the fourth leading cause of cancer death in the developed world. Both inherited high-penetrance mutations in BRCA2 (ref. 2), ATM, PALB2 (ref. 4), BRCA1 (ref. 5), STK11 (ref. 6), CDKN2A and mismatch-repair genes and low-penetrance loci are associated with increased risk. To identify new risk loci, we performed a genome-wide association study on 9,925 pancreatic cancer cases and 11,569 controls, including 4,164 newly genotyped cases and 3,792 controls in 9 studies from North America, Central Europe and Australia. We identified three newly associated regions: 17q25.1 (LINC00673, rs11655237, odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.19-1.34, P = 1.42 × 10(-14)), 7p13 (SUGCT, rs17688601, OR = 0.88, 95% CI = 0.84-0.92, P = 1.41 × 10(-8)) and 3q29 (TP63, rs9854771, OR = 0.89, 95% CI = 0.85-0.93, P = 2.35 × 10(-8)). We detected significant association at 2p13.3 (ETAA1, rs1486134, OR = 1.14, 95% CI = 1.09-1.19, P = 3.36 × 10(-9)), a region with previous suggestive evidence in Han Chinese. We replicated previously reported associations at 9q34.2 (ABO), 13q22.1 (KLF5), 5p15.33 (TERT and CLPTM1), 13q12.2 (PDX1), 1q32.1 (NR5A2), 7q32.3 (LINC-PINT), 16q23.1 (BCAR1) and 22q12.1 (ZNRF3). Our study identifies new loci associated with pancreatic cancer risk.

13 Article KRAS and guanine nucleotide-binding protein mutations in pancreatic juice collected from the duodenum of patients at high risk for neoplasia undergoing endoscopic ultrasound. 2015

Eshleman, James R / Norris, Alexis L / Sadakari, Yoshihiko / Debeljak, Marija / Borges, Michael / Harrington, Colleen / Lin, Elaine / Brant, Aaron / Barkley, Thomas / Almario, J Alejandro / Topazian, Mark / Farrell, James / Syngal, Sapna / Lee, Jeffrey H / Yu, Jun / Hruban, Ralph H / Kanda, Mitsuro / Canto, Marcia Irene / Goggins, Michael. ·Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland; Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. Electronic address: jeshlem@jhmi.edu. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Mayo Clinic, Rochester, Minnesota. · Dana Farber Cancer Institute, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. · Yale University, New Haven, Connecticut. · MD Anderson Cancer Center, Houston, Texas. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland; Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland; Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland; Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland; Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. Electronic address: mgoggins@jhmi.edu. ·Clin Gastroenterol Hepatol · Pubmed #25481712.

ABSTRACT: BACKGROUND & AIMS: Pancreatic imaging can identify neoplastic cysts but not microscopic neoplasms. Mutation analysis of pancreatic fluid after secretin stimulation might identify microscopic neoplasias in the pancreatic duct system. We determined the prevalence of mutations in KRAS and guanine nucleotide-binding protein α-stimulating genes in pancreatic juice from subjects undergoing endoscopic ultrasound for suspected pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasms, or pancreatic adenocarcinoma. METHODS: Secretin-stimulated juice samples were collected from the duodenum of 272 subjects enrolled in Cancer of the Pancreas Screening studies; 194 subjects were screened because of a family history of, or genetic predisposition to, pancreatic cancer, and 78 subjects were evaluated for pancreatic cancer (n = 30) or other disorders (controls: pancreatic cysts, pancreatitis, or normal pancreata, n = 48). Mutations were detected by digital high-resolution melt-curve analysis and pyrosequencing. The number of replicates containing a mutation determined the mutation score. RESULTS: KRAS mutations were detected in pancreatic juice from larger percentages of subjects with pancreatic cancer (73%) or undergoing cancer screening (50%) than controls (19%) (P = .0005). A greater proportion of patients with pancreatic cancer had at least 1 KRAS mutation detected 3 or more times (47%) than screened subjects (21%) or controls (6%, P = .002). Among screened subjects, mutations in KRAS (but not guanine nucleotide-binding protein α-stimulating) were found in similar percentages of patients with or without pancreatic cysts. However, a greater proportion of patients older than age 50 years had KRAS mutations (54.6%) than younger patients (36.3%) (P = .032); the older subjects also had more mutations in KRAS (P = .02). CONCLUSIONS: Mutations in KRAS are detected in pancreatic juice from the duodenum of 73% of patients with pancreatic cancer, and 50% of asymptomatic individuals with a high risk for pancreatic cancer. However, KRAS mutations were detected in pancreatic juice from 19% of controls. Mutations detected in individuals without pancreatic abnormalities, based on imaging analyses, likely arise from small pancreatic intraepithelial neoplasia lesions. ClinicalTrials.gov no: NCT00438906 and NCT00714701.

14 Article Having pancreatic cancer with tumoral loss of ATM and normal TP53 protein expression is associated with a poorer prognosis. 2014

Kim, Haeryoung / Saka, Burcu / Knight, Spencer / Borges, Michael / Childs, Erica / Klein, Alison / Wolfgang, Christopher / Herman, Joseph / Adsay, Volkan N / Hruban, Ralph H / Goggins, Michael. ·Authors' Affiliations: Departments of Pathology, Medicine, Oncology, Surgery and Radiation Oncology, and Molecular Radiation Sciences, The Sol Goldman Pancreatic Cancer Research Center; Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins Medical Institutions, Baltimore, Maryland; Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South Korea; and Department of Pathology, Emory University Hospital, Atlanta, Georgia. ·Clin Cancer Res · Pubmed #24486587.

ABSTRACT: PURPOSE: To determine how often loss of ataxia-telangiectasia-mutated (ATM) protein expression occurs in primary pancreatic ductal adenocarcinomas and to determine its prognostic significance. EXPERIMENTAL DESIGN: The expression of ATM and TP53 was determined by immunohistochemistry in 397 surgically resected pancreatic ductal adenocarcinomas (Hopkins; Johns Hopkins Medical Institutions, Baltimore, MD), a second set of 159 cases (Emory; Emory University Hospital, Atlanta, GA), and 21 cancers after neoadjuvant chemoradiotherapy. Expression was correlated with the clinicopathologic parameters, including survival. RESULTS: Tumoral ATM loss was observed in one cancer known to have biallelic inactivation of ATM and 50 of the first 396 (12.8%) cases, significantly more often in patients with a family history of pancreatic cancer (12/49; 24.5%) than in those without (38/347; 11.0%; P = 0.019). In the Hopkins series, ATM loss was associated with a significantly decreased overall survival in patients whose cancers had normal TP53 expression (P = 0.019) and was a significant independent predictor of decreased overall survival (P = 0.014). Seventeen (10.7%) of 159 Emory cases had tumoral ATM loss and tumoral ATM loss/normal TP53 was associated with poorer overall survival (P = 0.1). Multivariate analysis of the combined Hopkins/Emory cases found that tumoral ATM loss/normal TP53 was an independent predictor of decreased overall survival [HR = 2.61; confidence interval (CI), 1.27-5.37; P = 0.009]. Of 21 cancers examined after neoadjuvant chemoradiotherapy, one had tumoral loss of ATM; it had no histologic evidence of tumor response. CONCLUSIONS: Tumoral loss of ATM protein was detected more often in patients with a family history of pancreatic cancer than in those without. Patients whose pancreatic cancers had loss of ATM but normal TP53 had worse overall survival after pancreatic resection.

15 Article Mutant TP53 in duodenal samples of pancreatic juice from patients with pancreatic cancer or high-grade dysplasia. 2013

Kanda, Mitsuro / Sadakari, Yoshihiko / Borges, Michael / Topazian, Mark / Farrell, James / Syngal, Sapna / Lee, Jeffrey / Kamel, Ihab / Lennon, Anne Marie / Knight, Spencer / Fujiwara, Sho / Hruban, Ralph H / Canto, Marcia Irene / Goggins, Michael. ·Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA. ·Clin Gastroenterol Hepatol · Pubmed #23200980.

ABSTRACT: BACKGROUND & AIMS: Imaging tests can identify patients with pancreatic neoplastic cysts but not microscopic dysplasia. We investigated whether mutant TP53 can be detected in duodenal samples of secretin-stimulated pancreatic juice, and whether this assay can be used to screen for high-grade dysplasia and invasive pancreatic cancer. METHODS: We determined the prevalence of mutant TP53 in microdissected pancreatic intraepithelial neoplasias (PanINs), intraductal papillary mucinous neoplasms (IPMNs), and invasive adenocarcinomas. TP53 mutations were quantified by digital high-resolution melt-curve analysis and sequencing of secretin-stimulated pancreatic juice samples, collected from duodena of 180 subjects enrolled in Cancer of the Pancreas Screening trials; patients were enrolled because of familial and/or inherited predisposition to pancreatic cancer, or as controls. RESULTS: TP53 mutations were identified in 9.1% of intermediate-grade IPMNs (2 of 22), 17.8% of PanIN-2 (8 of 45), 38.1% of high-grade IPMNs (8 of 21), 47.6% of PanIN-3 (10 of 21), and 75% of invasive pancreatic adenocarcinomas (15 of 20); no TP53 mutations were found in PanIN-1 lesions or low-grade IPMNs. TP53 mutations were detected in duodenal samples of pancreatic juice from 29 of 43 patients with pancreatic ductal adenocarcinoma (67.4% sensitivity; 95% confidence interval, 0.52-0.80) and 4 of 8 patients with high-grade lesions (PanIN-3 and high-grade IPMN). No TP53 mutations were identified in samples from 58 controls or 55 screened individuals without evidence of advanced lesions. CONCLUSIONS: We detected mutant TP53 in secretin-stimulated pancreatic juice samples collected from duodena of patients with high-grade dysplasia or invasive pancreatic cancer. Tests for mutant TP53 might be developed to improve the diagnosis of and screening for pancreatic cancer and high-grade dysplasia. Clinical Trial numbers: NCT00438906 and NCT00714701.

16 Article Mutant GNAS detected in duodenal collections of secretin-stimulated pancreatic juice indicates the presence or emergence of pancreatic cysts. 2013

Kanda, Mitsuro / Knight, Spencer / Topazian, Mark / Syngal, Sapna / Farrell, James / Lee, Jeffrey / Kamel, Ihab / Lennon, Anne Marie / Borges, Michael / Young, Angela / Fujiwara, Sho / Seike, Junro / Eshleman, James / Hruban, Ralph H / Canto, Marcia Irene / Goggins, Michael. ·Johns Hopkins Medical Institutions, Department of Pathology, Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, 1550 Orleans Street, Baltimore, MD 21231, USA. ·Gut · Pubmed #22859495.

ABSTRACT: OBJECTIVE: Pancreatic cysts are commonly detected in patients undergoing pancreatic imaging. Better approaches are needed to characterise these lesions. In this study we evaluated the utility of detecting mutant DNA in secretin-stimulated pancreatic juice. DESIGN: Secretin-stimulated pancreatic juice was collected from the duodenum of 291 subjects enrolled in Cancer of the Pancreas Screening trials at five US academic medical centres. The study population included subjects with a familial predisposition to pancreatic cancer who underwent pancreatic screening, and disease controls with normal pancreata, chronic pancreatitis, sporadic intraductal papillary mucinous neoplasm (IPMN) or other neoplasms. Somatic GNAS mutations (reported prevalence ≈ 66% of IPMNs) were measured using digital high-resolution melt-curve analysis and pyrosequencing. RESULTS: GNAS mutations were detected in secretin-stimulated pancreatic juice samples of 50 of 78 familial and sporadic cases of IPMN(s) (64.1%), 15 of 33 (45.5%) with only diminutive cysts (<5 mm), but none of 57 disease controls. GNAS mutations were also detected in five of 123 screened subjects without a pancreatic cyst. Among 97 subjects who had serial pancreatic evaluations, GNAS mutations detected in baseline juice samples predicted subsequent emergence or increasing size of pancreatic cysts. CONCLUSION: Duodenal collections of secretin-stimulated pancreatic juice from patients with IPMNs have a similar prevalence of mutant GNAS to primary IPMNs, indicating that these samples are an excellent source of mutant DNA from the pancreas. The detection of GNAS mutations before an IPMN is visible suggests that analysis of pancreatic juice has the potential to help in the risk stratification and surveillance of patients undergoing pancreatic screening.

17 Article Genome-wide somatic copy number alterations in low-grade PanINs and IPMNs from individuals with a family history of pancreatic cancer. 2012

Hong, Seung-Mo / Vincent, Audrey / Kanda, Mitsuro / Leclerc, Julie / Omura, Noriyuki / Borges, Michael / Klein, Alison P / Canto, Marcia Irene / Hruban, Ralph H / Goggins, Michael. ·Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA. ·Clin Cancer Res · Pubmed #22723370.

ABSTRACT: PURPOSE: Characterizing the earliest chromosomal alterations of pancreatic precursor neoplasms from individuals with a familial aggregation of pancreatic cancer may provide clues as to the loci of pancreatic cancer susceptibility genes. EXPERIMENTAL DESIGN: We used Illumina 370/660K SNP arrays to conduct genome-wide copy number analysis in 60 benign neoplasms [58 mostly low-grade pancreatic intraepithelial neoplasias (PanIN) and intraductal papillary mucinous neoplasms (IPMN) and two pancreatic neuroendocrine tumors (PNET)] and matched normal tissues from 16 individuals with a family history of pancreatic cancer. PanINs and IPMNs were analyzed for KRAS codon 12/13 mutations. RESULTS: Of 40 benign neoplasms with adequate SNP calls and allele ratios, somatic chromosomal copy number changes were identifiable in only nine lesions, including eight of the 38 PanIN/IPMNs (two of which had identical alterations) and one of the two PNETs. Only two precursor lesions had more than one somatic copy number alteration. In contrast, the overwhelming majority (∼95%) of PanINs harbored KRAS mutations. The chromosomal alterations identified included nine chromosomal arms affected by chromosomal loss and two by chromosomal gain. Copy number loss spanning 9p21.3 was identified in three precursor lesions; two precursors had chromosomal losses affecting 6q and 17p. CONCLUSIONS: Low- and intermediate-grade PanINs and IPMNs from patients with a family history of pancreatic cancer harbor few if any somatic chromosomal alterations. The absence of a locus of recurrent chromosomal loss in most low-grade pancreatic cancer precursor lesions supports the hypothesis that there is no one tumor suppressor gene locus consistently involved in initiating familial pancreatic neoplasia.

18 Article Analysis of polymorphisms and haplotype structure of the human thymidylate synthase genetic region: a tool for pharmacogenetic studies. 2012

Ghosh, Soma / Hossain, M Zulfiquer / Borges, Michael / Goggins, Michael G / Ingersoll, Roxann G / Eshleman, James R / Klein, Alison P / Kern, Scott E. ·Department of Oncology, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America. ·PLoS One · Pubmed #22496803.

ABSTRACT: 5-Fluorouracil (5FU), a widely used chemotherapeutic drug, inhibits the DNA replicative enzyme, thymidylate synthase (Tyms). Prior studies implicated a VNTR (variable numbers of tandem repeats) polymorphism in the 5'-untranslated region (5'-UTR) of the TYMS gene as a determinant of Tyms expression in tumors and normal tissues and proposed that these VNTR genotypes could help decide fluoropyrimidine dosing. Clinical associations between 5FU-related toxicity and the TYMS VNTR were reported, however, results were inconsistent, suggesting that additional genetic variation in the TYMS gene might influence Tyms expression. We thus conducted a detailed genetic analysis of this region, defining new polymorphisms in this gene including mononucleotide (poly A:T) repeats and novel single nucleotide polymorphisms (SNPs) flanking the VNTR in the TYMS genetic region. Our haplotype analysis of this region used data from both established and novel genetic variants and found nine SNP haplotypes accounting for more than 90% of the studied population. We observed non-exclusive relationships between the VNTR and adjacent SNP haplotypes, such that each type of VNTR commonly occurred on several haplotype backgrounds. Our results confirmed the expectation that the VNTR alleles exhibit homoplasy and lack the common ancestry required for a reliable marker of a linked adjacent locus that might govern toxicity. We propose that it may be necessary in a clinical trial to assay multiple types of genetic polymorphisms in the TYMS region to meaningfully model linkage of genetic markers to 5FU-related toxicity. The presence of multiple long (up to 26 nt), polymorphic monothymidine repeats in the promoter region of the sole human thymidylate synthetic enzyme is intriguing.

19 Article Presence of somatic mutations in most early-stage pancreatic intraepithelial neoplasia. 2012

Kanda, Mitsuro / Matthaei, Hanno / Wu, Jian / Hong, Seung-Mo / Yu, Jun / Borges, Michael / Hruban, Ralph H / Maitra, Anirban / Kinzler, Kenneth / Vogelstein, Bert / Goggins, Michael. ·Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. ·Gastroenterology · Pubmed #22226782.

ABSTRACT: More information is needed about genetic factors that initiate development of pancreatic intraepithelial neoplasms-the most common precursors of pancreatic ductal adenocarcinoma. We show that more than 99% of the earliest-stage, lowest-grade, pancreatic intraepithelial neoplasm-1 lesions contain mutations in KRAS, p16/CDKN2A, GNAS, or BRAF. These findings could improve our understanding of the development and progression of these premalignant lesions.

20 Article Pancreatic cancers epigenetically silence SIP1 and hypomethylate and overexpress miR-200a/200b in association with elevated circulating miR-200a and miR-200b levels. 2010

Li, Ang / Omura, Noriyuki / Hong, Seung-Mo / Vincent, Audrey / Walter, Kimberly / Griffith, Margaret / Borges, Michael / Goggins, Michael. ·Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, Maryland 21231, USA. ·Cancer Res · Pubmed #20551052.

ABSTRACT: Aberrant DNA methylation and microRNA expression play important roles in the pathogenesis of pancreatic cancer. While interrogating differentially methylated CpG islands in pancreatic cancer, we identified two members of miR-200 family, miR-200a and miR-200b, that were hypomethylated and overexpressed in pancreatic cancer. We also identified prevalent hypermethylation and silencing of one of their downstream targets, SIP1 (ZFHX1B, ZEB2), whose protein product suppresses E-cadherin expression and contributes to epithelial mesenchymal transition. In a panel of 23 pancreatic cell lines, we observed a reciprocal correlation between miR-200, SIP1, and E-cadherin expression, with pancreatic cancer-associated fibroblasts showing the opposite expression pattern to most pancreatic cancers. In Panc-1 cells, which express SIP1, have low E-cadherin expression, and do not express miR-200a or miR-200b, treatment with miR-200a and miR-200b downregulated SIP1 mRNA and increased E-cadherin expression. However, most pancreatic cancers express miR-200a and miR-200b, but this expression does not affect SIP1 expression, as the SIP1 promoter is silenced by hypermethylation and in these cancers E-cadherin is generally expressed. Both miR-200a and miR-200b were significantly elevated in the sera of pancreatic cancer and chronic pancreatitis patients compared with healthy controls (P < 0.0001), yielding receiver operating characteristic curve areas of 0.861 and 0.85, respectively. In conclusion, most pancreatic cancers display hypomethylation and overexpression of miR-200a and miR-200b, silencing of SIP1 by promoter methylation, and retention of E-cadherin expression. The elevated serum levels of miR-200a and miR-200b in most patients with pancreatic cancer could have diagnostic utility.

21 Article Cyclooxygenase-deficient pancreatic cancer cells use exogenous sources of prostaglandins. 2010

Omura, Noriyuki / Griffith, Margaret / Vincent, Audrey / Li, Ang / Hong, Seung-Mo / Walter, Kimberly / Borges, Michael / Goggins, Michael. ·The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, CRBII Room 342, 1550 Orleans Street, Baltimore, MD 21231, USA. ·Mol Cancer Res · Pubmed #20530583.

ABSTRACT: Genes that are differentially expressed in pancreatic cancers and under epigenetic regulation are of considerable biological and therapeutic interest. We used global gene expression profiling and epigenetic treatment of pancreatic cell lines including pancreatic cancer cell lines, pancreatic cancer-associated fibroblasts, and cell lines derived from nonneoplastic pancreata. We examined expression and epigenetic alterations of cyclooxygenase-1 (COX-1) and COX-2 in pancreatic cancers and normal pancreas and performed proliferation, knockdown, and coculture experiments to understand the role of stromal sources of prostaglandins for pancreatic cancers. We identify COX-1 as a gene under epigenetic regulation in pancreatic cancers. We find that COX-1 expression is absent in many pancreatic cancer cells and some of these cancers also lack COX-2 expression. Suspecting that such cancers must rely on exogenous sources of prostaglandins, we show that pancreatic cancer stromal cells, such as fibroblasts expressing COX-1 and COX-2, are a likely source of prostaglandins for pancreatic cancer cells deficient in COX. Knocking down the prostaglandin transporter multidrug resistance-associated protein-4 in fibroblasts suppresses the proliferation of cocultured pancreatic cancer cells lacking COX. Pancreatic cancers that lack COX can use exogenous sources of prostaglandins. Blocking multidrug resistance-associated protein-4 may be a useful therapeutic strategy to deplete COX-deficient pancreatic cancers of prostaglandins.

22 Article In vivo and in vitro propagation of intraductal papillary mucinous neoplasms. 2010

Kamiyama, Hirohiko / Kamiyama, Mihoko / Hong, Seung-Mo / Karikari, Collins A / Lin, Ming-Tseh / Borges, Michael W / Griffith, Margaret / Young, Angela / Norris-Kirby, Alexis / Lubek, Conrad / Mizuma, Masamichi / Feldmann, Georg / Shi, Chanjuan / Liang, Hong / Goggins, Michael G / Maitra, Anirban / Hruban, Ralph H / Eshleman, James R. ·Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. ·Lab Invest · Pubmed #20231822.

ABSTRACT: Intraductal papillary mucinous neoplasms (IPMNs) are one of the three known curable precursor lesions of invasive pancreatic ductal adenocarcinoma, an almost uniformly fatal disease. Cell lines from IPMNs and their invasive counterparts should be valuable to identify gene mutations critical to IPMN carcinogenesis, and permit high-throughput screening to identify drugs that cause regression of these lesions. To advance the study of the biological features of IPMNs, we attempted in vivo and in vitro growth of selected IPMNs based on the hypothesis that IPMNs could be grown in the most severely immunodeficient mice. We examined 14 cases by implanting them into nude, severe combined immunodeficient (SCID), and NOD/SCID/IL2Rgamma(null) (NOG) mice, in addition to direct culture, to generate tumor xenografts and cell lines. One sample was directly cultured only. Thirteen tumors were implanted into the three types of mice, including 10 tumors implanted into the triple immunodeficient NOG mice, in which the majority (8 of 10) grew. This included five IPMNs lacking an invasive component. One of the explanted IPMNs, with an associated invasive carcinoma, was successfully established as a cell line. Tumorigenicity was confirmed by growth in soft agar, growth in immunodeficient mice, and the homozygous deletion of p16/cdkn2a. Epithelial differentiation of the cell line was documented by cytokeratin expression. Patient origin was confirmed using DNA fingerprinting. Most non-invasive IPMNs grow in NOG mice. We successfully established one IPMN cell line, and plan to use it to clarify the molecular pathogenesis of IPMNs.

23 Article Overexpression of smoothened activates the sonic hedgehog signaling pathway in pancreatic cancer-associated fibroblasts. 2010

Walter, Kimberly / Omura, Noriyuki / Hong, Seung-Mo / Griffith, Margaret / Vincent, Audrey / Borges, Michael / Goggins, Michael. ·Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA. ·Clin Cancer Res · Pubmed #20215540.

ABSTRACT: PURPOSE: Accumulating evidence suggests that cancer-associated stromal fibroblasts (CAF) contribute to tumor growth by actively communicating with cancer cells. Our aim is to identify signaling pathways involved in tumor-stromal cell interactions in human pancreatic cancer. EXPERIMENTAL DESIGN: We established primary fibroblast cultures from human pancreatic adenocarcinomas and nonneoplastic pancreas tissues. To identify differentially expressed genes in CAFs, we did gene expression profiling of human pancreatic CAFs and nonneoplastic pancreatic fibroblasts. RESULTS: The Hedgehog receptor Smoothened (SMO) was upregulated in CAFs relative to control fibroblasts. CAFs expressing SMO could transduce the Sonic hedgehog signal to activate Gli1 expression, and small interfering RNA knockdown of SMO blocked the induction of Gli1 in these cells. Stromal fibroblasts of human primary pancreatic adenocarcinomas overexpressed Smo compared with normal pancreatic fibroblasts. CONCLUSIONS: These findings implicate overexpression of Smo as a mechanism for the activation of Hedgehog signaling in human pancreatic CAFs and suggest that stromal cells may be a therapeutic target for Smo antagonists in pancreatic cancer.