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Pancreatic Neoplasms: HELP
Articles by Ayelet Eppel Borgida
Based on 23 articles published since 2009
(Why 23 articles?)
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Between 2009 and 2019, A. Borgida wrote the following 23 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Guideline Comparison of Practice Guidelines, BRCAPRO, and Genetic Counselor Estimates to Identify Germline BRCA1 and BRCA2 Mutations in Pancreatic Cancer. 2018

Grant, Robert C / Holter, Spring / Borgida, Ayelet / Dhani, Neesha C / Hedley, David W / Knox, Jennifer J / Akbari, Mohammad R / Zogopoulos, George / Gallinger, Steven. ·Division of Medical Oncology, University of Toronto, Toronto, Canada. robert.grant@utoronto.ca. · Ontario Institute for Cancer Research, Toronto, Canada. robert.grant@utoronto.ca. · Princess Margaret Cancer Centre-Ontario Power Generation, 700 University Avenue, Work Station 7W460, Toronto, ON, M5G 1Z5, Canada. robert.grant@utoronto.ca. · Ontario Pancreas Cancer Study, Toronto, Canada. · Division of Medical Oncology, University of Toronto, Toronto, Canada. · Wallace McCain Centre for Pancreatic Cancer, University of Toronto, Toronto, Canada. · Dalla Lana School of Public Health, University of Toronto, Toronto, Canada. · Women's College Research Institute, Toronto, Canada. · Research Institute of the McGill University Health Centre, Montreal, Canada. · Goodman Cancer Research Centre, McGill University, Montreal, Canada. · Ontario Institute for Cancer Research, Toronto, Canada. · Princess Margaret Cancer Centre-Ontario Power Generation, 700 University Avenue, Work Station 7W460, Toronto, ON, M5G 1Z5, Canada. · Division of General Surgery, University of Toronto, Toronto, Canada. ·J Genet Couns · Pubmed #29441441.

ABSTRACT: Germline BRCA1 and BRCA2 (BRCA) mutation carriers with pancreatic ductal adenocarcinoma (PDAC) may benefit from precision therapies and their relatives should undergo tailored cancer prevention. In this study, we compared strategies to identify BRCA carriers with PDAC. Incident cases of PDAC were prospectively recruited for BRCA sequencing. Probands were evaluated using the National Comprehensive Cancer Network (NCCN) and the Ontario Ministry of Health and Long-Term Care (MOHLTC) guidelines. The probability of each proband carrying a mutation was estimated by surveying genetic counselors and using BRCAPRO. BRCA mutations were detected in 22/484 (4.5%) probands. 152/484 (31.2%) and 16/484 (3.3%) probands met the NCCN and MOHLTC guidelines, respectively. The NCCN guidelines had higher sensitivity than the MOHLTC guidelines (0.864 versus 0.227, P < 0.001) but lower specificity (0.712 versus 0.976, P < 0.001). One hundred and nineteen genetic counselors completed the survey. Discrimination was similar between genetic counselors and BRCAPRO (area-under-the-curve: 0.755 and 0.775, respectively, P = 0.702). Genetic counselors generally overestimated (P = 0.008), whereas BRCAPRO severely underestimated (P < 0.001), the probability that each proband carried a mutation. Our results indicate that the NCCN guidelines and genetic counselors accurately identify BRCA mutations in PDAC, while the MOHLTC guidelines and BRCAPRO should be updated to account for the association between BRCA and PDAC.

2 Article Sensitive tumour detection and classification using plasma cell-free DNA methylomes. 2018

Shen, Shu Yi / Singhania, Rajat / Fehringer, Gordon / Chakravarthy, Ankur / Roehrl, Michael H A / Chadwick, Dianne / Zuzarte, Philip C / Borgida, Ayelet / Wang, Ting Ting / Li, Tiantian / Kis, Olena / Zhao, Zhen / Spreafico, Anna / Medina, Tiago da Silva / Wang, Yadon / Roulois, David / Ettayebi, Ilias / Chen, Zhuo / Chow, Signy / Murphy, Tracy / Arruda, Andrea / O'Kane, Grainne M / Liu, Jessica / Mansour, Mark / McPherson, John D / O'Brien, Catherine / Leighl, Natasha / Bedard, Philippe L / Fleshner, Neil / Liu, Geoffrey / Minden, Mark D / Gallinger, Steven / Goldenberg, Anna / Pugh, Trevor J / Hoffman, Michael M / Bratman, Scott V / Hung, Rayjean J / De Carvalho, Daniel D. ·Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. · Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada. · Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. · Genome Technologies, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · UMR_S 1236, Univ Rennes 1, Inserm, Etablissement Français du sang Bretagne, Rennes, France. · Department of Biochemistry and Molecular Medicine, UC Davis Comprehensive Cancer Center, Sacramento, CA, USA. · Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada. · Fred Litwin Centre for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. · Department of Surgery, Toronto General Hospital, Toronto, Ontario, Canada. · Department of Computer Science, University of Toronto, Toronto, Ontario, Canada. · Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada. rayjean.hung@lunenfeld.ca. · Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada. rayjean.hung@lunenfeld.ca. · Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. ddecarv@uhnresearch.ca. · Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. ddecarv@uhnresearch.ca. ·Nature · Pubmed #30429608.

ABSTRACT: The use of liquid biopsies for cancer detection and management is rapidly gaining prominence

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 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

5 Article Overall survival and clinical characteristics of BRCA mutation carriers with stage I/II pancreatic cancer. 2017

Golan, Talia / Sella, Tal / O'Reilly, Eileen M / Katz, Matthew H G / Epelbaum, Ron / Kelsen, David P / Borgida, Ayelet / Maynard, Hannah / Kindler, Hedy / Friedmen, Eitan / Javle, Milind / Gallinger, Steven. ·Department of Oncology, Sheba Medical Center, Ramat Gan 52621, Israel. · Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel. · Department of Medicine, Memorial Sloan Kettering Cancer Center New York, New York, NY 10065, USA. · Weill Cornell Medical College New York, New York, NY 10065, USA. · Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. · Department of Oncology, Rambam Health Care Campus, Haifa 3109601, Israel. · The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3109601, Israel. · Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada. · Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA. · The Susanne Levy Gertner Oncogenetics Unit, Sheba Medical Center, Ramat Gan 52621, Israel. · Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. ·Br J Cancer · Pubmed #28183138.

ABSTRACT: BACKGROUND: BRCA1/BRCA2 germ line (GL) mutation carriers with pancreatic adenocarcinoma (PDAC) may have distinct outcomes. We recently described an apparent more favourable prognosis of surgically resected BRCA-associated PDAC patients in a single-arm, uncontrolled, retrospective study. However, the prognostic impact of GL BRCA1/2 mutations in surgically resected PDAC has not been compared with a matched control population. METHODS: A larger multi-centre, case-control retrospective analysis was performed. Cases were patients with surgically resected, BRCA1/2-associated PDAC from 2004 to 2013. Controls included surgically resected PDAC cases treated during the same time period that were either BRCA non-carriers, or had no family history of breast, ovarian or pancreatic cancers. Cases and controls were matched by: age at diagnosis (within ±5-year period) and institution. Demographics, clinical history, overall survival (OS) and disease-free survival (DFS) were abstracted from patient records. Statistical comparisons were assessed using χ RESULTS: Twenty-five patients with BRCA1-(n=4) or BRCA2 (N=21)-associated resectable PDAC were identified. Mean age was 55.7 years (range, 34-78 years), 48% (n=12) were females and 76% (n=19) were Jewish. Cases were compared (1 : 2) with 49 resectable PDAC controls, and were balanced for age, ethnicity and other relevant clinical and pathological features. BRCA-associated PDAC patients received neoadjuvant, or adjuvant platinum-based treatment more frequently than controls (7 out of 8 vs 6 out of 14) and (7 out of 21 vs 3 out of 44), respectively. No significant difference in median OS (37.06 vs 38.77 months, P=0.838) and in DFS (14.3 vs 12.0 months, P=0.303) could be demonstrated between cases and controls. A trend to increased DFS was observed among BRCA-positive cases treated with neoadjuvant/adjuvant platinum-containing regimens (n=10) compared with similarly treated controls (n=7) (39.1 vs 12.4 months, P=0.255). CONCLUSIONS: In this retrospective analysis, the prognosis of surgically resectable BRCA-associated PDAC is no different than that of sporadic PDAC from the same institution. The role of platinum-based adjuvant therapy in this setting requires prospective investigation.

6 Article Senescent Carcinoma-Associated Fibroblasts Upregulate IL8 to Enhance Prometastatic Phenotypes. 2017

Wang, Tao / Notta, Faiyaz / Navab, Roya / Joseph, Joella / Ibrahimov, Emin / Xu, Jing / Zhu, Chang-Qi / Borgida, Ayelet / Gallinger, Steven / Tsao, Ming-Sound. ·Princess Margaret Cancer Centre, University Health Network, Toronto, Canada. · Department of Pathology, University Health Network, Toronto, Canada. · Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada. · Ontario Institute for Cancer Research, Toronto, Canada. · Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Canada. · Department of General Surgery, University Health Network, Toronto, Canada. · Department of Surgery, University of Toronto, Toronto, Canada. · Princess Margaret Cancer Centre, University Health Network, Toronto, Canada. ming.tsao@uhn.ca. ·Mol Cancer Res · Pubmed #27678171.

ABSTRACT: Carcinoma-associated fibroblasts (CAF) represent a significant component of pancreatic cancer stroma and are biologically implicated in tumor progression. However, evidence of both cancer-promoting and -restraining properties amongst CAFs suggests the possibility of multiple phenotypic subtypes. Here, it is demonstrated that senescent CAFs promote pancreatic cancer invasion and metastasis compared with nonsenescent control CAFs using in vitro Transwell invasion models and in vivo xenograft mouse models. Screening by gene expression microarray and cytokine ELISA assays revealed IL8 to be upregulated in senescent CAFs. Experimental modulation through IL8 overexpression or receptor inhibition implicates the IL8 pathway as a mediator of the proinvasive effects of senescent CAFs. In a cohort of human pancreatic cancer cases, more abundant stromal senescence as indicated by p16 immunohistochemistry correlated with decreased survival in patients with early-stage disease. These data support senescent fibroblasts as a pathologically and clinically relevant feature of pancreatic cancer. The inhibition of senescent stroma-cancer signaling pathways has the potential to restrain pancreatic cancer progression. IMPLICATIONS: Findings show that senescent cancer-associated fibroblasts secret excess IL8 to promote pancreatic cancer invasion and metastasis; thus, senescent CAFs represent a phenotypic subtype, challenging conventional assumptions that CAFs are a homogeneous population. Mol Cancer Res; 15(1); 3-14. ©2016 AACR.

7 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.

8 Article BRM polymorphisms, pancreatic cancer risk and survival. 2016

Segedi, Maja / Anderson, Laura N / Espin-Garcia, Osvaldo / Borgida, Ayelet / Bianco, Teresa / Cheng, Dangxiao / Chen, Zhuo / Patel, Devalben / Brown, M Catherine / Xu, Wei / Reisman, David / Gallinger, Steven / Cotterchio, Michelle / Hung, Rayjean / Liu, Geoffrey / Cleary, Sean P. ·Department of Surgery, University of British Columbia, Vancouver, BC, Canada. · Princess Margaret Cancer Centre-University Health Network-Ontario Cancer Institute, University of Toronto, Toronto, ON, Canada. · Mount Sinai Hospital-Lunenfeld Research Institute, Toronto, ON, Canada. · Medical Oncology, University of Florida, Gainesville, FL. · Prevention and Cancer Control, Cancer Care Ontario, Toronto, ON, Canada. · Princess Margaret Cancer Centre-University Health Network-Ontario Cancer Institute, University of Toronto, Toronto, ON, Canada. Geoffrey.Liu@uhn.ca. ·Int J Cancer · Pubmed #27487558.

ABSTRACT: Variant alleles of two promoter polymorphisms in the BRM gene (BRM-741, BRM-1321), create MEF2D transcription binding sites that lead to epigenetic silencing of BRM, the key catalytic component of the SWI/SNF chromatin remodeling complex. BRM suppression can be reversed pharmacologically.(1) Our group and others have reported associations with lung, head and neck, hepatocellular cancer risk,(1-3) and with lung and esophageal cancer prognosis (ASCO 2013; abstract 11057 & 4077). Herein, we assessed risk and survival associations with pancreatic cancer. A provincial population-based case-control study was conducted with 623 histologically confirmed pancreatic adenocarcinoma cases and 1,192 age/gender distribution-matched controls.(4) Survival of cases was obtained through the Ontario Cancer Registry. Logistic and Cox proportional hazard regression models were fitted, adjusting for relevant covariates. Median age was 65 y; 52% were male; Stage I (8%), II (55%), III (14%), IV (23%); 53% after curative resection, 79% after chemotherapy; and 83% had died. In the risk analysis, adjusted odds ratios (aOR) were 1.01 (95% CI: 0.1-2.0) and 0.96 (95% CI: 0.7-1.3) for the homozygotes of BRM-741 and BRM-1321, respectively; aOR of double-homozygotes was 1.11 (95% CI: 0.80-1.53), compared to the double-wildtype. For the survival analysis, adjusted hazard ratios (aHR) were 2.19 (95% CI: 1.9-2.5) for BRM-741 and 1.94 (95% CI: 1.7-2.2) for BRM-1321, per unit increase in variant alleles. Compared with the double-wildtype, aHR for carrying no, one, and two double-homozygotes were 2.14 (95% CI: 1.6-2.8), 4.17 (95% CI: 3.0-5.7), 8.03 (95% CI: 5.7-11.4), respectively. In conclusion, two functional promoter BRM polymorphisms were not associated with pancreatic adenocarcinoma risk, but are strongly associated with survival.

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 BRCA1 and BRCA2 mutations sensitize to chemotherapy in patient-derived pancreatic cancer xenografts. 2015

Lohse, I / Borgida, A / Cao, P / Cheung, M / Pintilie, M / Bianco, T / Holter, S / Ibrahimov, E / Kumareswaran, R / Bristow, R G / Tsao, M-S / Gallinger, S / Hedley, D W. ·Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 2M9. · Mount Sinai Hospital, Joseph and Wolf Lebovic Health Complex, Toronto, Ontario, Canada M5G 2M9. · 1] Mount Sinai Hospital, Joseph and Wolf Lebovic Health Complex, Toronto, Ontario, Canada M5G 2M9 [2] Translational Research Initiative in Pancreas Cancer, Ontario Institute for Cancer Research, Toronto, Ontario, Canada M5G 2M9. · 1] Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 2M9 [2] Mount Sinai Hospital, Joseph and Wolf Lebovic Health Complex, Toronto, Ontario, Canada M5G 2M9. · 1] Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 2M9 [2] Department of Pathology, University Health Network, Toronto, Ontario, Canada M5G 2M9 [3] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada M5G 2M9. · 1] Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 2M9 [2] Translational Research Initiative in Pancreas Cancer, Ontario Institute for Cancer Research, Toronto, Ontario, Canada M5G 2M9 [3] Department of Medical Oncology and Haematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada M5G 2M9. ·Br J Cancer · Pubmed #26180923.

ABSTRACT: BACKGROUND: Germline mutations of the BRCA tumour suppressors have been associated with increased risk of pancreatic cancer. Clinical evidence suggests that these patients may be more sensitive to treatment with cisplatin. As the frequency of germline BRCA mutations is low, definitive experimental data to support the clinical observations are still missing. METHODS: We tested gemcitabine and cisplatin sensitivity of four BRCA1 and BRCA2 mutant and three BRCA1 and BRCA2 wild-type (WT) patient-derived pancreatic cancer xenografts. RESULTS: We observed treatment sensitivity to gemcitabine and cisplatin in the BRCA WT and mutant models. The BRCA1 and BRCA2 mutant xenografts were significantly more sensitive to cisplatin although these models also showed sensitivity to gemcitabine. The BRCA1 and BRCA2 WT models showed sensitivity to gemcitabine but not cisplatin. Treatment sensitivity in the xenograft models closely resembled treatment response in the corresponding patients. DISCUSSION: We have characterised a panel of xenografts derived from pancreatic cancer patients carrying germline BRCA mutations, and shown that their genetic features resemble the patient donor. Our results support further clinical testing of treatment regimens combining gemcitabine and platinum drugs in this patient population, as well as preclinical research aiming to identify mechanisms of cisplatin resistance in BRCA mutant pancreatic cancers.

11 Article Germline BRCA Mutations in a Large Clinic-Based Cohort of Patients With Pancreatic Adenocarcinoma. 2015

Holter, Spring / Borgida, Ayelet / Dodd, Anna / Grant, Robert / Semotiuk, Kara / Hedley, David / Dhani, Neesha / Narod, Steven / Akbari, Mohammad / Moore, Malcolm / Gallinger, Steven. ·Spring Holter, Ayelet Borgida, Robert Grant, Kara Semotiuk, and Steven Gallinger, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital · Anna Dodd, David Hedley, Neesha Dhani, Malcolm Moore, and Steven Gallinger, McCain Pancreatic Cancer Centre, University Health Network · and Steven Narod and Mohammad Akbari, Women's College Research Institute, Toronto, Ontario, Canada. ·J Clin Oncol · Pubmed #25940717.

ABSTRACT: PURPOSE: The main purpose of this study was to determine the prevalence of pathogenic BRCA1 and BRCA2 mutations in a consecutively ascertained clinic-based cohort of patients with pancreatic ductal adenocarcinoma and describe the clinical and family history characteristics. PATIENTS AND METHODS: Unselected, consecutive, incident patients with pancreatic ductal adenocarcinoma were recruited at a single cancer center over a 2-year period. Participants provided blood for DNA analysis and cancer family history, and cancer treatment records were reviewed. DNA from all patients was analyzed by Sanger sequencing and multiplex ligation-dependent probe amplification for germline variants in BRCA1 and BRCA2. RESULTS: Three hundred six patients were eligible for analysis. Pathogenic germline BRCA mutations were identified in 14 patients (4.6%; 95% CI, 2.2% to 6.9%), including 11 patients with a BRCA2 mutation and three patients with a BRCA1 mutation. Having a cancer family history that met genetic testing criteria of the National Comprehensive Cancer Network or the Ontario Ministry of Health and Long-Term Care or self-reporting as Ashkenazi Jewish was significantly associated with BRCA mutation carrier status (P=.02, P<.001, and P=.05, respectively). However, the majority of the BRCA mutation-positive patients did not actually meet these genetic testing criteria. CONCLUSION: Pathogenic BRCA mutations were identified in 4.6% of a large cohort of clinic-based patients. Considering the implications for family members of BRCA carriers, and possibly tailored chemotherapeutic treatment of patients, our finding has implications for broader BRCA genetic testing for patients with pancreatic ductal adenocarcinoma.

12 Article Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer. 2015

Grant, Robert C / Selander, Iris / Connor, Ashton A / Selvarajah, Shamini / Borgida, Ayelet / Briollais, Laurent / Petersen, Gloria M / Lerner-Ellis, Jordan / Holter, Spring / Gallinger, Steven. ·Ontario Institute for Cancer Research, Canada; Department of Medicine, University of Toronto, Canada. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Canada. · Division of General Surgery, Department of Surgery, University Health Network, University of Toronto, Canada. · Laboratory Medicine and Pathobiology, University of Toronto, Canada. · Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota. · Ontario Institute for Cancer Research, Canada; Laboratory Medicine and Pathobiology, University of Toronto, Canada; Pathology and Laboratory Medicine, Mount Sinai Hospital, Canada. · Ontario Institute for Cancer Research, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Canada; Division of General Surgery, Department of Surgery, University Health Network, University of Toronto, Canada. Electronic address: steven.gallinger@uhn.on.ca. ·Gastroenterology · Pubmed #25479140.

ABSTRACT: BACKGROUND & AIMS: We investigated the prevalence of germline mutations in APC, ATM, BRCA1, BRCA2, CDKN2A, MLH1, MSH2, MSH6, PALB2, PMS2, PRSS1, STK11, and TP53 in patients with pancreatic cancer. METHODS: The Ontario Pancreas Cancer Study enrolls consenting participants with pancreatic cancer from a province-wide electronic pathology database; 708 probands were enrolled from April 2003 through August 2012. To improve the precision of BRCA2 prevalence estimates, 290 probands were selected from 3 strata, based on family history of breast and/or ovarian cancer, pancreatic cancer, or neither. Germline DNA was analyzed by next-generation sequencing using a custom multiple-gene panel. Mutation prevalence estimates were calculated from the sample for the entire cohort. RESULTS: Eleven pathogenic mutations were identified: 3 in ATM, 1 in BRCA1, 2 in BRCA2, 1 in MLH1, 2 in MSH2, 1 in MSH6, and 1 in TP53. The prevalence of mutations in all 13 genes was 3.8% (95% confidence interval, 2.1%-5.6%). Carrier status was associated significantly with breast cancer in the proband or first-degree relative (P < .01), and with colorectal cancer in the proband or first-degree relative (P < .01), but not family history of pancreatic cancer, age at diagnosis, or stage at diagnosis. Of patients with a personal or family history of breast and colorectal cancer, 10.7% (95% confidence interval, 4.4%-17.0%) and 11.1% (95% confidence interval, 3.0%-19.1%) carried pathogenic mutations, respectively. CONCLUSIONS: A small but clinically important proportion of pancreatic cancer is associated with mutations in known predisposition genes. The heterogeneity of mutations identified in this study shows the value of using a multiple-gene panel in pancreatic cancer.

13 Article The association of family history of cancer and medical history with pancreatic cancer risk. 2014

Fehringer, Gordon / Gallinger, Steven / Borgida, Ayelet / Zhang, Li Rita / Adams, Laura / Liu, Geoffrey / Hung, Rayjean J. ·Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada, Department of Surgery, University of Toronto, Toronto, Ontario, Canada Familial Gastrointestinal Cancer Registry, Digestive Diseases Clinical Research Centre, Joseph and Wolf Lebovic Centre, Mount Sinai Hospital Toronto, Ontario, Canada Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada University Health Network, Ontario Cancer Institute/Princess Margaret Hospital, Toronto, Ontario, Canada Department of Medicine, University of Toronto, Toronto, Ontario, Canada Lunenfeld-Tanenbaum Research Institute Mount Sinai Hospital, Toronto, Ontario, Canada rayjean.hung@lunenfeld.ca. ·Pancreas · Pubmed #24921205.

ABSTRACT: -- No abstract --

14 Article Interaction of polymorphisms in mitotic regulator genes with cigarette smoking and pancreatic cancer risk. 2013

Jang, Ji-Hyun / Cotterchio, Michelle / Borgida, Ayelet / Liu, Geoffrey / Gallinger, Steven / Cleary, Sean P. ·Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Prevention and Cancer Control, Cancer Care Ontario, Toronto, Ontario, Canada. ·Mol Carcinog · Pubmed #23908141.

ABSTRACT: Mitotic regulator genes have been associated with several cancers, however little is known about their possible association with pancreatic cancer. Smoking and family history are the strongest risk factors for this highly fatal disease. The main purpose of this study was to determine if polymorphisms of mitotic regulator genes are associated with pancreatic cancer and whether they modify the association between cigarette smoking and pancreatic cancer risk. A population-based case-control study was conducted in Ontario with 455 pathology-confirmed pancreatic cancer cases and 893 controls. Cigarette smoking history was collected using questionnaires and DNA obtained from blood samples. Genotypes were determined by mass-spectrometry. Odds ratio estimates were obtained using multivariate logistic regression. Interactions between genetic variant and smoking were assessed using stratified analyses and the likelihood ratio statistic (significance P < 0.05). Variants of MCPH1, FYN, APC, PRKCA, NIN, TopBP1, RIPK1, and SNW1 were not independently associated with pancreatic cancer risk. A significant interaction was observed between pack-years and MCPH1-2550-C > T (P = 0.02). Compared to never smokers, individuals with 10-27 pack-years and MCPH1-2550-CC genotype were at increased risk for pancreatic cancer (MVOR = 2.49, 95% confidence interval [95% CI]: 1.55, 4.00) as were those with >27 pack-years and MCPH1-2550-TC genotype (MVOR = 2.42, 95% CI: 1.45, 4.05). A significant interaction was observed between smoking status and TopBP1-3257-A > G (P = 0.04) using a dominant model. Current smokers with the TopBP1-3257 A allele were at increased risk for pancreatic cancer (MVOR = 2.55, 95% CI: 1.77, 3.67). MCPH1-2550-C > T and TopBP1-3257-A > G modify the association between smoking and pancreatic cancer. These findings provide insights into the potential molecular mechanisms behind smoking-associated pancreatic cancer.

15 Article Genetic variants in vitamin d pathway genes and risk of pancreas cancer; results from a population-based case-control study in ontario, Canada. 2013

Anderson, Laura N / Cotterchio, Michelle / Knight, Julia A / Borgida, Ayelet / Gallinger, Steven / Cleary, Sean P. ·Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. ·PLoS One · Pubmed #23826131.

ABSTRACT: Recent studies of 25-hydroxyvitamin D (25(OH)D) levels and pancreas cancer have suggested a potential role of the vitamin D pathway in the etiology of this fatal disease. Variants in vitamin-D related genes are known to affect 25(OH)D levels and function and it is unknown if these variants may influence pancreatic cancer risk. The association between 87 single nucleotide polymorphisms (SNPs) in 11 genes was evaluated within the Ontario Pancreas Cancer Study, a population-based case-control study. Pancreatic cancer cases with pathology confirmed adenocarcinoma were identified from the Ontario Cancer Registry (n = 628) and controls were identified through random digit dialing (n = 1193). Age and sex adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated by multivariate logistic regression. SNPs in the CYP24A1, CYP2R1, calcium sensing receptor (CASR), vitamin D binding protein (GC), retinoid X receptor-alpha (RXRA) and megalin (LRP2) genes were significantly associated with pancreas cancer risk. For example, pancreas cancer risk was inversely associated with CYP2R1 rs10741657 (AA versus GG, OR = 0.70; 95%CI: 0.51-0.95) and positively with CYP24A1 rs6127119 (TT versus CC. OR = 1.94; 95%CI: 1.28-2.94). None of the associations were statistically significant after adjustment for multiple comparisons. Vitamin D pathway gene variants may be associated with pancreas cancer risk and future studies are needed to understand the possible role of vitamin D in tumorigenesis and may have implications for cancer-prevention strategies.

16 Article Allergies and risk of pancreatic cancer: a pooled analysis from the Pancreatic Cancer Case-Control Consortium. 2013

Olson, Sara H / Hsu, Meier / Satagopan, Jaya M / Maisonneuve, Patrick / Silverman, Debra T / Lucenteforte, Ersilia / Anderson, Kristin E / Borgida, Ayelet / Bracci, Paige M / Bueno-de-Mesquita, H Bas / Cotterchio, Michelle / Dai, Qi / Duell, Eric J / Fontham, Elizabeth H / Gallinger, Steven / Holly, Elizabeth A / Ji, Bu-Tian / Kurtz, Robert C / La Vecchia, Carlo / Lowenfels, Albert B / Luckett, Brian / Ludwig, Emmy / Petersen, Gloria M / Polesel, Jerry / Seminara, Daniela / Strayer, Lori / Talamini, Renato / Anonymous6651223. ·Department of Epidemiology and Biostatistics, 307 East 63rd Street, New York, NY 10065, USA. olsons@mskcc.org ·Am J Epidemiol · Pubmed #23820785.

ABSTRACT: In order to quantify the risk of pancreatic cancer associated with history of any allergy and specific allergies, to investigate differences in the association with risk according to age, gender, smoking status, or body mass index, and to study the influence of age at onset, we pooled data from 10 case-control studies. In total, there were 3,567 cases and 9,145 controls. Study-specific odds ratios and 95% confidence intervals were calculated by using unconditional logistic regression adjusted for age, gender, smoking status, and body mass index. Between-study heterogeneity was assessed by using the Cochran Q statistic. Study-specific odds ratios were pooled by using a random-effects model. The odds ratio for any allergy was 0.79 (95% confidence interval (CI): 0.62, 1.00) with heterogeneity among studies (P < 0.001). Heterogeneity was attributable to one study; with that study excluded, the pooled odds ratio was 0.73 (95% CI: 0.64, 0.84) (Pheterogeneity = 0.23). Hay fever (odds ratio = 0.74, 95% CI: 0.56, 0.96) and allergy to animals (odds ratio = 0.62, 95% CI: 0.41, 0.94) were related to lower risk, while there was no statistically significant association with other allergies or asthma. There were no major differences among subgroups defined by age, gender, smoking status, or body mass index. Older age at onset of allergies was slightly more protective than earlier age.

17 Article Exome sequencing identifies nonsegregating nonsense ATM and PALB2 variants in familial pancreatic cancer. 2013

Grant, Robert C / Al-Sukhni, Wigdan / Borgida, Ayelet E / Holter, Spring / Kanji, Zaheer S / McPherson, Treasa / Whelan, Emily / Serra, Stefano / Trinh, Quang M / Peltekova, Vanya / Stein, Lincoln D / McPherson, John D / Gallinger, Steven. ·Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, M5G 1X5, Canada. ·Hum Genomics · Pubmed #23561644.

ABSTRACT: We sequenced 11 germline exomes from five families with familial pancreatic cancer (FPC). One proband had a germline nonsense variant in ATM with somatic loss of the variant allele. Another proband had a nonsense variant in PALB2 with somatic loss of the variant allele. Both variants were absent in a relative with FPC. These findings question the causal mechanisms of ATM and PALB2 in these families and highlight challenges in identifying the causes of familial cancer syndromes using exome sequencing.

18 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.

19 Article Genetic variants in carcinogen-metabolizing enzymes, cigarette smoking and pancreatic cancer risk. 2012

Jang, Ji-Hyun / Cotterchio, Michelle / Borgida, Ayelet / Gallinger, Steven / Cleary, Sean P. ·Population Studies and Surveillance, Cancer Care Ontario, 620 University Avenue, Toronto, Ontario, Canada M5G 2L7. ·Carcinogenesis · Pubmed #22301281.

ABSTRACT: Individual susceptibility to the toxic effects of cigarette smoke may be modified by inherited variability in carcinogen metabolism. The purpose of the present study was to investigate pancreatic cancer risk associated with cigarette smoking and 33 variants within carcinogen metabolism genes and examine whether these variants modify the association between smoking and pancreatic cancer. A population-based study was conducted with 455 pancreatic cancer cases and 893 controls. Epidemiological and smoking data were collected from questionnaires and variants were genotyped by mass spectrometry. Age- and sex-adjusted odds ratio (ASOR) and multivariate-adjusted odds ratio (MVOR) estimates were obtained using multivariate logistic regression, and interactions between each variant and smoking were investigated. Current smoker status [MVOR = 2.29, 95% confidence interval (95% CI): 1.62, 3.22], 10-27 pack-years (MVOR = 1.57, 95% CI: 1.13, 2.18), >27 pack-years (MVOR = 1.77, 95% CI: 1.27, 2.46) and longer durations of smoking (19-32 years: MVOR = 1.46, 95% CI: 1.05, 2.05; >32 years: MVOR = 1.78, 95% CI: 1.30, 2.45) were associated with increased pancreatic cancer risk. CYP1B1-4390-GG (ASOR = 0.36, 95% CI: 0.15, 0.86) and Uridine 5'-diphospho glucuronosyltransferase 1 family, polypeptide A7-622-CT (ASOR = 0.77, 95% CI: 0.60, 0.99) were associated with reduced risk. N-acetyltransferase 1-640-GT/GG (ASOR = 1.75, 95% CI: 1.00, 3.05), GSTM1 (rs737497)-GG (ASOR = 1.41, 95% CI: 1.02, 1.95), GSTM1 gene deletion (ASOR = 4.89, 95% CI: 3.52, 6.79) and glutathione S-transferase theta-1 gene deletion (ASOR = 4.41, 95% CI: 2.67, 7.29) were associated with increased risk. Significant interactions were observed between pack-years and EPHX1-415 (P = 0.04) and smoking status and N-acetyltransferase 2-857 (P = 0.03). Variants of carcinogen metabolism genes are independently associated with pancreatic cancer risk and may modify the risk posed by smoking.

20 Article Screening for pancreatic cancer in a high-risk cohort: an eight-year experience. 2012

Al-Sukhni, Wigdan / Borgida, Ayelet / Rothenmund, Heidi / Holter, Spring / Semotiuk, Kara / Grant, Robert / Wilson, Stephanie / Moore, Malcolm / Narod, Steven / Jhaveri, Kartik / Haider, Masoom A / Gallinger, Steven. ·Hepatobiliary/Pancreatic Surgical Oncology Program, Division of General Surgery, Department of Surgery, University Health Network, University of Toronto, Toronto, Canada. ·J Gastrointest Surg · Pubmed #22127781.

ABSTRACT: BACKGROUND: Pancreatic adenocarcinoma is the fourth leading cause of cancer death. METHODS: A prospective cohort study was undertaken between 2003 and 2011 at a tertiary care centre in Toronto, Canada. Two hundred and sixty-two subjects were enrolled based on an elevated estimated lifetime risk for pancreatic cancer due to known genetic mutations and/or cancer family history. Subjects underwent annual magnetic resonance imaging, followed by additional investigations if abnormal findings were detected. Evidence of malignancy or suspicious macroscopic abnormalities prompted referral for surgical intervention. RESULTS: Average length of follow-up was 4.2 years, during which 84/262 (32%) subjects demonstrated pancreatic abnormalities. Three participants developed pancreatic adenocarcinoma (one 1.5-cm tumor was resected but recurred, while the other two subjects developed metastatic cancer), and a fourth participant developed a pancreatic neuroendocrine tumor that was resected. Fifteen subjects had radiologic evidence of branch-duct intraductal papillary mucinous neoplasms, of which two underwent surgical resection. Sixty-five subjects had simple pancreatic cysts that have remained stable. CONCLUSION: Magnetic resonance imaging can detect small pancreatic tumors and cystic lesions, but further improvement in sensitivity is needed. An understanding of the natural history of pre-invasive lesions in members of high-risk families is necessary for developing a more effective screening program.

21 Article Moderators of cancer-related distress and worry after a pancreatic cancer genetic counseling and screening intervention. 2012

Hart, Stacey L / Torbit, Lindsey A / Crangle, Cassandra J / Esplen, Mary Jane / Holter, Spring / Semotiuk, Kara / Borgida, Ayelet / Ardiles, Paola / Rothenmund, Heidi / Gallinger, Steve. ·Ryerson University, Psychology, Toronto, Ontario, Canada. stacey.hart@psych.ryerson.ca ·Psychooncology · Pubmed #21774034.

ABSTRACT: OBJECTIVES: Although the hereditary breast and ovarian cancer literature has demonstrated short-term gains in psychological adjustment following genetic counseling, there has been limited research examining long-term outcomes and moderators. Moreover, there has been minimal research into the psychological effects of this intervention in populations at high risk for pancreatic cancer. This study examines the long-term effects of pancreatic cancer screening and genetic counseling on cancer-related distress and cancer worry in a high-risk population at 1-year follow-up. Additionally, this study explores potential moderators of the effectiveness of this intervention. METHODS: One hundred twenty-nine participants with familial pancreatic cancer or with the BRCA2 gene mutation completed a baseline questionnaire prior to their first pancreatic cancer screening and genetic counseling session. Participants also completed questionnaires at 3- and 12-month follow-up. RESULTS: Cancer-related intrusive thoughts decreased significantly over time, whereas cancer-related worry decreased at 3 months and showed a small but significant increase at 1 year. Age and baseline distress exhibited moderator effects. Younger individuals showed a significant decrease in cancer-related intrusive thoughts, cancer-related avoidant thoughts, and cancer worry. Additionally, individuals with greater baseline distress showed a significant decrease in cancer-related intrusive thoughts over time. CONCLUSIONS: Analysis of the long-term effects of pancreatic cancer screening and genetic testing reveal psychological gains that are maintained at 1-year follow-up. This intervention is particularly effective for younger participants and individuals with greater baseline distress.

22 Article Management of pancreatic adenocarcinoma in Ontario, Canada: a population-based study using novel case ascertainment. 2011

Borgida, Ayelet Eppel / Ashamalla, Shady / Al-Sukhni, Wigdan / Rothenmund, Heidi / Urbach, David / Moore, Malcolm / Cotterchio, Michelle / Gallinger, Steven. ·Mount Sinai Hospital, Joseph and Wolf Lebovic Health Complex, 69 Murray Street, Toronto, Ontario. aborgida@mtsinai.on.ca ·Can J Surg · Pubmed #21251433.

ABSTRACT: BACKGROUND: Pancreatic adenocarcinoma (PA) is largely incurable, although recent progress has been made in the safety of surgery for PA and in adjuvant and palliative chemotherapy. The purpose of this study was to describe the management of PA in Ontario, Canada. METHODS: The Pathology Information Management System (PIMS), which uses electronic pathology reporting (E-path), was used to rapidly identify and recruit patients based on a pathologic diagnosis of PA between 2003 and 2006. Patients were mailed questionnaires for additional data. RESULTS: The patient participation rate was 26% (351 of 1325). Nonresponders were more likely to be older than 70 years (43% v. 28%, p < 0.001) and to have received treatment in nonacademic centres (53% v. 34%, p < 0.001). Fifty-four percent of responders underwent a potentially curative operation, and most (77%) were 70 years or younger (p = 0.03). Completed resections were documented in 83% of patients who underwent exploratory surgery with curative intent; 17% of patients had unresectable and/or metastatic disease at laparotomy. Of the completed resections, 24% were performed in nonacademic centres with a 32% positive margin rate; 76% were performed in academic centres with a 29% positive margin rate (p = 0.84). Resections with curative intent were less frequently aborted in academic centres (10% v. 33%, p < 0.001). Of the patients who responded to our questionnaire, 43% received chemotherapy and 7% participated in clinical trials. CONCLUSION: Despite using PIMS and E-path, the response rate for this study was low (< 30%). Nonresponders were older and more commonly treated in nonacademic centres. Patients undergoing surgery in academic centres had higher resection rates. The rate of adjuvant and palliative chemotherapy was stage-dependent and low.

23 Minor Analysis of the gene coding for the BRCA2-interacting protein PALB2 in familial and sporadic pancreatic cancer. 2009

Tischkowitz, Marc D / Sabbaghian, Nelly / Hamel, Nancy / Borgida, Ayelet / Rosner, Chaim / Taherian, Nassim / Srivastava, Archana / Holter, Spring / Rothenmund, Heidi / Ghadirian, Parviz / Foulkes, William D / Gallinger, Steven. · ·Gastroenterology · Pubmed #19635604.

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