Endoplasmic stress-inducing variants in carboxyl ester lipase and pancreatic cancer risk |
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| Institution: | 1. Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA;2. Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA;3. Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, USA;4. Surgery, Johns Hopkins Medical Institutions, Baltimore, MD, USA;5. The Sol Goldman Pancreatic Cancer Research Center, And the Bloomberg School of Public Health, Johns Hopkins Medical Institutions, Baltimore, MD, USA;1. Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland;2. Center for Exocrine Disorders, Department of Molecular and Cell Biology, Boston University, Henry M. Goldman School of Dental Medicine, Boston, MA, 02118, United States;3. Pediatric Nutritional Medicine & Else Kröner-Fresenius-Centre for Nutritional Medicine EKFZ, Technical University Munich TUM, Freising, Germany;4. Univ Brest, Inserm, EFS, UMR 1078, GGB, F-29200, Brest, France;5. Service de Génétique Médicale et de Biologie de la Reproduction, CHRU Brest, F-29200, Brest, France;6. Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan;7. Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, German Red Cross Blood Service of Baden-Württemberg, Mannheim, Germany;8. Department of Gastroenterology and Pancreatology, CHU Rangueil and University of Toulouse, Toulouse, France;9. Institute of Computer Science, Warsaw University of Technology, Warsaw, Poland;10. Department of Gastroenterology, Hepatology, Feeding Disorders and Pediatrics, The Children''s Memorial Health Institute, Warsaw, Poland;11. Department of Biophysics, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland;12. Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland;13. Collegium Medicum, Jan Kochanowski University of Kielce, Poland;14. Department of Internal Medicine I, Martin Luther University, Halle, Germany;15. Department of Pediatric, Karolinska University Hospital, Stockholm, Sweden;p. Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden;q. Pancreatology and Digestive Oncology Department, Beaujon Hospital, Clichy, APHP, Université de Paris, Paris, France;r. Heim Pál National Pediatric Institute, Budapest, Hungary;s. Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary;t. Center for Translational Medicine, Semmelweis University, Budapest, Hungary;u. Division of Pancreatic Diseases, Heart and Vascular Center, Semmelweis University, Budapest, Hungary;v. Department of Surgery, University of California Los Angeles, Los Angeles, CA, 90095, United States;1. Mech-Sense, Department of Radiology, Aalborg University Hospital, Aalborg, Denmark;2. Department of Clinical Medicine, Aalborg University, Aalborg, Denmark;3. Centre for Pancreatic Diseases, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark;4. Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark;1. Department of Pancreatic Surgery, General Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan Province, China;2. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan Province, China;3. Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, 410008, Hunan Province, China;1. Department of Genetics, Hyogo Medical University, Nishinomiya, Hyogo, 663-8501, Japan;2. Division of Functional Pathology, Department of Pathology, Hyogo Medical University, Nishinomiya, Hyogo, 663-8501, Japan;1. Department of Hepatobiliary and Pancreatic Surgery, The Catholic University of Korea Incheon St. Mary''s Hospital, Incheon, South Korea;2. Department of Surgery, Yongin Severance Hospital, Yongin-si, Gyeonggi-do, South Korea;3. Department of Hepatobiliary and Pancreatic Surgery, Yonsei University College of Medicine, Seoul, South Korea |
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| Abstract: | BackgroundEndoplasmic reticulum (ER) stress-inducing variants in several pancreatic secretory enzymes have been associated with pancreatic disease. Multiple variants in CEL, encoding carboxyl ester lipase, are known to cause maturity-onset diabetes of the young (MODY8) but have not been implicated in pancreatic cancer risk.MethodsThe prevalence of ER stress-inducing variants in the CEL gene was compared among pancreatic cancer cases vs. controls. Variants were identified by next-generation sequencing and confirmed by Sanger sequencing. Variants of uncertain significance (VUS) were assessed for their effect on the secretion of CEL protein and variants with reduced protein secretion were evaluated to determine if they induced endoplasmic reticulum stress.ResultsER stress-inducing CEL variants were found in 34 of 986 cases with sporadic pancreatic ductal adenocarcinoma, and 21 of 1045 controls (P = 0.055). Most of the variants were either the CEL-HYB1 variant, the I488T variant, or the combined CEL-HYB1/I488T variant; one case had a MODY8 variant.ConclusionThis case/control analysis finds ER stress-inducing CEL variants are not associated with an increased likelihood of having pancreatic cancer. |
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| Keywords: | CEL Pancreatic cancer Endoplasmic reticulum stress Variant Inherited susceptibility |
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