title: SLC22A3 polymorphisms do not modify pancreatic cancer risk, but may influence overall patient survival.
abstract: Expression of the solute carrier (SLC) transporter SLC22A3 gene is associated with overall survival of pancreatic cancer patients. This study tested whether genetic variability in SLC22A3 associates with pancreatic cancer risk and prognosis. Twenty four single nucleotide polymorphisms (SNPs) tagging the SLC22A3 gene sequence and regulatory elements were selected for analysis. Of these, 22 were successfully evaluated in the discovery phase while six significant or suggestive variants entered the validation phase, comprising a total study number of 1,518 cases and 3,908 controls. In the discovery phase, rs2504938, rs9364554, and rs2457571 SNPs were significantly associated with pancreatic cancer risk. Moreover, rs7758229 associated with the presence of distant metastases, while rs512077 and rs2504956 correlated with overall survival of patients. Although replicated, the association for rs9364554 did not pass multiple testing corrections in the validation phase. Contrary to the discovery stage, rs2504938 associated with survival in the validation cohort, which was more pronounced in stage IV patients. In conclusion, common variation in the SLC22A3 gene is unlikely to significantly contribute to pancreatic cancer risk. The rs2504938 SNP in SLC22A3 significantly associates with an unfavorable prognosis of pancreatic cancer patients. Further investigation of this SNP effect on the molecular and clinical phenotype is warranted.
authors.affiliation: Department of Toxicogenomics, National Institute of Public Health, Prague, Czech Republic.|Department of Oncology, Palacky University Medical School and Teaching Hospital, Olomouc, Czech Republic.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Mohelnikova-Duchonova
authors.affiliation: Department of Oncology, Palacky University Medical School and Teaching Hospital, Olomouc, Czech Republic.
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authors.affiliation: Department of Physiology &Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors.forename: David J
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authors.lastname: Hughes
authors.affiliation: Institute of Hygiene and Epidemiology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: Ivana
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authors.affiliation: Department of Transplantation Surgery, Institute of Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Martin
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authors.affiliation: Department of Surgery, The University Hospital and Faculty of Medicine, Brno Bohunice, Czech Republic.
authors.forename: Zdenek
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authors.affiliation: Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Biology, University of Pisa, Pisa, Italy.
authors.forename: Daniele
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authors.lastname: Campa
authors.affiliation: Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
authors.forename: Cosmeri
authors.initials: C
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authors.affiliation: Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Federico
authors.initials: F
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authors.affiliation: Department of Digestive Diseases, Sant'Orsola-Malpighi Hospital, Bologna, Italy.
authors.forename: Raffaele
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authors.affiliation: Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland.
authors.forename: Renata
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authors.affiliation: Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland.
authors.forename: Ewa
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authors.affiliation: Department of Surgery, Oncology and Gastroenterology -DiSCOG, University of Padova, Italy.
authors.forename: Cosimo
authors.initials: C
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authors.affiliation: Department of Medicine - DIMED, University of Padova, Italy.
authors.forename: Carlo
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authors.affiliation: Clinica Chirurgica 4, University of Padova, Italy.
authors.forename: Sergio
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authors.affiliation: Department of Laboratory Medicine, University-Hospital of Padova, Italy.
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authors.lastname: Fogar
authors.affiliation: Department of Surgery, Oncology and Gastroenterology -DiSCOG, University of Padova, Italy.
authors.forename: Anna Caterina
authors.initials: AC
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authors.affiliation: Digestive and Liver Disease Unit, S. Andrea Hospital, 'Sapienza' University of Rome, Rome, Italy.
authors.forename: Gabriele
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authors.lastname: Capurso
authors.affiliation: Digestive and Liver Disease Unit, S. Andrea Hospital, 'Sapienza' University of Rome, Rome, Italy.
authors.forename: Gianfranco
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authors.affiliation: Digestive and Liver Disease Unit, S. Andrea Hospital, 'Sapienza' University of Rome, Rome, Italy.
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authors.affiliation: Department of Basic Medical Sciences, Laboratory of Biology, School of Medicine, University of Athens, Athens, Greece.
authors.forename: Maria
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authors.affiliation: Department of Surgery and Oncology, University and Hospital Trust of Verona, Verona, Italy.
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authors.affiliation: ARC-NET Applied research on Cancer Centre, University and Hospital Trust of Verona, Verona, Italy.
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authors.affiliation: Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany.
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authors.affiliation: Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany.
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authors.affiliation: Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Nathalia
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authors.affiliation: Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Science of Czech Republic, Prague, Czech Republic and First Faculty of Medicine, Charles University in Prague, Czech Republic.|Biomedical Centre, Faculty of Medicine in Pilsen, Charles University in Prague, Pilsen, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Vodicka
authors.affiliation: Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Science of Czech Republic, Prague, Czech Republic and First Faculty of Medicine, Charles University in Prague, Czech Republic.|Biomedical Centre, Faculty of Medicine in Pilsen, Charles University in Prague, Pilsen, Czech Republic.
authors.forename: Ludmila
authors.initials: L
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authors.affiliation: Department of Biology, University of Pisa, Pisa, Italy.
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authors.affiliation: Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy.
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authors.initials: F
authors.lastname: Tavano
authors.affiliation: Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy.
authors.forename: Domenica
authors.initials: D
authors.lastname: Gioffreda
authors.affiliation: Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy.
authors.forename: Ada
authors.initials: A
authors.lastname: Piepoli
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authors.forename: Valerio
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authors.affiliation: Department of Oncology, Azienda USL 1 Massa Carrara, Massa Carrara, Italy.
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authors.affiliation: Department of Oncology, Azienda USL 1 Massa Carrara, Massa Carrara, Italy.
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authors.affiliation: Department of Oncology, Azienda USL 1 Massa Carrara, Massa Carrara, Italy.
authors.forename: Maurizio
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authors.affiliation: Blood Transfusion Service, Children's Hospital Meyer, Azienda Ospedaliero Universitaria, Florence, Italy.
authors.forename: Franco
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authors.affiliation: Blood Transfusion Service, Children's Hospital Meyer, Azienda Ospedaliero Universitaria, Florence, Italy.
authors.forename: Stefano
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authors.affiliation: Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
authors.forename: Niccola
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authors.affiliation: Department of Oncology, Palacky University Medical School and Teaching Hospital, Olomouc, Czech Republic.
authors.forename: Radmila
authors.initials: R
authors.lastname: Lemstrova
authors.affiliation: Department of Toxicogenomics, National Institute of Public Health, Prague, Czech Republic.|Biomedical Centre, Faculty of Medicine in Pilsen, Charles University in Prague, Pilsen, Czech Republic.
authors.forename: Pavel
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authors.lastname: Soucek
mesh_terms: D000328:Adult; D000368:Aged; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000473:pathology; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D027701:Organic Cation Transport Proteins / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D012307:Risk Factors; D000099254:Organic Cation Transporter 3
chemical_list: D027701:Organic Cation Transport Proteins; D000099254:Organic Cation Transporter 3