title: Prognostic effect of hENT1, dCK and HuR expression by morphological type in periampullary adenocarcinoma, including pancreatic cancer.
abstract: BACKGROUND
  Putative biomarkers of gemcitabine response have been extensively studied in pancreatic cancer, but less so in other types of periampullary adenocarcinoma. The most studied biomarker is human equilibrative nucleoside transporter 1 (hENT1), and the activating enzyme deoxycytidine kinase (dCK) has also been linked to treatment response. The RNA-binding protein human antigen R (HuR) has been demonstrated to confer increased dCK levels in vitro and to predict gemcitabine response in vivo. Here, we investigated the prognostic impact of hENT1, dCK and HuR in pancreatobiliary (PB) and intestinal (I) type periampullary cancers, respectively.
  
  
  METHODS
  Immunohistochemical expression of hENT1, dCK and HuR was evaluated in tissue microarrays with all primary tumours and 103 paired lymph node metastases from a consecutive retrospective cohort of 175 patients with resected periampullary adenocarcinomas.
  
  
  RESULTS
  In patients with PB-type tumours, neither hENT1 nor dCK expression was prognostic. A high HuR cytoplasmic/nuclear ratio was associated with a significantly reduced five-year overall survival (OS) in patients receiving adjuvant gemcitabine (HR 2.07, 95% CI 1.03-4.17) but not in untreated patients (pinteraction = 0.028). In patients with I-type tumours receiving adjuvant chemotherapy, high dCK expression was significantly associated with a prolonged recurrence-free survival (RFS) (HR 0.09, 95% CI 0.01-0.73, pinteraction = 0.023). Furthermore, HuR expression was associated with a prolonged OS and RFS in unadjusted but not in adjusted analysis and hENT1 expression was an independent predictor of a prolonged RFS (HR 0.24, 95% CI 0.10-0.59), regardless of adjuvant treatment.
  
  
  CONCLUSIONS
  hENT1 expression is a favourable prognostic factor in I-type, but not in PB-type tumours. High dCK expression is a favourable prognostic factor in patients with I-type tumours receiving adjuvant treatment and a high cytoplasmic/nuclear HuR ratio is a negative prognostic factor in gemcitabine-treated PB-type tumours. Morphological subtype should always be considered in biomarker studies on periampullary cancer.
authors.affiliation: a Department of Clinical Sciences, Division of Oncology and Pathology , Lund University, Skåne University Hospital , Lund , Sweden.
authors.forename: Jacob
authors.initials: J
authors.lastname: Elebro
authors.affiliation: a Department of Clinical Sciences, Division of Oncology and Pathology , Lund University, Skåne University Hospital , Lund , Sweden.
authors.forename: Liv
authors.initials: L
authors.lastname: Ben Dror
authors.affiliation: a Department of Clinical Sciences, Division of Oncology and Pathology , Lund University, Skåne University Hospital , Lund , Sweden.
authors.forename: Margareta
authors.initials: M
authors.lastname: Heby
authors.affiliation: a Department of Clinical Sciences, Division of Oncology and Pathology , Lund University, Skåne University Hospital , Lund , Sweden.
authors.forename: Björn
authors.initials: B
authors.lastname: Nodin
authors.affiliation: a Department of Clinical Sciences, Division of Oncology and Pathology , Lund University, Skåne University Hospital , Lund , Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Jirström
authors.affiliation: a Department of Clinical Sciences, Division of Oncology and Pathology , Lund University, Skåne University Hospital , Lund , Sweden.
authors.forename: Jakob
authors.initials: J
authors.lastname: Eberhard
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D000368:Aged; D014670:Ampulla of Vater / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D003842:Deoxycytidine Kinase / Q000378:metabolism*; D000067780:ELAV-Like Protein 1 / Q000378:metabolism*; D033721:Equilibrative Nucleoside Transporter 1 / Q000378:metabolism*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D033721:Equilibrative Nucleoside Transporter 1; C438649:SLC29A1 protein, human; D003842:Deoxycytidine Kinase