title: Sonic hedgehog and Gli1 expression predict outcome in resected pancreatic adenocarcinoma.
abstract: OBJECTIVE
  Aberrant activation of the hedgehog (Hh) pathway is implicated in pancreatic ductal adenocarcinoma (PDAC) tumorigenesis. We investigated the prognostic and predictive value of four Hh signaling proteins and of the tumor stromal density.
  
  
  METHODS
  Using tissue microarray and immunohistochemistry, the expression of Shh, Gli1, SMO, and PTCH1 was assessed in 567 patients from three independent cohorts who underwent surgical resection for PDAC. In 82 patients, the tumor stromal index (SI) was calculated, and its association with overall survival (OS) and disease-free survival (DFS) was investigated.
  
  
  RESULTS
  Shh and Gli1 protein abundance were independent prognostic factors in resected PDACs; low expressors for those proteins experiencing a better OS and DFS. The combination of Shh and Gli1 levels was the most significant predictor for OS and defined 3 clinically relevant subgroups of patients with different prognosis (Gli1 and Shh low; HR set at 1 vs. 3.08 for Shh or Gli1 high vs. 5.69 for Shh and Gli1 high; P < 0.001). The two validating cohorts recapitulated the findings of the training cohort. After further stratification by lymph node status, the prognostic significance of combined Shh and Gli1 was maintained. The tumor SI was correlated with Shh levels and was significantly associated with OS (P = 0.023).
  
  
  CONCLUSIONS
  Shh and Gli1 are prognostic biomarkers for patients with resected PDAC.
authors.affiliation: Saint Antoine Department of Gastroenterology and Gastrointestinal Cancer Unit, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium. Laboratory of Experimental Gastroenterology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium. raphael.marechal@erasme.ulb.ac.be.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Maréchal
authors.affiliation: Medical University Pierre et Marie Curie, UFR Paris VI, Paris, France. EA4340 "Epidémiologie et oncogènes des tumeurs digestives," Versailles Saint-Quentin-en-Yvelines University, Versailles, France. Department of Hepato-Gastroenterology, Pitié Salpêtrière Hospital, APHP, Paris, France.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Bachet
authors.affiliation: Saint Antoine Department of Gastroenterology and Gastrointestinal Cancer Unit, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium. Laboratory of Experimental Gastroenterology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Annabelle
authors.initials: A
authors.lastname: Calomme
authors.affiliation: Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, and DiaPath, Brussels, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Demetter
authors.affiliation: Department of Surgery, Institute Paoli Calmettes, Marseille, France. Aix Marseille Université, Marseille, France.
authors.forename: Jean Robert
authors.initials: JR
authors.lastname: Delpero
authors.affiliation: Department of Pathology, Saint Antoine Hospital, APHP, Paris, France.
authors.forename: Magali
authors.initials: M
authors.lastname: Svrcek
authors.affiliation: Department of Pathology, Beaujon Hospital, APHP, Clichy, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Cros
authors.affiliation: Medical University Pierre et Marie Curie, UFR Paris VI, Paris, France. Department of Pathology, Pitié Salpêtrière Hospital, APHP, Paris, France.
authors.forename: Armelle
authors.initials: A
authors.lastname: Bardier-Dupas
authors.affiliation: Saint Antoine Department of Gastroenterology and Gastrointestinal Cancer Unit, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium. Laboratory of Experimental Gastroenterology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Francesco
authors.initials: F
authors.lastname: Puleo
authors.affiliation: Department of Pathology, Institute Paoli Calmettes, Marseille, France.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Monges
authors.affiliation: Department of Gastroenterology, Beaujon Hospital, APHP, Clichy, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Hammel
authors.affiliation: Medical University Pierre et Marie Curie, UFR Paris VI, Paris, France. Department of Oncology, Institut Mutualiste Montsouris, Paris, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Louvet
authors.affiliation: Medical University Pierre et Marie Curie, UFR Paris VI, Paris, France. Department of Surgery, Saint Antoine Hospital, APHP, Paris, France.
authors.forename: François
authors.initials: F
authors.lastname: Paye
authors.affiliation: Department of Surgery, University Hospital of Hautepierre, Strasbourg, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Bachelier
authors.affiliation: Department of Digestive Surgery, Conception Hospital, Marseille, France.
authors.forename: Yves Patrice
authors.initials: YP
authors.lastname: Le Treut
authors.affiliation: Medical University Pierre et Marie Curie, UFR Paris VI, Paris, France. Department of Digestive Surgery, Pitié Salpêtrière Hospital, Paris, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Vaillant
authors.affiliation: Department of Digestive Surgery, Beaujon Hospital, APHP, Clichy, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Sauvanet
authors.affiliation: Department of Oncology, Saint-Antoine Hospital, APHP, Paris, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: André
authors.affiliation: Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, and DiaPath, Brussels, Belgium. DIAPath - Center for Microscopy and Molecular Imaging (CMMI), Université Libre de Bruxelles, Gosselies, Belgium.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Salmon
authors.affiliation: Saint Antoine Department of Gastroenterology and Gastrointestinal Cancer Unit, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium. Laboratory of Experimental Gastroenterology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Jacques
authors.initials: J
authors.lastname: Devière
authors.affiliation: EA4340 "Epidémiologie et oncogènes des tumeurs digestives," Versailles Saint-Quentin-en-Yvelines University, Versailles, France. Department of Pathology, Ambroise Paré Hospital, APHP, Boulogne Billancourt, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Emile
authors.affiliation: Saint Antoine Department of Gastroenterology and Gastrointestinal Cancer Unit, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Van Laethem
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology / Q000628:therapy; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000628:therapy; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D015870:Gene Expression; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology / Q000628:therapy; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D063868:Patient Outcome Assessment; D011379:Prognosis; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D000072086:Smoothened Receptor; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D000071676:Zinc Finger Protein GLI1
chemical_list: D015415:Biomarkers; D053823:Hedgehog Proteins; D015513:Oncogene Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor; D015534:Trans-Activators; D000071676:Zinc Finger Protein GLI1