Sonic hedgehog and Gli1 expression predict outcome in resected pancreatic adenocarcinoma.

Raphaël Maréchal, Jean-Baptiste Bachet, Annabelle Calomme, Pieter Demetter, Jean Robert Delpero, Magali Svrcek, Jérôme Cros, Armelle Bardier-Dupas, Francesco Puleo, Geneviève Monges, Pascal Hammel, Christophe Louvet, François Paye, Philippe Bachelier, Yves Patrice Le Treut, Jean-Christophe Vaillant, Alain Sauvanet, Thierry André, Isabelle Salmon, Jacques Devière, Jean-François Emile, Jean-Luc Van Laethem

Journal: Clinical cancer research : an official journal of the American Association for Cancer Research 2016;21(5):1215-24

PMID: 25552484

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Abstract

PURPOSE

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.

EXPERIMENTAL DESIGN

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.

Address: 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. [email protected].; 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.; 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.; Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, and DiaPath, Brussels, Belgium.; Department of Surgery, Institute Paoli Calmettes, Marseille, France. Aix Marseille Université, Marseille, France.; Department of Pathology, Saint Antoine Hospital, APHP, Paris, France.; Department of Pathology, Beaujon Hospital, APHP, Clichy, France.; Medical University Pierre et Marie Curie, UFR Paris VI, Paris, France. Department of Pathology, Pitié Salpêtrière Hospital, APHP, Paris, France.; Department of Pathology, Institute Paoli Calmettes, Marseille, France.; Department of Gastroenterology, Beaujon Hospital, APHP, Clichy, France.; Medical University Pierre et Marie Curie, UFR Paris VI, Paris, France. Department of Oncology, Institut Mutualiste Montsouris, Paris, France.; Medical University Pierre et Marie Curie, UFR Paris VI, Paris, France. Department of Surgery, Saint Antoine Hospital, APHP, Paris, France.; Department of Surgery, University Hospital of Hautepierre, Strasbourg, France.; Department of Digestive Surgery, Conception Hospital, Marseille, France.; Medical University Pierre et Marie Curie, UFR Paris VI, Paris, France. Department of Digestive Surgery, Pitié Salpêtrière Hospital, Paris, France.; Department of Digestive Surgery, Beaujon Hospital, APHP, Clichy, France.; Department of Oncology, Saint-Antoine Hospital, APHP, Paris, France.; 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.; 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.; Saint Antoine Department of Gastroenterology and Gastrointestinal Cancer Unit, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium.

DOI: 10.1158/1078-0432.CCR-14-0667