Sonic hedgehog and Gli1 expression predict outcome in resected pancreatic adenocarcinoma

• Published in: Clinical cancer research 2015-03, Vol.21 (5), p.1215-1224
• Main Authors: Maréchal, Raphaël, Bachet, Jean-Baptiste, Calomme, Annabelle, Demetter, Pieter, Delpero, Jean Robert, Svrcek, Magali, Cros, Jérôme, Bardier-Dupas, Armelle, Puleo, Francesco, Monges, Geneviève, Hammel, Pascal, Louvet, Christophe, Paye, François, Bachelier, Philippe, Le Treut, Yves Patrice, Vaillant, Jean-Christophe, Sauvanet, Alain, André, Thierry, Salmon, Isabelle, Devière, Jacques, Emile, Jean-François, Van Laethem, Jean-Luc
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Adenocarcinoma - mortality; Adenocarcinoma - pathology; Adenocarcinoma - therapy; Adult; Aged; Aged, 80 and over; Biomarkers - metabolism; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - mortality; Carcinoma, Pancreatic Ductal - pathology; Carcinoma, Pancreatic Ductal - therapy; Cohort Studies; Female; Follow-Up Studies; Gene Expression; Hedgehog Proteins - genetics; Hedgehog Proteins - metabolism; Humans; Immunohistochemistry; Male; Middle Aged; Neoplasm Grading; Neoplasm Metastasis; Neoplasm Staging; Oncogene Proteins - genetics; Oncogene Proteins - metabolism; Pancreatic Neoplasms; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - mortality; Pancreatic Neoplasms - pathology; Pancreatic Neoplasms - therapy; Patched Receptors; Patched-1 Receptor; Patient Outcome Assessment; Prognosis; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Smoothened Receptor; Stromal Cells - metabolism; Stromal Cells - pathology; Trans-Activators - genetics; Trans-Activators - metabolism; Zinc Finger Protein GLI1
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-14-0667

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. 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. 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). Shh and Gli1 are prognostic biomarkers for patients with resected PDAC.