β-Catenin Activation Is Associated with Specific Clinical and Pathologic Characteristics and a Poor Outcome in Adrenocortical Carcinoma

Purpose: Activation of the Wnt/beta-catenin signaling pathway is frequent in adrenocortical carcinoma (ACC) and might be associated with a more aggressive phenotype. The objective of this study was to assess the prognostic value of beta-catenin immunohistochemistry and CTNNB1 (beta-catenin gene)/APC (adenomatous polyposis coli gene) mutations in patients with resected primary ACC. Experimental design: In 79 patients with resected primary ACC from a French cohort (Cochin-COMETE), beta-catenin expression was assessed on tumor specimens by immunohistochemistry. For patients with available DNA (n = 49), CTNNB1, and APC hotspot (mutation cluster region), were sequenced. Association between these results and the clinicopathologic characteristics of the ACC and overall and disease-free survival were studied. Results were confirmed on a tissue microarray from an independent multicentric cohort of 92 ACC from Germany (German-ENSAT cohort). Results: In the Cochin-COMETE cohort, the presence of a beta-catenin nuclear staining was significantly associated with a higher ENSAT tumor stage (i.e., stages III and IV), higher Weiss score, more frequent necrosis, mitoses, and CTNNB1/APC mutations. beta-Catenin nuclear staining and the presence of CTNNB1/APC mutations were both associated with decreased overall and disease-free survival, and were independent predictive factors of survival in multivariate analysis. The same results were observed in the German-ENSAT cohort. Conclusions: Wnt/beta-catenin activation, confirmed by the presence of beta-catenin nuclear staining, is an independent prognostic factor of overall and disease-free survival in patients with resected primary ACC. Clin Cancer Res; 17(2); 328-36. (C)2010 AACR.