Genetic landscape of sporadic unilateral adrenocortical adenomas without PRKACA p.Leu206Arg mutation

Context: Adrenocortical adenomas (ACAs) are among the most frequent human neoplasias. Genetic alterations affecting the cAMP/protein kinase A signaling pathway are common in cortisolproducing ACAs, whereas activating mutations in the gene encoding \u3b2-catenin (CTNNB1) have been reported in a subset of both benign and malignant adrenocortical tumors. However, the molecular pathogenesis of most ACAs is still largely unclear. Objective: The aim of the study was to define the genetic landscape of sporadic unilateral ACAs. Design and Setting: Next-generation whole-exome sequencing was performed on fresh-frozen tumor samples and corresponding normal tissue samples. Patients: Ninety-nine patients with ACAs (74 cortisol-producing and 25 endocrine inactive) negative for p.Leu206Arg PRKACA mutation. Main Outcome Measures: Identification of known and/or new genetic alterations potentially involved in adrenocortical tumorigenesis and autonomous hormone secretion, genotype-phenotype correlation. Results: A total of 706 somatic protein-altering mutations were detected in 88 of 99 tumors (median, six per tumor). We identified several mutations in genes of the cAMP/protein kinase A pathway, including three novel mutations in PRKACA, associated with female sex and Cushing's syndrome. We also found genetic alterations in different genes involved in the Wnt/\u3b2-catenin pathway, associated with larger tumors and endocrine inactivity, and notably, inmanygenes of the Ca2+-signaling pathway. Finally, by comparison of our genetic data with those available in the literature, we describe a comprehensive genetic landscape of unilateral ACAs. Conclusions: This study provides the largest sequencing effort on ACAs to date. We thereby identified somatic alterations affecting known and novel pathways potentially involved in adrenal tumorigenesis