Targeted Molecular Analysis in Adrenocortical Carcinomas: A Strategy Toward Improved Personalized Prognostication

• Published in: The journal of clinical endocrinology and metabolism 2018-12, Vol.103 (12), p.4511-4523
• Main Authors: Lippert, Juliane, Appenzeller, Silke, Liang, Raimunde, Sbiera, Silviu, Kircher, Stefan, Altieri, Barbara, Nanda, Indrajit, Weigand, Isabel, Gehrig, Andrea, Steinhauer, Sonja, Riemens, Renzo J M, Rosenwald, Andreas, Müller, Clemens R, Kroiss, Matthias, Rost, Simone, Fassnacht, Martin, Ronchi, Cristina L
• Format: Article
• Language: English
• Subjects: Adrenal Cortex - pathology; Adrenal Cortex Neoplasms - drug therapy; Adrenal Cortex Neoplasms - genetics; Adrenal Cortex Neoplasms - mortality; Adrenal Cortex Neoplasms - pathology; Adrenocortical Carcinoma - drug therapy; Adrenocortical Carcinoma - genetics; Adrenocortical Carcinoma - mortality; Adrenocortical Carcinoma - pathology; Adult; Aged; Aged, 80 and over; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Biomarkers, Tumor - antagonists & inhibitors; Biomarkers, Tumor - genetics; BRCA1 protein; BRCA2 protein; Carcinoma; Copy number; Cyclin-dependent kinase 4; DNA Copy Number Variations; DNA Methylation; DNA Mutational Analysis; DNA repair; Epidermal growth factor receptors; Female; Follow-Up Studies; Genomes; High-Throughput Nucleotide Sequencing; Humans; Male; MDM2 protein; Medical prognosis; Middle Aged; Molecular Targeted Therapy; Mutation; Neuroendocrine tumors; Next-generation sequencing; p53 Protein; Paraffin; Patients; Point Mutation; Precision medicine; Precision Medicine - methods; Prognosis; Progression-Free Survival; Promoter Regions, Genetic - genetics; Rare diseases; Retrospective Studies; Survival Analysis; Therapeutic targets; Wnt protein; Young Adult; β-Catenin
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2018-01348

Adrenocortical carcinoma (ACC) has a heterogeneous prognosis, and current medical therapies have limited efficacy in its advanced stages. Genome-wide multiomics studies identified molecular patterns associated with clinical outcome. Here, we aimed at identifying a molecular signature useful for both personalized prognostic stratification and druggable targets, using methods applicable in clinical routine. In total, 117 tumor samples from 107 patients with ACC were analyzed. Targeted next-generation sequencing of 160 genes and pyrosequencing of 4 genes were applied to formalin-fixed, paraffin-embedded (FFPE) specimens to detect point mutations, copy number alterations, and promoter region methylation. Molecular results were combined with clinical/histopathological parameters (tumor stage, age, symptoms, resection status, and Ki-67) to predict progression-free survival (PFS). In addition to known driver mutations, we detected recurrent alterations in genes not previously associated with ACC (e.g., NOTCH1, CIC, KDM6A, BRCA1, BRCA2). Best prediction of PFS was obtained integrating molecular results (more than one somatic mutation, alterations in Wnt/β-catenin and p53 pathways, high methylation pattern) and clinical/histopathological parameters into a combined score (P < 0.0001, χ2 = 68.6). Accuracy of prediction for early disease progress was 83.3% (area under the receiver operating characteristic curve: 0.872, 95% confidence interval 0.80 to 0.94). Furthermore, 17 potentially targetable alterations were found in 64 patients (e.g., in CDK4, NOTCH1, NF1, MDM2, and EGFR and in DNA repair system). This study demonstrates that molecular profiling of FFPE tumor samples improves prognostication of ACC beyond clinical/histopathological parameters and identifies new potential drug targets. These findings pave the way to precision medicine in this rare disease.