TY - JOUR
T1 - Targeted Molecular Analysis in Adrenocortical Carcinomas
T2 - A Strategy Toward Improved Personalized Prognostication
AU - Lippert, Juliane
AU - Appenzeller, Silke
AU - Liang, Raimunde
AU - Sbiera, Silviu
AU - Kircher, Stefan
AU - Altieri, Barbara
AU - Nanda, Indrajit
AU - Weigand, Isabel
AU - Gehrig, Andrea
AU - Steinhauer, Sonja
AU - Riemens, Renzo J. M.
AU - Rosenwald, Andreas
AU - Mueller, Clemens R.
AU - Kroiss, Matthias
AU - Rost, Simone
AU - Fassnacht, Martin
AU - Ronchi, Cristina L.
PY - 2018/12
Y1 - 2018/12
N2 - Context: 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.Objective: Here, we aimed at identifying a molecular signature useful for both personalized prognostic stratification and druggable targets, using methods applicable in clinical routine.Design: 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).Results: 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/beta-catenin and p53 pathways, high methylation pattern) and clinical/histopathological parameters into a combined score (P <0.0001, chi(2) = 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., inCDK4, NOTCH1, NF1, MDM2, and EGFR and in DNA repair system).Conclusions: 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.
AB - Context: 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.Objective: Here, we aimed at identifying a molecular signature useful for both personalized prognostic stratification and druggable targets, using methods applicable in clinical routine.Design: 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).Results: 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/beta-catenin and p53 pathways, high methylation pattern) and clinical/histopathological parameters into a combined score (P <0.0001, chi(2) = 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., inCDK4, NOTCH1, NF1, MDM2, and EGFR and in DNA repair system).Conclusions: 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.
KW - GENOMIC CHARACTERIZATION
KW - DNA METHYLATION
KW - MISMATCH-REPAIR
KW - TUMORS
KW - REVEALS
KW - PATHWAY
KW - CANCER
KW - CLASSIFICATION
KW - CHEMOTHERAPY
KW - MULTICENTER
U2 - 10.1210/jc.2018-01348
DO - 10.1210/jc.2018-01348
M3 - Article
C2 - 30113656
SN - 0021-972X
VL - 103
SP - 4511
EP - 4523
JO - Journal of Clinical Endocrinology & Metabolism
JF - Journal of Clinical Endocrinology & Metabolism
IS - 12
ER -