Targeted molecular analysis in adrenocortical carcinomas: a strategy towards improved personalized prognostication

Juliane Lippert, Silke Appenzeller, Raimunde Liang, Silviu Sbiera, Stefan Kircher, Barbara Altieri, Indrajit Nanda, Isabel Weigand, Andrea Gehrig, Sonja Steinhauer, Renzo JM Riemens, Andreas Rosenwald, Clemens R Mueller, Matthias Kroiss, Simone Rost, Martin Fassnacht, Cristina Ronchi

Research output: Contribution to journalArticlepeer-review

40 Citations (Scopus)
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Abstract

Context: Adrenocortical carcinoma (ACC) has a heterogeneous prognosis and current medical therapies have limited efficacy in its advanced stages. Genome-wide multi-omics-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: 117 tumor samples from 107 ACC patients 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 Ki67) 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 (>1 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 ROC curve: 0.872, 0.80-0.94). Furthermore, 17 potentially targetable alterations were found in 64 patients (e.g. in CDK4, NOTCH1, NF1, MDM2, 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.
Original languageEnglish
Pages (from-to)4511–4523
Number of pages13
JournalJournal of Clinical Endocrinology and Metabolism
Volume103
Issue number12
Early online date2 Aug 2018
DOIs
Publication statusPublished - Dec 2018

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