Endocrine Abstracts (2017) 49 GP119 | DOI: 10.1530/endoabs.49.GP119

Targeted molecular analysis in adrenocortical carcinomas: a way towards personalized medicine

Cristina L Ronchi1, Juliane Lippert2, Silke Appenzeller3, Silviu Sbiera1, Sonja Steinhauer1, Raimunde Liang1, Andrea Gehrig2, Matthias Kroiss1, Simone Rost2, Andreas Rosenwald4, Clemens Müller-Reible2 & Martin Fassnacht1

1Division of Endocrinology and Diabetes, University Hospital of Wuerzburg, Wuerzburg, Germany; 2Institute of Human Genetic, University of Wuerzburg, Wuerzburg, Germany; 3Core Unit Bioinformatics, Comprehensive Cancer Center Mainfranken, University Hospital of Wuerzburg, Wuerzburg, Germany; 4Department of Pathology, University of Wuerzburg, Wuerzburg, Germany.

Adrenocortical carcinoma (ACC) is a rare tumor with heterogeneous outcome and no available targeted therapy. The aim of the study is to identify prognostic molecular markers and novel potential drug targets.

A total of 43 FFPE tumor samples were retrospectively investigated for somatic mutations and copy number variations (CNV) by next-generation sequencing (160 cancer-related genes, Qiagen). Gene expression was evaluated by quantitative RT-PCR in a subgroup of 25 ACC samples (84 cancer drug targets, Qiagen). The major clinical endpoint was progression free survival (PFS).

We observed 123 protein-altering mutations in 47 genes (median 2 per sample), with the most frequent known to be ACC-related: TP53 (28% of samples), CTNNB1 (26%), ZNRF3 (19%), NF1 (16%) and GNAS (14%). Notably, we also detected recurrent mutations in genes previously not clearly associated with ACC (i.e. ABL1, KDM6A, TSC1, FBXW7, DNMT3A, BRCA1, BRCA2). Some focal CNV were found in >30% samples (i.e. gains of CDK4, MDM2, IL7R, and losses of TNFRSF14). A noisy pattern was associated to a shorter median PFS than chromosomal or quiet pattern (4.5 vs 7 vs 14 months, respectively, P=0.07). Most affected genes were involved in p53/Rb or Wnt/β-catenin pathway or chromatin remodeling, but also in immune response or DNA repair mechanisms. Patients with alterations in DNA repair genes had longer PFS than others (P=0.067, HR=1.78). At mRNA level, most frequently overexpressed genes (>2.5 fold change) were IGF2 (92%), TOP2A (92%), CDK1 (72%) and PLK1 (60%). Tumors with increased BUB1B-PINK1 (>5.9) were associated with a trend to worst PFS (P=0.16, HR=1.98).

This pilot study demonstrates the feasibility of molecular analysis in FFPE samples. We identified some genetic variants previously not associated with ACC and new potential drug target genes. These results will be validated in a larger series in order to path the way to a personalized medicine in ACC.