Integrated genomic characterization of adrenocortical carcinoma

Adrenocortical carcinomas (ACCs) are aggressive cancers originating in the cortex of the adrenal gland1. Despite overall poor prognosis,ACC outcome is heterogeneous2,3. We performed exome sequencing and SNP array analysis of
45ACCs and identified recurrent alterations in known driver genes4,5 (CTNNB1, TP53, CDKN2A, RB1 and MEN1) and in genes not previously reported inACC (ZNRF3, DAXX, TERT and MED12), which we validated in an independent cohort of 77ACCs. ZNRF3, encoding a cell surface E3 ubiquitin ligase6, was the most frequently altered gene (21%) and is a potential new tumor suppressor gene related to the b-catenin pathway. Our integrated genomic analyses further identified two distinct molecular subgroups with opposite outcome.The C1A group of ACCs with poor outcome displayed numerous mutations and DNA
methylation alterations, whereas the C1B group ofACCs with good prognosis displayed specific deregulation of two microRNA clusters.Thus, aggressive and indolentACCs correspond to two distinct molecular entities driven by different oncogenic alterations.