Integrated genomic characterization of adrenocortical carcinoma

Nat Genet. 2014 Jun;46(6):607-12. doi: 10.1038/ng.2953. Epub 2014 Apr 20.


Adrenocortical carcinomas (ACCs) are aggressive cancers originating in the cortex of the adrenal gland. Despite overall poor prognosis, ACC outcome is heterogeneous. We performed exome sequencing and SNP array analysis of 45 ACCs and identified recurrent alterations in known driver genes (CTNNB1, TP53, CDKN2A, RB1 and MEN1) and in genes not previously reported in ACC (ZNRF3, DAXX, TERT and MED12), which we validated in an independent cohort of 77 ACCs. ZNRF3, encoding a cell surface E3 ubiquitin ligase, was the most frequently altered gene (21%) and is a potential new tumor suppressor gene related to the β-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 of ACCs with good prognosis displayed specific deregulation of two microRNA clusters. Thus, aggressive and indolent ACCs correspond to two distinct molecular entities driven by different oncogenic alterations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adrenal Cortex Neoplasms / genetics*
  • Adrenocortical Carcinoma / genetics*
  • Adult
  • Aged
  • Aged, 80 and over
  • Cohort Studies
  • DNA Methylation
  • DNA Mutational Analysis
  • Exome
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Genomics
  • Humans
  • Loss of Heterozygosity
  • Male
  • MicroRNAs / metabolism
  • Middle Aged
  • Multigene Family
  • Mutation
  • Polymorphism, Single Nucleotide
  • Prognosis
  • Telomere / ultrastructure
  • Ubiquitin-Protein Ligases / metabolism
  • Young Adult
  • beta Catenin / metabolism


  • MicroRNAs
  • beta Catenin
  • Ubiquitin-Protein Ligases

Associated data

  • GEO/GSE49280