Integrated genomic characterization of adrenocortical carcinoma.
Résumé
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.
Mots clés
adolescent
Adrenal Cortex Neoplasms/*genetics
Adrenocortical Carcinoma/*genetics
Adult
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