Comprehensive Pan-Genomic Characterization of Adrenocortical Carcinoma

• Standardized molecular data from 91 cases of adrenocortical carcinoma
• Driver genes including TP53, ZNFR3, CTNNB1, PRKAR1A, CCNE1, and TERF2
• Whole-genome doubling event is a marker for ACC progression
• Three prognostic molecular subtypes captured by a DNA-methylation signature

SummaryWe describe a comprehensive genomic characterization of adrenocortical carcinoma (ACC). Using this dataset, we expand the catalogue of known ACC driver genes to include PRKAR1A, RPL22, TERF2, CCNE1, and NF1. Genome wide DNA copy-number analysis revealed frequent occurrence of massive DNA loss followed by whole-genome doubling (WGD), which was associated with aggressive clinical course, suggesting WGD is a hallmark of disease progression. Corroborating this hypothesis were increased TERT expression, decreased telomere length, and activation of cell-cycle programs. Integrated subtype analysis identified three ACC subtypes with distinct clinical outcome and molecular alterations which could be captured by a 68-CpG probe DNA-methylation signature, proposing a strategy for clinical stratification of patients based on molecular markers.

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