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Despite recent advances in elucidating molecular pathways underlying adrenocortical carcinoma (ACC), this orphan malignancy is associated with poor survival. Identification of targetable genomic alterations is critical to improve outcomes. The objective of this study was to characterize the genomic profile of a large cohort of patient ACC samples to identify actionable genomic alterations. Three hundred sixty-four individual patient ACC tumors were analyzed. The median age of the cohort was 52 years and 60.9% (n = 222) were female. ACC samples had common alterations in epigenetic pathways with 38% of tumors carrying alterations in genes involved in histone modification, 21% in telomere lengthening, and 21% in SWI/SNF complex. Tumor suppressor genes and WNT signaling pathway were each mutated in 51% of tumors. Fifty (13.7%) ACC tumors had a genomic alteration in genes involved in the DNA mismatch repair (MMR) pathway with many tumors also displaying an unusually high number of mutations and a corresponding MMR mutation signature. In addition, genomic alterations in several genes not previously associated with ACC were observed, including IL7R, LRP1B, FRS2 mutated in 6, 8 and 4% of tumors, respectively. In total, 58.5% of ACC (n = 213) had at least one potentially actionable genomic alteration in 46 different genes. As more than half of ACC have one or more potentially actionable genomic alterations, this highlights the value of targeted sequencing for this orphan cancer with a poor prognosis. In addition, significant incidence of MMR gene alterations suggests that immunotherapy is a promising therapeutic for a considerable subset of ACC patients.

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy affecting individuals across a broad age spectrum. Disease rarity, scarcity of pre-clinical models, lack of effective targeted therapy and limited clinical trials have contributed to poor prognosis for patients with ACC. Identifying targetable genetic drivers and pathways to guide precision medicine approaches is therefore critical to improve outcomes. The purpose of this study was to analyze the genomic profile of a large cohort of ACC to identify potential therapeutic targets. FoundationOne (Foundation Medicine Inc.; FMI, Cambridge, MA) is a next-generation sequencing-based platform for somatic genetic testing in solid tumors. The FoundationOne genomic data and limited demographic data through 2018 for 364 unique ACC specimens were analyzed. The cohort of 364 tumors were from 222 females and 141 males (1 gender unknown). The mean age (SD) was 48.6 (13.6) for females and 50.6 (12.20) for males with overall median age of 52 years. A total of 3117 genomic alterations were identified impacting 457 genes. The median number of genomic alterations per tumor was 7 (range 1–56), with single nucleotide variants and indels being the most common alterations (median=4), followed by copy number alterations (median=1) and rearrangements (median=0). The most frequently altered genes were TP53 (38%), CTNNB1 (28%), ZNRF3 (17%), CDKN2A (13%), ATRX (11%), TERT promoter (10%). Several novel recurrent alterations were identified including IL7R (6%), LRP1B (8%), FRS2 (4%), PTCH1 (4%) and KRAS (3%). Pathway enrichment analysis confirmed that tumor suppressor genes (51%) and Wnt signaling pathways (51%) are the most commonly dysregulated in ACC tumors. Epigenetic alterations, including histone modification (38%), SWI/SNF (21%) and DNA methylation (8%), affected upwards of one third of ACC tumors. Mutation signature analysis identified tumors with signatures 6, 15 and 26 associated with defective DNA mismatch repair (MMR), which was not reported previously. In addition, fifty ACCs (13.7%) exhibited 60 genomic alterations in MMR genes, MLH1, MSH2, MSH6 and PMS2, which included 49 SNVs/indels, 10 CNAs and one truncating rearrangement. In addition to MMR gene alterations, potentially actionable (www.oncokb.org) genomic alterations were found in 46 genes in 213 (58.5%) ACCs. In summary, this study represents the largest to date genomic analysis of ACC that showed that over 50% of ACC tumors had potentially actionable genomic alterations. Approximately 13% of tumors had an alteration in MMR pathway, suggesting that immunotherapy is a relevant therapeutic modality in a significant subset of patients with ACC.