Abstract
Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy with few therapies; however, patients with locoregional disease have variable outcomes. The Cancer Genome Atlas project on ACC (ACC-TCGA) identified that cancers of patients with homogeneously rapidly recurrent or fatal disease bear a unique CpG island hypermethylation phenotype, "CIMP-high." We sought to identify a biomarker that faithfully captures this subgroup.Experimental Design: We analyzed ACC-TCGA data to characterize differentially regulated biological processes, and identify a biomarker that is methylated and silenced exclusively in CIMP-high ACC. In an independent cohort of 114 adrenocortical tumors (80 treatment-naive primary ACC, 22 adrenocortical adenomas, and 12 non-naive/nonprimary ACC), we evaluated biomarker methylation by a restriction digest/qPCR-based approach, validated by targeted bisulfite sequencing. We evaluated expression of this biomarker and additional prognostic markers by qPCR. We show that CIMP-high ACC is characterized by upregulation of cell cycle and DNA damage response programs, and identify that hypermethylation and silencing of G0S2 distinguishes this subgroup. We confirmed G0S2 hypermethylation and silencing is exclusive to 40% of ACC, and independently predicts shorter disease-free and overall survival (median 14 and 17 months, respectively). Finally, G0S2 methylation combined with validated molecular markers (BUB1B-PINK1) stratifies ACC into three groups, with uniformly favorable, intermediate, and uniformly dismal outcomes. G0S2 hypermethylation is a hallmark of rapidly recurrent or fatal ACC, amenable to targeted assessment using routine molecular diagnostics. Assessing G0S2 methylation is straightforward, feasible for clinical decision-making, and will enable the direction of efficacious adjuvant therapies for patients with aggressive ACC.
Highlights
Adrenocortical carcinoma (ACC) is a rare cancer of the adrenal cortex affecting 0.5–2 individuals/million/year globally [1,2]
We show that CIMP-high ACC is characterized by upregulation of cell cycle and DNA damage response programs, and identify that hypermethylation and silencing of G0S2 distinguishes this subgroup
Given the striking clinical phenotype associated with the CIMP-high signature, we sought to determine if other molecular classes and somatic alterations identified by ACC
Summary
Adrenocortical carcinoma (ACC) is a rare cancer of the adrenal cortex affecting 0.5–2 individuals/million/year globally [1,2]. ACC is frequently aggressive with 35% 5-year survival [3]. Therapies for metastatic ACC are primarily palliative, limited to administration of adrenolytic drug mitotane and/or cytotoxic chemotherapy [3]. Patients with locoregional ACC routinely receive surgery and adjuvant mitotane, but 50–70% recur and develop metastases even after complete (R0) resection [4,5]. Retrospective studies suggest adjuvant mitotane prolongs recurrence free survival [6,7], but its efficacy is limited by its poor pharmacokinetic properties and dose-limiting toxicities. There is a substantial proportion of ACC patients who experience rapid recurrence (
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