MON-326 - Integrated Genomic Profiling Distinguishes Adrenocortical Carcinoma from Benign Adrenocortical Adenomas

Background: The molecular landscape of adrenocortical carcinoma (ACC) is heterogeneous, but it remains unclear which genetic alterations are specific to ACC and which are shared with benign adrenocortical adenomas (ACA). We integrated sequence variant and copy-number alterations (CVA) data to identify genomic signatures distinguishing ACC from ACA.

Methods: We analyzed aggregated targeted sequencing data from 29 ACCs and 39 ACAs profiled using the Oncomine Comprehensive Assay v3 (Thermo Fisher Scientific, cat. no. A35805), performed on the 540 chip on the Ion Torrent S5XL. Diagnosis of ACC was based on standard histopathological criteria, including a Weiss Score of ≥ 3, ± Ki-67 ≥ 5%, and/or the presence of locoregional and/or distant metastases. The absence of these features and a Weiss score of < 3 were consistent with ACA. All frequencies were expressed as the proportion of tumors harboring a given alteration.

Results: ACC showed a broader genomic alteration burden than ACA at both the sequence-variant and copy-number levels. For sequence variants, 113 alterations across 47 genes were identified in 29 ACCs (average 3.9 alterations per tumor) versus 70 across 40 genes in 39 benign ACAs (average 1.8 alterations per tumor). The most frequent ACC variants were in NF1 and TP53 (31.0% each), CTNNB1 (27.6%), MSH2 (24.1%), and SMARCB1 and BRCA2 (20.7% each). Benign ACAs were characterized mainly by ATRX (12.8%), CTNNB1 (12.8%), and FOXL2 (10.3%). For CNA, ACC harbored 85 CNA across 23 genes, compared with 14 across 4 genes in ACA. The most frequent ACC amplifications were RICTOR (27.6%), KRAS (24.1%), FGFR4, ERBB3, CCNE1, and PDGFRB (20.7% each), followed by MET, PDGFRA, and FGFR1 (17.2% each). ACAs were dominated by CCND2 amplification (28.2%). Integrated analysis indicated that ACC is characterized by concurrent tumor-suppressor, mismatch-repair, and chromatin-remodeling alterations, together with broad receptor tyrosine kinase, KRAS, RICTOR, and cell-cycle amplifications.

Conclusions: Compared with TCGA ACC data, our cohort confirms recurrent TP53- and CTNNB1-related alterations but, by including benign adenomas, shows that some genetic alterations, particularly CTNNB1 and occasional KRAS amplification, are not ACC-specific. The discriminatory genomic signature in ACC appears to lie more in the accumulation of TP53, NF1, mismatch-repair, and chromatin-remodeling abnormalities together with widespread RTK/cell-cycle amplifications, supporting molecular separation between malignant and benign adrenocortical neoplasms.

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