ORF13-04 - Dual TP53 and MYC Pathway Alterations Identify a Clinically Aggressive Molecular Subtype of Adrenocortical Carcinoma

Background:
Adrenocortical carcinoma (ACC) is an aggressive malignancy. TP53 and MYC pathway alterations have individually been implicated in tumor progression. However, the transcriptional and clinical significance of dual TP53/MYC pathway dysregulation in ACC remain poorly defined. We aimed to characterize the transcriptional alterations and clinical outcomes in this sub-population.

Methods:
ACC patients from The Cancer Genome Atlas (TCGA) with available genomic, recurrence, metastasis, and survival data were included. MYC/TP53 alteration was defined based on transcriptional overexpression, consistent with TCGA pathway-level annotation. Survival outcomes were assessed using Kaplan–Meier analysis. Differential gene expression was performed using Hallmark Gene Set Enrichment Analysis (GSEA) to investigate biologic pathway dysregulation.

Results:
Ninety-two patients underwent adrenalectomy for ACC, with a median overall survival of 39 months (IQR 20–68). TP53+MYC dual-altered tumors comprised 21.7% of the cohort and demonstrated the poorest prognosis, with a 5-year survival of 18% compared with 58.3% in TP53-only-altered and 77.3% in MYC-only-altered tumors (p = 0.003). Dual-altered tumors were associated with higher recurrence (OR 14.5 95% CI 3.2–107) and distant metastasis (OR 6.4 95% CI 1.8–24.1), even after adjusting for clinical covariates. Transcriptomic analysis revealed that TP53+MYC tumors harbor differential gene expression involved in mitochondrial function and cellular proliferation compared to tumors harboring either alteration alone.
Transcriptomic analysis revealed that TP53+MYC tumors exhibited marked downregulation of genes involved in mitochondrial protein synthesis and cellular metabolism, including COQ9 and MRPL22, compared with tumors harboring either alteration alone, alongside suppression of solute transport and ketone metabolism pathways. In contrast, genes associated with proliferative and transcriptional activity including POLRC3 and SDCCAG8 were upregulated. Consistent with these findings, GSEA demonstrated enrichment of G2M checkpoint and DNA replication pathways, with concurrent suppression of fatty acid and ketone metabolism.

Conclusions:
ACC tumors harboring concurrent TP53 and MYC alterations showed dysregulation of genes involved in cellular proliferation and mitochondrial protein handling and synthesis. These molecular alterations could provide a possible rationale for the increased recurrence, metastatic spread, and shortened survival observed in this population. Although these findings require further in vitro validation, these findings support the need for future investigation of therapeutic strategies targeting proliferative and metabolic vulnerabilities in dual-altered ACC.