RNA Export Machinery Predicts the Prognosis of Adrenocortical Carcinoma

Background: Adrenocortical carcinoma (ACC) is a rare but aggressive endocrine malignancy with poor prognosis. Despite its clinical importance, there have been limited investigations on personalized genomic survival indicators, specifically for recurrence free survival (RFS) and early-stage overall survival (OS). Nuclear trafficking machinery, including nuclear pore complexes (NPC) and TRanscription EXport (TREX), plays an important role in cell fates from senescence to malignancies but its association with ACC has never been addressed.  Methods: Univariate and multivariable survival analyses with stepwise variable selections were performed in 78 patient data from The Cancer Genome Atlas (TCGA), using the gene expression levels of NPC, TREX and NPC-TREX (N-TREX) as covariates. It was further validated using two independent microarray-based datasets. In a meta-analytic approach, we combined the datasets to form the cross-platform reference ACC dataset and further examined the prognostic values. Findings: Multivariable analyses showed the average expression level of N-TREX was a significant prognostic indicator for OS, early-stage OS, and RFS in TCGA RNA-seq dataset, which was consistent in the microarray cohorts. In the combined cross-platform reference dataset, N-TREX was still highly significant for OS (N-TREX HR=2137.53, 95% confidence interval [CI] 55.10-82927.86, p < 0.001), early-stage OS, and RFS, which was consistent in Kaplan-Meier analysis.  Interpretation: N-TREX, the functional genomic group of nuclear trafficking machinery, is a reliable molecular prognostic indicator, particularly for early-stage OS and RFS, as well as OS in ACC patients. In addition, we have developed an individualized ACC prognostic web application for clinicians.  Funding Information: National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (NRF-2019R1F1A1062023). Declaration of Interests: The authors declare no potential conflicts of interest.