Mitochondrial Nicotinamide Nucleotide Transidrogenase (NNT) and NNT-AS1 impairment is associated with worse outcomes in patients with adrenocortical tumors

Bodoni Aline Faccioli; Junier Gutierrez; Juliana Gebenlian; Laccini Fernanda Coeli; Bueno Ana Carolina; Vencio Ricardo Zorzetto; Castro Margaret de; Sonir Antonini

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ESPE Abstracts (2024) 98 RFC8.5

ESPE2024 Rapid Free Communications Adrenals and HPA Axis 2 (6 abstracts)

Mitochondrial Nicotinamide Nucleotide Transidrogenase (NNT) and NNT-AS1 impairment is associated with worse outcomes in patients with adrenocortical tumors

Aline Faccioli Bodoni ¹ , Junier Gutierrez ¹ , Juliana Gebenlian ² , Fernanda Coeli Laccini ¹ , Ana Carolina Bueno ² , Ricardo Zorzetto Vencio ³ , Margaret de Castro ¹ & Sonir Antonini ²

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¹Department of Internal Medicine, Ribeirão Preto Medical School University of São Paulo, Ribeirão Preto, Brazil. ²Departments of Pediatrics, Ribeirão Preto Medical School University of São Paulo, Ribeirão Preto, Brazil. ³Department of Computing and Mathematics (DCM) at University of Sao Paulo, Ribeirão Preto, Brazil.

Background: Deregulation of oxidative stress and accumulation of reactive oxygen species are metabolic factors that may affect tumor behavior. New recent insights revealed that the inner mitochondrial protein Nicotinamide Nucleotide Transidrogenase (NNT) is essential in the antioxidant defense mechanisms in the adrenal cortex. Studies have shown that long non-coding RNAs (lncRNAs) are important in cancer regulation. Recent studies demonstrated that lncRNA NNT-AS1 played an important role in several tumors.

Aims: To assess the association of NNT and NNT-AS1 expression in adrenocortical tumors (ACT) with clinical outcomes.

Methods: The mRNA expression of the NNT and NNT-AS1 genes was evaluated by qPCR in 42 adrenocortical tumors from pediatric patients (ACTp) in our center. Most patients were female (80.9%) at a mean age of 4 years [0.2-18], As control samples, we used ten normal adrenal cortices. Using RNAseq available data from the TCGA cohort, we also analyzed the expression of these genes in 76 adrenocortical carcinomas from adult patients (ACCa) diagnosed at a mean age of 50 years [22-77], female (61.7%). The association between gene expression and clinical outcomes (disease staging, event-free survival, and overall survival) was tested using the Mann-Whitney-Wilcoxon test or log-rank test. The false discovery rate (FDR) was controlled by the Benjamini-Hochberg test.

Results: There was no association between NNT expression and the clinical outcomes of pediatric patients with ACTp. However, lower expression of NNT-AS1 mRNA was significantly associated with lower overall survival in these patients (Log-rank test: P = 0.02). On the other hand, in adult patients, lower expression of NNT in ACCa was significantly associated with advanced disease stage (ENSAT I/II vs. III/IV. P = 0.01) and death (P = 0.01). Moreover, lower expression of NNT-AS1 was associated with advanced disease stage (P = 0.008) and lower overall survival (Log-rank test: P = 0.0004).

Conclusion: Increased oxidative stress and accumulation of reactive oxygen species appear to modify adrenocortical tumor behavior. Reduced NNT and NNT-AS1 mRNA expression is associated with the worst prognosis in pediatric patients with ACTp as well as in adult patients with ACCa.