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Multi-genomic analysis of 260 adrenocortical cancer patient tumors identifies novel network BIRC5-hsa-miR-335-5p-PAX8-AS1 strongly associated with poor survival

  • Chitra Subramanian
    Affiliations
    Department of Surgery, Michigan Medicine, Ann Arbor, MI
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  • Reid McCallister
    Affiliations
    Department of Surgery, Michigan Medicine, Ann Arbor, MI
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  • Mark S. Cohen
    Correspondence
    Reprint requests: Mark S. Cohen MD, FSSO, FACS, Professor of Surgery, Pharmacology, and Biomedical Engineering, Vice Chair in Surgery for Clinical Operations, Director, Medical School Pathway of Excellence in Innovation and Entrepreneurship, Director Center for Surgical Innovation, Department of Surgery, University of Michigan Hospital and Health Systems, 2920K Taubman Center, SPC 5331, 1500 East Medical Center Drive, Ann Arbor, MI 48109-5331.
    Affiliations
    Department of Surgery, Michigan Medicine, Ann Arbor, MI

    Department of Pharmacology, University of Michigan, Ann Arbor, MI

    Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI
    Search for articles by this author
Published:October 03, 2022DOI:https://doi.org/10.1016/j.surg.2022.08.025

      Abstract

      Background

      Adrenocortical carcinoma is a rare endocrine cancer with poor overall survival. Linking survival outcomes to a common target across multiple genomic datasets incorporating microRNA-long non-coding RNA dysregulation have not been well described. We hypothesized that a multi-database analysis of microRNA-long noncoding RNA-messenger RNA regulatory networks associated with survival will identify novel biomarkers.

      Methods

      Significantly dysregulated genes or microRNA in adrenocortical carcinoma compared to normal adrenal was identified from sequencing data for 260 human adrenocortical carcinomas using GEO2R. The miRnet identified hub microRNA and genes and long noncoding RNA and microRNA associated with survival genes. The R2 generated Kaplan-Meier curves. The database miRTarBase linked genes associated with poor survival and dysregulated microRNA.

      Results

      Analysis of genes and microRNAs differentially regulated in >50% of datasets revealed 75 genes and 12 microRNAs were upregulated, and 167 genes and 12 microRNAs were downregulated (bonf. P < .05). Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed cell cycle, P53 signaling, arachidonic acid and innate immune response, and PI3/Akt are altered in adrenocortical carcinoma. A microRNA-target interaction network of differentially regulated microRNAs identified upregulated miRNA107, 103a-3p and 27a-3p, 16-5p, and downregulated 335-5p to have the highest degree of interaction with upregulated (ie, TPX2, CDK1, BIRC5, PRC1, CCNB1, GINS1) and downregulated (ie, RSPO3, NR2F1, TLR4, HOXA5, USP53, SLC16A9) hub genes as well as hub long noncoding RNAs XIST, NEAT1, KCNQ1OT1, and PAX8-AS1. Survival analysis revealed that the hub genes are associated with poor overall survival (P < .05) of adrenocortical carcinoma in the Cancer Genome Atlas data.

      Conclusion

      A messenger RNA–microRNA–long noncoding RNA network analysis identified the BIRC5-miR335-5p-PAX8-AS1 network as one that was associated with poor overall survival in adrenocortical carcinoma, warranting further validation as a potential therapeutic target.
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