PD03-02 NOVEL STRUCTURAL VARIANTS IN CTNNB1 AND MOLECULAR CLASSIFICATION IN CORTISOL-PRODUCING ADENOMA

Abstract

You have accessJournal of UrologyCME1 Apr 2023PD03-02 NOVEL STRUCTURAL VARIANTS IN CTNNB1 AND MOLECULAR CLASSIFICATION IN CORTISOL-PRODUCING ADENOMA Yoichi Fujii, Seiichiro Higuchi, Yusuke Sato, Yuichi Shiraishi, Kenichi Yoshida, Satoru Miyano, Haruki Kume, Tomohiko Ichikawa, Atsushi Iwama, Tomoaki Tanaka, and Seishi Ogawa Yoichi FujiiYoichi Fujii More articles by this author , Seiichiro HiguchiSeiichiro Higuchi More articles by this author , Yusuke SatoYusuke Sato More articles by this author , Yuichi ShiraishiYuichi Shiraishi More articles by this author , Kenichi YoshidaKenichi Yoshida More articles by this author , Satoru MiyanoSatoru Miyano More articles by this author , Haruki KumeHaruki Kume More articles by this author , Tomohiko IchikawaTomohiko Ichikawa More articles by this author , Atsushi IwamaAtsushi Iwama More articles by this author , Tomoaki TanakaTomoaki Tanaka More articles by this author , and Seishi OgawaSeishi Ogawa More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003220.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Cortisol-producing adenoma (CPA) is the most common hormone-producing adrenal tumor. Although several hotspot mutations of driver genes (PRKACA, GNAS, and CTNNB1) have been identified in the previous studies, genotypes have not been confirmed in approximately 30% of CPAs. In addition, the association between genotypes and clinical characteristics of CPAs are poorly understood. METHODS: Genomic DNA and RNA was extracted from 125 surgical specimens of adrenal CPAs, including 60 cases with Cushing’s syndrome (CS) and 65 with subclinical Cushing’s syndrome (SCS), and subjected to targeted-capture sequencing and RNA sequencing. RESULTS: Novel structural variants (SVs) in CTNNB1, including long deletion and inversion, were identified in 8% (10/125) of CPA cases. All these SVs resulted in the lack of exon 3, which encodes the phosphorylation site of beta-catenin and plays an important role in its degradation, leading to the constitutive activation of the Wnt pathway by disrupting the degradation of beta-catenin. In addition, several mutations in PRKACA, which encodes the catalytic subunit of cyclic adenosine monophosphate (cAMP)–dependent protein kinase (PKA), were identified around the known hotspot p.L206. Subsequent functional assay showed that these PRAKACA mutants abolished its binding ability to PRKAR1A, the regulatory subunit of PKA, leading to the constitutive, cAMP-independent PKA activation. In total, 82.4% (103/125) of CPAs had alterations in PRKACA, GNAS, and wnt pathway genes (CTNNB1, APC, and MED12) in almost mutually exclusive manner, based on which CPAs are classified into three distinct subgroups. These mutational subtypes showed distinct genetic and clinical characteristics. RNA sequencing revealed that the expression level of steroidogenic enzymes such as CYP17A1 and CYP21A2 were more upregulated in PRKACA-mutated subtype than wnt-mutated subtype. Consistent with this observation, PRKACA-mutated subtype showed significantly higher cortisol-producing autonomous secretion level, more frequent CS than wnt-mutated subtype. In contrast, wnt-mutated subtype more tended to be SCS, showed lower cortisol-producing ability and largar tumor volume compared to the other two subtypes. CONCLUSIONS: Novel CTNNB1 structural variants were identified. CPAs showed distinct genetic landscape, associated with various clinical features. Source of Funding: No © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e74 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yoichi Fujii More articles by this author Seiichiro Higuchi More articles by this author Yusuke Sato More articles by this author Yuichi Shiraishi More articles by this author Kenichi Yoshida More articles by this author Satoru Miyano More articles by this author Haruki Kume More articles by this author Tomohiko Ichikawa More articles by this author Atsushi Iwama More articles by this author Tomoaki Tanaka More articles by this author Seishi Ogawa More articles by this author Expand All Advertisement PDF downloadLoading ...