MP63-09 GENOMIC PROFILING OF UROTHELIAL CARCINOMA IN SITU OF BLADDER

Abstract

You have accessJournal of UrologyCME1 Apr 2023MP63-09 GENOMIC PROFILING OF UROTHELIAL CARCINOMA IN SITU OF BLADDER Meenakshi Anurag, Trine Strandgaard, Sung Han Kim, Eva-Maria Comperat, Hikmat A AL-Ahmadie, Brant A Inman, Lars Dyrskjøt, and Seth Lerner Meenakshi AnuragMeenakshi Anurag More articles by this author , Trine StrandgaardTrine Strandgaard More articles by this author , Sung Han KimSung Han Kim More articles by this author , Eva-Maria ComperatEva-Maria Comperat More articles by this author , Hikmat A AL-AhmadieHikmat A AL-Ahmadie More articles by this author , Brant A InmanBrant A Inman More articles by this author , Lars DyrskjøtLars Dyrskjøt More articles by this author , and Seth LernerSeth Lerner More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003321.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Urothelial carcinoma in situ (CIS) is a high-grade intraepithelial cancer whose natural history is associated with ahigh probability of progression. It can be broadly categorized by RNA expression into luminal and basal-likesubtypes, however the molecular drivers unique to CIS as compared to adjacent papillary tumor or normalurothelium are underexplored. Comprehensive genomic analysis of CIS and comparisons to papillary andprogressed tumors may help define progression pathways and BCG treatment response/resistance mechanisms. Todetermine feasibility and proof of concept, we performed molecular characterization of CIS, paired papillary tumorsand normal urothelium METHODS: TUR and matched bladder biopsies were obtained from 32 samples in 19 patients. A total of 10 CIS, 9 papillarytumor and 8 normal samples underwent whole transcriptome RNA sequencing. Wilcoxon test was used to filterdifferentially expressed genes. TCGA single sample classifier was used to assign molecular subtypes. Whole exomesequencing (WES) was performed for 19 patients with matched CIS and papillary tumor samples (nCIS=34 andntumor=33). Using multiplex IF and IHC analyses, 24 samples from 15 patients were analyzed for the presence ofcytotoxic T-cells (CTLs), T-helper cells, regulatory T-cells (Tregs), B-cells, M1 and M2 macrophages and PD-1 andPD-L1-expressing cells RESULTS: M:F ratio was 15:4 and the CIS TCGA subtypes were 3 basal, 2 luminal, 5 luminal infiltrative, 7 luminal papillary,and 1 neuronal. We identified a 46-gene signature of differentially expressed genes in CIS samples that includedknown druggable targets: MTOR, TYK2, AXIN1, CPT1B, GAK and PIEZO1 and selectively downregulated BRD2 andNDUFB2 (p<0.05). We assessed the robustness of these markers in an independent dataset from Dyrskjøt et al (GSE3167)and a reduced 36-gene signature accurately identified the CIS samples (AUC=0.90). We validatedselective overexpression of MTOR, GUSBP11, KMT2D, URB1 and under expression of HMGB1, RPS7, NDUFB4,BRD2, HNRNPK, CANX and HSP90B1in CIS samples. In the WES cohort, KDM6A was the most frequently mutatedgene across CIS and papillary tumor samples. When analyzing CIS samples alone, CCDC138 was the mostcommonly mutated gene. We observed clonality between CIS lesions and matched papillary tumors. We observedfewer immune cells within the tumorareas compared to stromal regions and significantly higher fractions of T-helper cells and B-cells in all stromal areas combined compared to areas of epithelial origin. Additionally, there wasa significantly larger fraction of PD1-expressing cells in CIS regions compared to papillary regions (p=0.031) CONCLUSIONS: We identified CIS lesions having a unique molecular signature and potentially actionable mutations. KDM6A andCCDC138 were commonly mutated, and levels of T-helper and B-cells were highest in stromal regions while CISharbored more PD1-expressing cells. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e874 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Meenakshi Anurag More articles by this author Trine Strandgaard More articles by this author Sung Han Kim More articles by this author Eva-Maria Comperat More articles by this author Hikmat A AL-Ahmadie More articles by this author Brant A Inman More articles by this author Lars Dyrskjøt More articles by this author Seth Lerner More articles by this author Expand All Advertisement PDF downloadLoading ...