Mp50-11 integrative multi-omics profiling in penile squamous cell carcinoma

You have accessJournal of UrologyCME1 Apr 2023MP50-11 INTEGRATIVE MULTI-OMICS PROFILING IN PENILE SQUAMOUS CELL CARCINOMA Timothy Shaw, Alyssa Obermayer, Dalia Ercan, Paul Stewart, Jad Chahoud, Peter Johnstone, Philippe Spiess, Steven Eschrich, and Daniel Grass Timothy ShawTimothy Shaw More articles by this author , Alyssa ObermayerAlyssa Obermayer More articles by this author , Dalia ErcanDalia Ercan More articles by this author , Paul StewartPaul Stewart More articles by this author , Jad ChahoudJad Chahoud More articles by this author , Peter JohnstonePeter Johnstone More articles by this author , Philippe SpiessPhilippe Spiess More articles by this author , Steven EschrichSteven Eschrich More articles by this author , and Daniel GrassDaniel Grass More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003298.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Penile squamous cell carcinoma (PSCC) is rare and about 50% of cases are related to HPV. Relapse after definitive therapy or first-line chemotherapy portends poor survival, thus we hypothesized novel targeting strategies in PSCC may be revealed by relating molecular pathways and patient survival. METHODS: We performed RNA-Seq on 37 PSCC tumors (HPV+=16, HPV-=16, unknown=5) from patients at our institution; 16 samples also underwent bulk proteomics with mass spectrometry. PATH-SURVEIOR is a framework for analyzing and visualizing “on-the-fly” associations of pathways with clinical endpoints. We applied PATH-SURVEIOR to perform single sample gene set enrichment (ssGSEA) on the PSCC RNA and protein expression data. Pathway scores and gene expression were dichotomized by the median to group samples as above/below for each pathway or individual gene expression. Multi-omics integration of pathways related to HPV status was assessed with DRPPM-EASY. TCGA data was downloaded from cBioportal. Uniform manifold projection (UMAP) was performed with the umap R package. RESULTS: We first performed an unsupervised analysis on PSCC and TCGA RNA data and UMAP found similarities with PSCC and other SCCs. Next, we associated pathways/genes and overall survival (OS) through univariable Cox regression and filtered results by hazard ratio (HR>1) and p-value<0.05, followed by HR ranking to define pathways/genes related with high-risk patients. Genes related to OS risk in PSCC included higher levels of DLL4, MET, and MSLN. Also, a cisplatin resistance gene set was linked to poor OS in a subset of PSCC patients. Systematic analysis of gene sets found expression associated with HPV as one prognostic feature based on an unsupervised pathway-level survival analysis; projection of this gene-set feature in the TCGA manifold space revealed an HPV-related cluster that included PSCC and other HPV-related cancers. By integrative GSEA of RNA and proteomics data, we found E2F and DNA damage repair pathways were enriched in HPV+ tumors, whereas HPV-tumors had features of EMT and inflammation. Whereas most RNAs and proteins aligned in direction of expression, several genes (e.g., TP53, MAGI3) were discordant to protein expression in HPV+ tumors, which may imply HPV-mediated translational regulation of protein subsets. CONCLUSIONS: Integrative analysis relating multi-omics data to patient survival from PSCC and TCGA samples identified features consistent with other HPV-related cancers, as well as potential novel targets to consider in PSCC. Source of Funding: Congressionally Directed Medical Research Programs: Rare Cancer Research Programs © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e689 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Timothy Shaw More articles by this author Alyssa Obermayer More articles by this author Dalia Ercan More articles by this author Paul Stewart More articles by this author Jad Chahoud More articles by this author Peter Johnstone More articles by this author Philippe Spiess More articles by this author Steven Eschrich More articles by this author Daniel Grass More articles by this author Expand All Advertisement PDF downloadLoading ...