Abstract 6099: Differential gene expression related to TMPRSS2-ERG fusion, CDK12, RB1, TP53, AR and ZEB1 based on transcriptomic analysis of the TCGA PRAD cohort

Abstract

Abstract Prostate Cancer (PCa) is considered an immunologically excluded tumor, unable to generate an effective T-cell response against cancer cells. Inactivating mutations of the PTEN tumor suppressor are one of the most common events in human malignancies that contribute to tumorigenesis by affecting many cancer Hallmark pathways. The CDK12, RB1, TP53, AR and ZEB1 genes have been variously implicated in pathways of PCa progression and immune evasion. Here, we present a comprehensive analysis of The Cancer Genome Atlas derived PCa cohort (n=488, 96 homozygous and 64 hemizygous PTEN loss). Differential gene expression (DGE) and pathway enrichment analysis were performed for all five genes using the DESeq2 tool from the Bioconductor package for R. All comparisons were designed to compensate for gene expression changes caused by PTEN loss (Table 1). Functional pathway analysis showed that fusion positive samples presented several downregulated pathways, including leukocyte mediated cytotoxicity, IFN type I response and IFN-γ production. AR high presented upregulation of pathways such as DNA replication and chromatin remodeling, while AR low presented upregulation of pathways such as T cell activation and lymphocyte proliferation. ZEB1 high presented a wide range of enriched pathways, including upregulation of mesenchymal cell differentiation and T cell activation. CDK12-Hom group exhibited upregulation of T cell activation, T cell differentiation and IFN-γ production. TP53 mutation revealed upregulation of various pathways including DNA replication and cell division. RB1 loss showed enrichment of pathways such as T cell activation and lymphocyte activation. Our analysis showed that variation in these five genes can promote gene expression changes associated with clinically relevant pathways independently of PTEN and that AR, CDK12, TMPRSS2-ERG fusion, ZEB1 and RB1 status are potential biomarkers for immunotherapy response. Table 1. Differential genes expression results summary Comparison # of upregulated (LFC>0) # of downregulated (LFC<0) Fusion positive vs. Fusion negative 2997 5418 AR low vs. AR medium 4133 4167 AR high vs. AR medium 4365 2589 CDK12-Hom vs. CDK12 WT 2416 713 CDK12-Hem vs. CDK12 WT 704 387 ZEB1 high vs. ZEB1 normal 6439 6792 RB1 mut vs. RB1 WT 78 335 TP53 mut vs. TP43 WT 859 1193 Citation Format: William Lautert-Dutra, Camila Morais Melo, Luiz Paulo Chaves, André Luiz Caliari, Francisco Cesar Souza Silva, Jeremy Andrew Squire. Differential gene expression related to TMPRSS2-ERG fusion, CDK12, RB1, TP53, AR and ZEB1 based on transcriptomic analysis of the TCGA PRAD cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6099.