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Pan-cancer molecular analysis of the RB-pathway

ABSTRACT: The retinoblastoma tumor suppressor (RB1) plays a critical role in coordinating multiple pathways that impact on tumor initiation, disease progression, and therapeutic responses. Here we interrogated the TCGA pan-cancer data collection to probe fundamental molecular features associated with the RB-pathway across 31 tumor-types. While the RB-pathway has been purported to exhibit multiple mutually exclusive events, only RB1 is mutually exclusive with multiple genetic events that deregulate CDK4/6 activity. Using an isogenic ER+ breast cancer model with targeted RB1 deletion, we identified gene expression features that link CDK4/6 activity and RB-dependency (CDK4/6-RB integrated signature). This gene expression signature is associated with prognosis across a spectrum of tumors that exhibit average lower signature value indicative of more indolent diseases. Single copy loss on chromosome 13q encompassing the RB1 locus is prevalent in many cancers, and is associated with reduced expression of multiple genes on 13q including RB1, and inversely related to the CDK4/6-RB integrated signature supporting a genetic cause/effect relationship. To probe the broader implications on tumor biology, we investigated genes that are positively and inversely correlated with the CDK4/6-RB integrated signature. This approach defined tumor-specific pathways that could represent new therapeutic vulnerabilities associated with RB-pathway activity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE145316 | GEO | 2020/03/02

REPOSITORIES: GEO

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Project description:Chemotherapy resistance is one of the reasons for the loss of the eye in retinoblastoma (RB) pa-tients. RB chemotherapy resistance has been investigated in different cell culture models like WERI RB1. Furthermore, chemotherapy resistant RB subclones like the etoposide resistant WERI ETOR cell line have been established to improve understanding of chemotherapy resistance in RB. Ob-jective of this study was to characterize the cell line models of an etoposide sensitive WERI RB1 and its etoposide resistant subclone WERI ETOR by proteomics analysis. Subsequently, quantitative proteomic data served for correlation analysis with known drug perturbation profiles. . WERI RB1 and WERI ETOR were cultured and prepared for quantitative mass spectrometry. Comparative proteomic profiling was performed with electrospray ionization tandem mass spectrometry in data-independent acquisition mode (SWATH). The raw SWATH files were processed using neural networks in library free mode along with machine learning algorithms. Pathway enrichment was performed using the REACTOME pathway resource and correlated to the Molecular Signature Database (MSigDB) hallmark gene set collections for functional annotation. Also, a drug connec-tivity analysis using the L1000 database was used to correlate the mechanism-of-action (MOA) for different anticancer reagents to WERI RB1 / WERI ETOR signatures. A total 4,756 proteins were identified across all samples which revealed a distinct clustering between groups. Of these pro-teins, 64 proteins were significantly altered (q < 0.05 & log2FC |>2|, 22% higher in WERI ETOR). Pathway analysis showed an enriched metabolic pathway for retinoid metabolism and transport pathway in WERI ETOR and for sphingolipid de novo biosynthesis in WERI RB1. In addition, this study showed similar protein signatures of topoisomerase inhibitors and WERI ETOR as well as of ATPase inhibitors, acetylcholine receptor antagonists and VEGFR inhibitors and WERI RB1. In this study, WERI RB1 and WERI ETOR were characterized as a cell line model for chemotherapy re-sistance in RB by using data-independent mass spectrometry. The global proteome revealed the activation of sphingolipid de novo biosynthesis in WERI RB1 and potential treatment options for etoposide resistant RB.

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Pan-cancer molecular analysis of the RB-pathway

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