Dataset Information

BCOR mutations deregulate cell cycle and hypoxic adaptation pathways in retinoblastoma

ABSTRACT: Retinoblastoma (RB) is the most common pediatric eye cancer. Most cases of RB are initiated by bi-allelic mutational inactivation of the RB1 gene, yet most RB tumors harbor additional genomic aberrations that may promote tumor progression. After RB1, the gene that is most commonly mutated gene in RB is BCOR, which is mutated in approximately 20% of RB tumors and is associated with a more aggressive tumor phenotype and worse patient outcomes. Despite its importance, little is known about the role of BCOR in RB. Here, we interrogated BCOR in low passage RB cell lines using mass spectrometry, chromatin immunoprecipitation sequencing, and RNA sequencing. We show that the BCOR protein interacts with members of the ncPRC1.1 Polycomb Repressive Complex and localizes at gene loci with traditionally activating and repressing chromatin markers. Loss of BCOR downregulates the expression of genes associated with cell cycle regulation and upregulates genes associated with hypoxic adaptation. We conclude that BCOR mutations slow cell proliferation and drive hypoxic adaptation in RB via epigenetic mechanisms that may be amenable to targeted therapy. BCOR pulldowns are compared with IgG controls for 3 cell lines (RB006, RB026, and RB028).

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Precursor Cell

DISEASE(S): Retinoblastoma

SUBMITTER: John Koomen

LAB HEAD: J. William Harbour

PROVIDER: PXD067854 | Pride | 2026-01-12

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20191115_U-Miami_Harbour_RB006_BCOR.raw	Raw
	20191115_U-Miami_Harbour_RB006_BCOR.raw__F005697_.dta	Raw
	20191115_U-Miami_Harbour_RB006_BCOR.raw__F005697_.mzid	Mzid
	20191115_U-Miami_Harbour_RB006_BCOR.raw__F005697_.mzid_20191115_U-Miami_Harbour_RB006_BCOR.raw__F005697_.MGF	Mzid
	20191115_U-Miami_Harbour_RB006_IgG.raw	Raw

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Publications

BCOR mutations deregulate cell cycle and hypoxic adaptation pathways in retinoblastoma.

Zhang Michelle G MG Kuznetsoff Jeffim N JN Cetta Natalie C NC Salazar Sebastian S Volonterio Renata L RL Kurtenbach Stefan S Correa Zelia M ZM Pelaez Daniel D Harbour J William JW

Molecular cancer research : MCR 20251105

Retinoblastoma (RB) is the most common pediatric eye cancer. Most cases of RB are initiated by bi-allelic mutational inactivation of the RB1 gene, yet most RB tumors harbor additional genomic aberrations that may promote tumor progression. After RB1, the gene that is most commonly mutated gene in RB is BCOR, which is mutated in approximately 20% of RB tumors and is associated with a more aggressive tumor phenotype and worse patient outcomes. Despite its importance, little is known about the role ...[more]

PMID: 41191430

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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.

Project description:Background: Retinoblastoma (RB) is the most common malignant childhood tumor of the eye and results from inactivation of both alleles of the RB1 gene. Nowadays RB genetic diagnosis requires classical chromosome investigations, Multiplex Ligation-dependent Probe Amplification analysis (MLPA) and Sanger sequencing. Nevertheless, these techniques show some limitations. We report our experience on a cohort of RB patients using a combined approach of Next-Generation Sequencing (NGS) and RB1 custom array-Comparative Genomic Hybridization (aCGH). Methods: A total of 65 patients with retinoblastoma were studied: 29 cases of bilateral RB and 36 cases of unilateral RB. All patients were previously tested with conventional cytogenetics and MLPA techniques. Fifty-three samples were then analysed using NGS. Eleven cases were analysed by RB1 custom aCGH. One last case was studied only by classic cytogenetics. Finally, it has been tested, in a lab sensitivity assay, the capability of NGS to detect artificial mosaicism series in previously recognized samples prepared at 3 different mosaicism frequencies: 10%, 5%, 1%. Results: Of the 29 cases of bilateral RB, 28 resulted positive (96.5%) to the genetic investigation: 22 point mutations and 6 genomic rearrangements (four intragenic and two macrodeletion). A novel germline intragenic duplication, from exon18 to exon 23, was identified in a proband with bilateral RB. Of the 36 available cases of unilateral RB, 8 patients resulted positive (22%) to the genetic investigation: 3 patients showed point mutations while 5 carried large deletion. Finally, we successfully validated, in a lab sensitivity assay, the capability of NGS to accurately measure level of artificial mosaicism down to 1%. Conclusions: NGS and RB1-custom aCGH have demonstrated to be an effective combined approach in order to optimize the overall diagnostic procedures of RB. Custom aCGH is able to accurately detect genomic rearrangements allowing the characterization of their extension. NGS is extremely accurate in detecting single nucleotide variants, relatively simple to perform, cost savings and efficient and has confirmed a high sensitivity and accuracy in identifying low levels of artificial mosaicisms.