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Y chromosome loss in bladder cancer contributes to T cell exhaustion and sensitivity to immune checkpoint blockade [WES]

ABSTRACT: Loss of the Y chromosome (LOY) is observed in several common cancer types, including 10-40% of bladder cancers, but the clinical and biological significance of this finding is unknown. Through genomic and transcriptomic studies, we report that low LOY gene signature scores correlate with poor prognoses in patients with bladder cancer. We then performed in-depth studies of natural occurring bladder cancer cells with LOY mutants as well as those with targeted deletion of Y chromosome by CRISPR/Cas9. Both Y+ and Y- tumors had similar growth kinetics in vitro, while Y- tumors grew faster than Y+ tumors in immune competent hosts in a T cell-dependent manner

ORGANISM(S): Mus musculus

PROVIDER: GSE230819 | GEO | 2023/06/10

REPOSITORIES: GEO

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Y chromosome loss in cancer drives growth by evasion of adaptive immunity [RNA-seq]

Project description:Loss of the Y chromosome (LOY) is observed in several common cancer types, including 10-40% of bladder cancers, but the clinical and biological significance of this finding is unknown. Through genomic and transcriptomic studies, we report that low LOY gene signature scores correlate with poor prognoses in patients with bladder cancer. We then performed in-depth studies of natural occurring bladder cancer cells with LOY mutants as well as those with targeted deletion of Y chromosome by CRISPR/Cas9. Both Y+ and Y- tumors had similar growth kinetics in vitro, while Y- tumors grew faster than Y+ tumors in immune competent hosts in a T cell-dependent manner

2023-06-10 | GSE229233 | GEO

Frequent truncating mutations of STAG2 in bladder cancer

Project description:Here we report the discovery of truncating mutations of the gene encoding the cohesin subunit STAG2, which regulates sister chromatid cohesion and segregation, in 36% of papillary non-invasive urothelial carcinomas and 16% of invasive urothelial carcinomas of the bladder. Our studies suggest that STAG2 has a role in controlling chromosome number but not the proliferation of bladder cancer cells. These findings identify STAG2 as one of the most commonly mutated genes in bladder cancer. Affymetrix CytoScan HD Arrays were performed according to the manufacturer's directions on genomic DNA extracted directly from 12 snap-frozen human urothelial carcinoma primary tumors with somatic mutations of the STAG2 gene.

2013-06-30 | GSE41581 | GEO

Evidence of Y Chromosome LncRNAs involved in Radiation Response of Male Non-Small Cell Lung Cancer Cells

Project description:Numerous studies have implicated changes in the Y chromosome in male cancers, however few have investigated the biological importance of Y chromosome non-coding RNAs. Here, we demonstrate a group of Y chromosome-expressed long non-coding RNAs (lncRNAs) involved in male non-small cell lung cancer (NSCLC) radiation sensitivity. Radiosensitive male NSCLC cell lines demonstrated a dose-dependent induction of linc-SPRY3-2/3/4 following irradiation, not observed in radioresistant male NSCLC cell lines. Cytogenetics revealed the loss of chromosome Y (LOY) in the radioresistant male NSCLC cell lines. Gain- and loss-of-function experiments indicated that linc-SPRY3-2/3/4 transcripts affect cell viability and apoptosis. UV Cross-linking and Immunoprecipitation (CLIP) and RNA stability assays identify IGF2BP3 as a binding partner for the linc-SPRY3-2/3/4 RNAs which alters the half-life of the anti-apoptotic HMGA2 mRNA as well as the oncogenic c-MYC mRNA. To assess the clinical relevance of these findings, we examined the presence of the Y chromosome in NSCLC tissue microarrays and the expression of linc-SPRY3-2/3/4 in NSCLC RNAseq and microarray data. We observed a negative correlation between the loss of the Y chromosome or linc-SPRY3-2/3/4 and overall survival. Thus, linc-SPRY3-2/3/4 expression and LOY could represent an important marker of radiation therapy in NSCLC.

2020-03-30 | GSE147708 | GEO

Mosaic loss of Y chromosome is associated with aging and epithelial injury in chronic kidney disease

Project description:Background Mosaic loss of Y chromosome (LOY) is the most common chromosomal alteration in aging men. Here, we use single cell RNA and ATAC sequencing to show that LOY is present in the kidney and increases with age and chronic kidney disease. Results The likelihood of a cell having LOY varies depending on its location in the nephron. Cortical epithelial cell types have a greater proportion of LOY than medullary or glomerular cell types, which may reflect their proliferative history. Proximal tubule cells are the most abundant cell type in the cortex and are susceptible to hypoxic injury. A subset of these cells acquires a pro-inflammatory transcription and chromatin accessibility profile associated with expression of HAVCR1, VCAM1 and PROM1. These injured epithelial cells have the greatest proportion of LOY and their presence predicts future kidney function decline. Moreover, proximal tubule cells with LOY are more likely to harbor additional large chromosomal gains and express pro-survival pathways. Spatial transcriptomics localizes injured proximal tubule cells to a pro-fibrotic microenvironment where they adopt a secretory phenotype and likely communicate with infiltrating immune cells. Conclusions We hypothesize that LOY is an indicator of increased DNA damage and potential marker of cellular senescence that can be applied to single cell datasets in other tissues.

2024-01-05 | GSE232222 | GEO

SNP data from 20 bladder tumors

Project description:We present the first computational approach to reconstruct the sequence of copy number alterations driving carcinogenesis from the analysis of several tumor samples of a same patient. Applied to BAC array-CGH and SNP array data from bladder and breast cancers, this method proved highly valuable to establish the clonal relationships between primary tumors and recurrences and to identify the chromosome aberrations at the initiation of tumorigenesis. An algorithm was developed to reconstruct tumors lineage and the sequence of copy number alterations along tumorigenesis from the analysis of several samples from a same patient. The data here consist in Illumina SNP data from 20 bladder tumors. 15 of these tumors (REF1 to REF15) come from independent samples and were used to compute the frequencies of breakpoints at each location. The 5 other samples (S4_A, S4_B, S5_A, S5_B, and S5_C) are multiple tumors from 2 patients. They were used to reconstruct the sequence of chromosome aberrations along cancer development in these 2 patients.

2010-06-25 | E-GEOD-19189 | biostudies-arrayexpress

CGH data from 58 bladder tumors

Project description:We present the first computational approach to reconstruct the sequence of copy number alterations driving carcinogenesis from the analysis of several tumor samples of a same patient. Applied to BAC array-CGH and SNP array data from bladder and breast cancers, this method proved highly valuable to establish the clonal relationships between primary tumors and recurrences and to identify the chromosome aberrations at the initiation of tumorigenesis. Keywords: Comparative Genomic Hybridization An algorithm was developed to reconstruct tumors lineage and the sequence of copy number alterations along tumorigenesis from the analysis of several samples from a same patient. The data here consist in CGH data from 58 bladder tumors. 50 of these tumors come from independent samples and were used to compute the frequencies of breakpoints at each location. The 8 other samples (S1_A, S1_B, S2_A, S2_B, S3_A, S3_B, S3_C and S3_D) are multiple tumors from 3 patients. They were used to reconstruct the sequence of chromosome aberrations along cancer development in these 3 patients.

2010-05-19 | E-GEOD-19193 | biostudies-arrayexpress

Transcriptomic profiling for differential gene expression in ARID1A-wt and ARID1A-deficient bladder cancer cells with and without GSK126 (an EZH2 inhibitor) treatment

Project description:Metastatic urothelial carcinoma of the bladder is generally incurable with current systemic therapies. Chromatin modifiers are frequently mutated in bladder cancer, with ARID1A inactivating mutations present in 20% of tumors. EZH2 is a histone methyltransferase that acts as an oncogene that functionally opposes ARID1A. In addition, PI3K signaling is activated in over 20% of bladder cancers. Here we show that ARID1A-mutant tumors are more sensitive to EZH2 inhibition than ARID1A-wild-type tumors. Mechanistic studies reveal that: 1) ARID1A deficiency results in a dependency on PI3K/AKT/mTOR signaling via upregulation of a non-canonical PI3K regulatory subunit PIK3R3, and: 2) EZH2 inhibitor sensitivity is due to upregulation of PIK3IP1, an inhibitor protein of PI3K signaling. Thus, our studies suggest that a subset of bladder cancers with ARID1A mutations can be treated with inhibitors of EZH2 and/or PI3K, and reveal novel mechanistic insights into the role of non-canonical PI3K constituents in bladder cancer biology.

2022-08-22 | GSE183777 | GEO

Identification of subsets of urothelial carcinoma

Project description:Identification of bladder cancer subsets 142 primary bladder tumors including superficial and invasive tumors were arrayed. 73 invasive tumors out of 142 tumors were used for muscle invasive baldder cancer classification

2014-02-10 | E-GEOD-48075 | biostudies-arrayexpress

Gene expression profiling of urothelial carcinoma

Project description:Identification of bladder cancer subsets 128 FFPE bladder tumors were used to validate the bladder cancer subsets

2014-02-10 | E-GEOD-48276 | biostudies-arrayexpress

Genome-wide map of cohesin positions in RT112 bladder cancer cells

Project description:Bladder cancer is one of the most common genitourinary malignancies worldwide. It is a heterogeneous disease at the clinical, pathological, and genetic levels. In an exome-sequencing study of bladder cancer, we identified genes mutated in bladder cancer coding for proteins involved in chromatin modification, cell division, and DNA repair. STAG2, a constituent of the cohesin complex, was commonly mutated or lost, mainly in tumors of low stage or grade. Loss of STAG2 expression was often observed in genomically stable tumors, suggesting that STAG2 may act as a tumor suppressor through mechanisms other than chromosome segregation (Balbás-Martínez et al. 2013). In addition to mediating sister chromatid cohesion, cohesin plays a central role in DNA looping and organization of the genome into Topologically Associating Domains (TADs). Two variant cohesin complexes that contain either STAG1 or STAG2 are present in all cell type. Here we addressed their genome wide binding in bladder cancer cells.

2021-03-15 | GSE111913 | GEO

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