Y chromosome loss in cancer drives growth by evasion of adaptive immunity [RNA-seq]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE229233 | GEO | 2023/06/10
REPOSITORIES: GEO
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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 | GSE230819 | GEO
Project description:Densely ionizing radiation is a major component of the space radiation environment and has potentially greater carcinogenic effect compared to sparsely ionizing radiation that is prevalent in the terrestrial environment. It is unknown to what extent the irradiated microenvironment contributes to the differential carcinogenic potential of densely ionizing radiation. To address this gap, 10-week old BALB/c mice were irradiated with 100 cGy sparsely ionizing g-radiation or 10, 30, or 80 cGy of densely ionizing, 350 MeV/amu Si particles and transplanted 3 days later with syngeneic Trp53 null mammary fragments. Tumor appearance was monitored for 600 days. Tumors arising in Si-particle irradiated mice had a shorter median time to appearance, grew faster and were more likely to metastasize. Most tumors arising in sham-irradiated mice were ER-positive, pseudo-glandular and contained both basal keratin 14 and luminal keratin 8/18 cells (designated K14/18), while most tumors arising in irradiated hosts were K8/18 positive (designated K18) and ER negative. Comparison of K18 vs K14/18 tumor expression profiles showed that genes increased in K18 tumors were associated with ERBB2 and KRAS while decreased genes overlapped with those down regulated in metastasis and by loss of E-cadherin. Consistent with this, K18 tumors grew faster than K14/18 tumors and more mice with K18 tumors developed lung metastases compared to mice with K14/18 tumors. However, K18 tumors arising in Si-particle irradiated mice grew even faster and were more metastatic compared to control mice. A K18 Si-irradiated host profile was enriched in genes involved in mammary stem cells, stroma, and Notch signaling. Thus systemic responses to densely ionizing radiation enriches for a ER-negative, K18-positive tumor, whose biology is more aggressive compared to similar tumors arising in non-irradiated hosts. Key Words: ionizing radiation; breast cancer; heavy ion radiation;initiation; promotion 3 different dose of Si were used. Total RNA was extracted from mammary tumors derived from transplantations of non-irradiated p53null mammary fragments into irradiated hosts. We analyzed a total of 45 Trp53-null tumors: 18 from sham-irradiated hosts, 9 from 10 cGy Si-irradiated hosts, 10 from 30 cGy Si-irradiated hosts, and 8 from irradiated hosts.
2014-10-10 | E-GEOD-56704 | biostudies-arrayexpress
Project description:Densely ionizing radiation is a major component of the space radiation environment and has potentially greater carcinogenic effect compared to sparsely ionizing radiation that is prevalent in the terrestrial environment. It is unknown to what extent the irradiated microenvironment contributes to the differential carcinogenic potential of densely ionizing radiation. To address this gap, 10-week old BALB/c mice were irradiated with 100 cGy sparsely ionizing g-radiation or 10, 30, or 80 cGy of densely ionizing, 350 MeV/amu Si particles and transplanted 3 days later with syngeneic Trp53 null mammary fragments. Tumor appearance was monitored for 600 days. Tumors arising in Si-particle irradiated mice had a shorter median time to appearance, grew faster and were more likely to metastasize. Most tumors arising in sham-irradiated mice were ER-positive, pseudo-glandular and contained both basal keratin 14 and luminal keratin 8/18 cells (designated K14/18), while most tumors arising in irradiated hosts were K8/18 positive (designated K18) and ER negative. Comparison of K18 vs K14/18 tumor expression profiles showed that genes increased in K18 tumors were associated with ERBB2 and KRAS while decreased genes overlapped with those down regulated in metastasis and by loss of E-cadherin. Consistent with this, K18 tumors grew faster than K14/18 tumors and more mice with K18 tumors developed lung metastases compared to mice with K14/18 tumors. However, K18 tumors arising in Si-particle irradiated mice grew even faster and were more metastatic compared to control mice. A K18 Si-irradiated host profile was enriched in genes involved in mammary stem cells, stroma, and Notch signaling. Thus systemic responses to densely ionizing radiation enriches for a ER-negative, K18-positive tumor, whose biology is more aggressive compared to similar tumors arising in non-irradiated hosts. Key Words: ionizing radiation; breast cancer; heavy ion radiation;initiation; promotion
2014-10-10 | GSE56704 | GEO
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
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
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
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
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
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
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