Ontology highlight
ABSTRACT:
PROVIDER: PRJNA783364 | ENA |
REPOSITORIES: ENA
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Project description:Whole Genome Sequencing of the murine breast cancer cell line 4T1 and of the murine melanoma cell line B16-ova was carried out with the aim of identifying somatic mutations. We also ran deep Mass Spectrometry proteomics analysis on the same cell lines, aiming to determine which somatic mutations carry over to the protein expression level. Further, we tested these cancer specific protein epitopes (putative neoantigens) for immunogenicity using mouse models. Finally, the putative neoantigens that showed good immunogenic potential were used in tumor growth control experiments with mice engrafted with the two tumor cell lines. In these experiments we tested whether cancer vaccines based on individual neoantigen peptides (MHC-I) restricted the growth of the tumor compared to adequate controls. The overall aim of the project is to validate the ability of our multi-omics/bioinformatics pipeline to identify and deliver neoantigens that can be used to suppress tumor growth. File names Sample names P10859_101_S1_L001_R1_001_BHKWV3CCXY 4T1_S1_L001_R1_001_BHKWV3CCXY P10859_101_S1_L001_R2_001_BHKWV3CCXY 4T1_S1_L001_R2_001_BHKWV3CCXY P10859_101_S1_L002_R1_001_BHKWV3CCXY 4T1_S1_L002_R1_001_BHKWV3CCXY P10859_101_S1_L002_R2_001_BHKWV3CCXY 4T1_S1_L002_R2_001_BHKWV3CCXY P10859_102_S2_L003_R1_001_BHKWV3CCXY B16-OVA_S2_L003_R1_001_BHKWV3CCXY P10859_102_S2_L003_R2_001_BHKWV3CCXY B16-OVA_S2_L003_R2_001_BHKWV3CCXY P10859_102_S2_L004_R1_001_BHKWV3CCXY B16-OVA_S2_L004_R1_001_BHKWV3CCXY P10859_102_S2_L004_R2_001_BHKWV3CCXY B16-OVA_S2_L004_R2_001_BHKWV3CCXY
2024-01-31 | E-MTAB-13635 | biostudies-arrayexpress
Project description:Immunogenicity of somatic mutations in gastrointestinal cancers
| PRJNA298330 | ENA
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:Somatic mutations in 60 bladder cancer patients for specific genes
| PRJNA218872 | ENA
Project description:Aneuploidy is among the most common hallmarks of cancer, yet the underlying genetic mechanisms are still poorly defined. We have recently identified STAG2 as a gene that is mutated in human cancer and whose inactivation leads directly to chromosomal instability and aneuploidy. However, no single tumor type has yet been identified in which inactivation of a cohesin subunit represents a predominant mutational event. Here we used immunohistochemistry to screen a panel of 2,214 tumors from each of the major human tumor types to identify additional tumor types harboring somatic loss of STAG2. Strikingly, STAG2 expression was completely absent in 18% of urothelial carcinomas, the most common type of bladder cancer and the fifth most common cancer in the United States. DNA sequencing revealed that somatic mutations of STAG2 were present in 21% of urothelial carcinomas, which were found to be a group of highly aneuploid tumors. The acquisition of STAG2 mutations was shown to be an early event in the pathogenesis of urothelial carcinoma. STAG2 loss was significantly associated with lymph node invasion, increased disease recurrence, and reduced cancer-specific survival. These results identify STAG2 as one of the most commonly mutated genes in bladder cancer discovered to date, and demonstrate that STAG2 inactivation defines an aggressive subtype of bladder cancer with particularly poor prognosis. Affymetrix CytoScan HD Arrays were performed according to the manufacturer's directions on genomic DNA extracted directly from snap-frozen human urothelial carcinoma primary tumors. Copy number analysis using Affymetrix CytoScan HD Arrays was performed for 12 human urothelial carcinomas of the bladder with truncating mutations of the STAG2 gene.
2013-06-30 | E-GEOD-41581 | biostudies-arrayexpress
Project description:Cancer genome sequencing consortiums have recently catalogued an abundance of somatic mutations in the chromatin-modifying enzymes that regulate enhancer chromatin function across a wide range of human cancers. Defining the molecular mechanisms underlying the potential oncogenic function for these epigenetic mutations could serve as the basis for precision medicine approaches for cancer treatment. MLL4 (KMT2D) is a key histone lysine mono-methyltransferase within the COMplex of Proteins ASsociated with Set1 (COMPASS) family that regulates chromatin at enhancers, potentially functions as a tumor suppressor and is highly mutated in a large number of human cancers. We report that the mutations which cause MLL4 protein truncation also alter its subcellular localization, resulting in loss-of-function in the nucleus and gain-of-function in the cytoplasm. We demonstrate that isogenic correction of MLL4 truncation mutation rescues the aberrant localization phenotype and restores multiple MLL4 regulatory functions, including COMPASS integrity and stabilization, histone H3K4 mono-methylation, enhancer activation, and gene regulation. Moreover, isogenic correction diminishes the sensitivity of MLL4-mutated cancer cells to targeted metabolic inhibition. Using immunohistochemistry (IHC), we identified cytoplasmic MLL4 unique to the tissue of bladder cancer patients with MLL4 mutations. Using a preclinical carcinogen bladder cancer mouse model, we demonstrate that truncated, cytoplasmic MLL4 can be a biomarker for MLL4-mutated bladder cancers and predicts response to targeted metabolic inhibition therapy. We propose using the cytoplasmic MLL4 truncation phenotype as a prognostic marker in bladder cancer. We also highlight the broader potential for patient stratification based on MLL4 mutation status in MLL4 truncation diseases, including human cancers and Kabuki Syndrome.
2023-12-05 | GSE246058 | GEO
Project description:Bladder cancer prognosis is closely linked to the underlying differentiation state of the tumor, ranging from the less aggressive and most differentiated luminal tumors to the more aggressive and least differentiated basal tumors. Sequencing of bladder cancer has revealed that loss-of-function mutations in chromatin regulators and mutations that activate receptor tyrosine kinase (RTK) signaling frequently occur in bladder cancer. However, little is known as to whether and how these two types of mutations functionally interact or cooperate to regulate tumor growth and differentiation state. Here, we focus on loss of the histone demethylase UTX (also known as KDM6A) and activation of the RTK FGFR3, two events that commonly co-occur in muscle invasive bladder tumors. We show that UTX loss and FGFR3 activation cooperate to disrupt the balance of luminal and basal gene expression in bladder cells. UTX localized to enhancers surrounding many genes that are important for luminal cell fate, and supported the transcription of these genes in a catalytic-independent manner. In contrast to UTX, FGFR3 activation was associated with lower expression of luminal genes in tumors and FGFR inhibition increased transcription of these same genes in cell culture models. This suggests an antagonistic relationship between UTX and FGFR3. In support of this model, UTX loss-of-function potentiated FGFR3-dependent transcriptional effects and the presence of UTX blocked an FGFR3-mediated increase in the colony formation of bladder cells. Taken together, our study reveals how mutations in UTX and FGFR3 converge to disrupt bladder differentiation programs that could serve as a therapeutic target.
2020-09-15 | GSE157090 | GEO
Project description:The Notch signaling pathway controls cell fates through interactions between neighboring cells by positively or negatively affecting, in a context-dependent manner, processes of proliferation, differentiation, and apoptosis1. It has been implicated in human cancer both as an oncogene and a tumor suppressor2. Here we report, for the first time, novel inactivating mutations in the Notch pathway components in over forty percent of the human bladder cancers examined. Bladder cancer is the fourth most commonly diagnosed malignancy in the US male population3. Thus far, driver mutations in the FGFR3 and less commonly RAS proteins have been identified4,5. We show that Notch activation in bladder cancer cells suppresses proliferation both in vitro and in vivo by directly upregulating dual specificity phosphatases (DUSPs), thus reducing ERK1/2 phosphorylation. In mouse models, genetic inactivation of Notch signaling leads to ERK1/2 phosphorylation resulting in tumorigenesis in the urinary tract. In recent years, the tumor suppressor role of Notch has been recognized by loss-of-function mutations identified in myeloid cancers6 as well as squamous cell carcinomas of the skin, lung7, and the head and neck8,9. Of the 4 Notch receptors (N1-4), only N1 and 2 have been implicated in human cancer. two biological replicates from normal and tumor urothelial tissue were hybridized on Affymetrix mm 430 2.0 chips
2014-07-01 | E-GEOD-54589 | biostudies-arrayexpress
Project description:Point mutations within the TERT promoter are the most common recurrent somatic non-coding mutation identified across different cancer types, including glioblastoma, melanoma, hepatocellular carcinoma and bladder cancer. They are most abundant at C146T and C124T and more rare at A57C, with the latter originally described as a familial case but subsequently shown also to occur somatically. All three mutations create de novo ETS (E-twenty-six specific) binding sites and result in the reactivation of the TERT gene, allowing cancer cells to achieve replicative immortality. Here, we employed a systematic proteomics screen to identify transcription factors preferentially binding to the C146T, C124T and A57C mutations. While we confirmed binding of multiple ETS factors to the mutant C146T and C124T sequences, we identified E4F1 a an A57C-specific binder and ZNF148 as a TERT WT binder that is excluded from the TERT promoter by the C124T allele. Both proteins are activating transcription factors that bind specifically to the A57C and wildtype (at position 124) TERT promoter sequence in corresponding cell lines and upregulate TERT transcription and telomerase activity.
2023-11-04 | PXD037776 | Pride