Genome and Targeted Sequencing of Bladder Cancer
Ontology highlight
ABSTRACT: One primary bladder cancer and paired peripheral blood sample were subjected to whole genome sequencing on an Illumina HiSeq 2000 platform. This technology was utilized to investigate the genetic basis of a durable remission of metastatic bladder cancer in a patient treated with everolimus, a drug that inhibits the mTOR (mammalian target of rapamycin) signaling pathway. Among the somatic mutations found was a loss-of-function mutation in TSC1 (Tuberous Sclerosis Complex 1), a regulator of mTOR pathway activation. Targeted sequencing using an exon capture and sequencing assay was performed on 13 tumors derived from patients on the same everolimus trial as the index patient and the sequencing data from these tumors is included. TSC1 mutation status was correlated with response to everolimus. The index patient responder tumor and peripheral blood DNA were also subjected to exon capture and sequencing.
SECONDARY ACCESSION(S): PRJNA172878PRJNA172879
REPOSITORIES: dbGaP
Similar Datasets
Project description:<p>One primary bladder cancer and paired peripheral blood sample were subjected to whole genome sequencing on an Illumina HiSeq 2000 platform. This technology was utilized to investigate the genetic basis of a durable remission of metastatic bladder cancer in a patient treated with everolimus, a drug that inhibits the mTOR (mammalian target of rapamycin) signaling pathway. Among the somatic mutations found was a loss-of-function mutation in TSC1 (Tuberous Sclerosis Complex 1), a regulator of mTOR pathway activation. Targeted sequencing using an exon capture and sequencing assay was performed on 13 tumors derived from patients on the same everolimus trial as the index patient and the sequencing data from these tumors is included. TSC1 mutation status was correlated with response to everolimus. The index patient responder tumor and peripheral blood DNA were also subjected to exon capture and sequencing.</p>
| phs000535.v1.p1 | EGA
Project description:This is a comprehensive genomic characterization of 40 urothelial bladder carcinoma (UBC) cell lines including information on origin, mutation status of genes implicated in bladder cancer (FGFR3, PIK3CA, TP53, and RAS), copy number alterations assessed using high density SNP arrays, uniparental disomy (UPD) events, and gene expression. Based on gene mutation patterns and genomic changes we identify lines representative of the FGFR3-driven tumor pathway and of the TP53/RB tumor suppressor-driven pathway. High-density array copy number analysis identified significant focal gains (1q32, 5p13.1-12, 7q11, and 7q33) and losses (i.e. 6p22.1) in regions altered in tumors but not previously described as affected in bladder cell lines. We also identify new evidence for frequent regions of UPD, often coinciding with regions reported to be lost in tumors. Previously undescribed chromosome X losses found in UBC lines also point to potential tumor suppressor genes. Cell lines representative of the FGFR3-driven pathway showed a lower number of UPD events. Overall, there is a predominance of more aggressive tumor subtypes among the cell lines. We provide a cell line classification that establishes their relatedness to the major molecularly-defined bladder tumor subtypes. The compiled information should serve as a useful reference to the bladder cancer research community and should help to select cell lines appropriate for the functional analysis of bladder cancer genes, for example those being identified through massive parallel sequencing. Copy Number Variations were assessed in 45 bladder cell lines, included in the UBC-40 Urothelial Bladder Cell Line Index, with Human1M-Duov3 DNA Analysis BeadChip platform
2015-06-19 | E-GEOD-64572 | biostudies-arrayexpress
Project description:This is a comprehensive genomic characterization of 40 urothelial bladder carcinoma (UBC) cell lines including information on origin, mutation status of genes implicated in bladder cancer (FGFR3, PIK3CA, TP53, and RAS), copy number alterations assessed using high density SNP arrays, uniparental disomy (UPD) events, and gene expression. Based on gene mutation patterns and genomic changes we identify lines representative of the FGFR3-driven tumor pathway and of the TP53/RB tumor suppressor-driven pathway. High-density array copy number analysis identified significant focal gains (1q32, 5p13.1-12, 7q11, and 7q33) and losses (i.e. 6p22.1) in regions altered in tumors but not previously described as affected in bladder cell lines. We also identify new evidence for frequent regions of UPD, often coinciding with regions reported to be lost in tumors. Previously undescribed chromosome X losses found in UBC lines also point to potential tumor suppressor genes. Cell lines representative of the FGFR3-driven pathway showed a lower number of UPD events. Overall, there is a predominance of more aggressive tumor subtypes among the cell lines. We provide a cell line classification that establishes their relatedness to the major molecularly-defined bladder tumor subtypes. The compiled information should serve as a useful reference to the bladder cancer research community and should help to select cell lines appropriate for the functional analysis of bladder cancer genes, for example those being identified through massive parallel sequencing. Expression levels were assessed in 20 bladder cell lines, included in the UBC-40 Urothelial Bladder Cell Line Index, with Affymetrix U133 array platform
2015-06-19 | E-GEOD-64279 | biostudies-arrayexpress
Project description:We found a high frequency of heterozygous Fanconi-BRCA pathway mutations in pediatric T-ALL. BRCA2 was the most commonly mutated gene. We transduced Cas9-expressing Jurkat cells, which lacked an identifiable BRCA2 mutation, with an integration-defective lentiviral guide RNA expression construct targeting exon 11 of BRCA2 (NM_000059). Single-cell cloning and sequencing analysis revealed two distinct clones harboring monoallelic BRCA2 frameshift mutations, termed clones W4 and W5. Each of these clones was subjected to RNA sequencing analysis.
2019-02-20 | GSE126780 | GEO
Project description:Activation of the phosphatidylinositol 3-kinase (PI3K) pathway occurs in over 40% of bladder urothelial cancers. The aim of this study is to determine the therapeutic potential, the underlying action and resistant mechanisms of drugs targeting the PI3K pathway. Urothelial cancer cell lines and patient-derived xenografts (PDXs) were analyzed for alterations of the PI3K pathway and for their sensitivity to the small molecule inhibitor pictilisib alone and in combination with cisplatin and/or gemcitabine. Potential predictive biomarkers for pictilisib were evaluated and RNA-sequencing was performed to explore drug resistance mechanisms. The bladder cancer cell line TCCSUP, which harbors a PIK3CA E545K mutation, was sensitive to pictilisib compared to cell lines with wild type PIK3CA. Pictilisib exhibited stronger anti-tumor activity in bladder cancer PDX models with PI3KCA H1047R mutation or amplification than a model with wild-type. Pictilisib synergized with cisplatin and/or gemcitabine in vitro, significantly delayed tumor growth and prolonged survival compared with single drug targeted treatment in the PDX models. The phosphorylation of ribosomal protein S6 correlated with response to pictilisib both in vitro and in vivo, and could potentially serve as biomarker to predict response to pictilisib. The inhibitor activated the compensatory MEK/ERK pathway that likely contributed to pictilisib resistance, which was reversed by co-treatment with the RAF inhibitor sorafenib. RNA-sequencing of tumors resistant to treatment suggested that LSP1 down-regulation might play a role in inducing drug resistance. These preclinical results provide new insight into the therapeutic potential of targeting the PI3K pathway for the treatment of bladder cancer.
2017-10-24 | GSE101419 | GEO
Project description:<p>We sought to identify genomic variants that differed between individuals who developed familial breast cancer and individuals who had a family history of breast cancer but who had not developed breast cancer. We aggregated these data at the pathway level to identify pathways that play a role in familial breast cancer development. We profiled peripheral blood cells, extracted DNA, and sequenced the DNA using exome-capture sequencing to identify genomic variants in these samples. For 34 of the 35 samples, we also profiled peripheral blood using Affymetrix Human Exon 1.0 ST Array microarrays. Those data can be found in Gene Expression Omnibus under accession identifier GSE47862.</p>
| phs001044 | dbGaP
Project description:The study included 15 patients (7 males, 8 females) with JMML. Peripheral blood and/or bone marrow aspirates were collected on EDTA at diagnosis. Non-hematopoietic tissues (fibroblasts) was derived from skin biopsy for each patient. Exome sequencing was performed in several distinct series between 2012 and 2017, which explains the differences in capture kit versions and reference genome version.Targeted enrichment and massive parallel sequencing were performed on paired genomic DNA from leukocytes and fibroblasts. Exome capture was carried out using the SureSelect Human All Exon V4+UTRs or V5 or V5+UTRs or SureSelect Clinical Research (Agilent Technologies, Santa Clara, CA, USA) according to manufacturer’s instruction and protocols by IntegraGen (Evry, France). Paired-end 75 bases sequencing was performed on a HiSeq2000 or HiSeq4000 instrument (Illumina, San Diego, CA, USA). Image analysis and base calling were performed using the Real Time Analysis (RTA) pipeline v. 1.14 (Illumina) with default parameters. The alignment of paired-end reads to the reference human genome (UCSC GRCh37/hg19 or UCSC GRCh38), variant calling and generation of Quality variants scores were carried out using the CASAVA v.1.8 pipeline (Illumina).
2018-03-14 | E-MTAB-6461 | biostudies-arrayexpress
Project description:RBM20 heterozygous (Het) mutation was created by genome editing in an iPS cell line generated from a healthy female patient. Those cells were differentiated into cardiomyocytes by modulating the WNT signaling pathway, and then are subjected to the lactate purification method.
2021-06-03 | GSE176045 | GEO
Project description:This study reports two unrelated patients with a combined immunodeficiency. Whole-exome sequencing of both patients, their healthy parents and siblings identified a single de novo missense variant in ITPR3 (NM_002224.3:c.7570C>T, p.Arg2524Cys) in both index cases. While the mRNA level in patients remained the same as in healthy siblings and controls, the level of protein expression was diminished. It was also shown that the ITPR3 heterozygous p.Arg2524Cys mutation impairs calcium flux function in dermal fibroblast of one patient and in a knock-in Jurkat T cell line. Two additional patients with related phenotypes and the same mutation were further identified and described in the study. The present dataset corresponds to the RNAseq performed on PBMC of patient 2 of the study and healthy controls.
2023-01-02 | E-MTAB-12432 | biostudies-arrayexpress
Project description:Bladder cancer is common in elderly men, and it is a highly mutated tumor with frequent TP53 and FGFR3 mutation. Young-onset bladder cancer (YBC) is extremely rare; therefore, its genomic characteristics are unknown and appropriate management strategy is yet to be defined. Through a nation-wide search for bladder cancer diagnosed at 20 years or younger, 29 cases of biopsy-proven YBCs were collected. Whole exome sequencing and RNA sequencing were performed on 21 and 11 cases, respectively, and the results were compared with those of adult bladder cancer (ABC) retrieved from public database. Almost all YBCs were low grade, non-invasive papillary tumors. YBC had low mutation burden and less complex copy number alterations. Driver mutations were found in all cases. Common mutations included HRAS mutations (10 cases) with a preference in exon 5 and FGFR3 gene fusions (7 cases) with various partner genes, which occurred in a mutually exclusive manner. Other alterations included KRAS mutations (2 cases), arm-level deletion of chromosomes 4p and 10q (1 case), and ERCC2 mutation (1 case). TP53 and FGFR3 point mutations were not found. The gene expression profiles of YBC corresponded to those of the good prognostic group of ABC. No YBC cases had progressed to muscle-invasive tumor during follow-up. In addition, ABCs with YBC-like mutations also showed no progression to muscle-invasive tumor. In conclusion, YBC had distinct driver genetic alterations such as HRAS mutation and FGFR3 gene fusion and showed good prognosis. YBCs and ABCs with YBC-like mutations may be managed with less aggressive surveillance.
2020-03-30 | GSE133192 | GEO