Whole Exome Sequencing of Signet Ring/Plasmacytoid Variant Bladder Cancer
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ABSTRACT: In this study, six plasmacytoid bladder cancers were analyzed by whole exome sequencing. The results show loss of the CDH1 gene in every sample and correlate with E-cadherin loss of expression by immunohistochemistry. A separate validation cohort of plasmacytoid samples showed loss of E-cadherin expression by CDH1 mutation or promoter hypermethylation.
SECONDARY ACCESSION(S): PRJNA310265PRJNA310264
REPOSITORIES: dbGaP
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Project description:We sought to test the hypothesis that ascertainment of genome-wide copy number alterations in bladder cancer may have value for clinical management. We performed a genome wide analysis of 164 bladder cancer samples and 27 bladder cancer cell lines to identify genetic changes associated with disease characteristics. Multiplex inversion probe (MIP) analysis, a newly developed genomic technique, was used to study 80 bladder cancers to identify mutations and copy number changes. Selected amplification events were then analyzed in a validation cohort of 84 bladder cancers by multiplex ligation-dependent probe assay (MLPA). In the MIP analysis, 44 regions of significant copy number change were identified using GISTIC. Nine gene-containing regions of amplification were selected for validation in the second cohort by MLPA. Amplification events at these 9 genomic regions were found to correlate strongly with stage, being seen in only 2 of 23 (9%) Ta grade 1 or 1-2 cancers, in contrast to 31 of 61 (51%) Ta grade 3 and T2 grade 2 cancers, p < 0.001. These observations suggest that analysis of genomic amplification of these 9 regions might serve as a guide for clinical decision making, in terms of management decisions following transurethral resection of bladder cancers. This approach is facilitated by the capability of each of the MIP and MLPA methods to analyze formalin-fixed paraffin-embedded DNA, as done here. Furthermore several of the amplified genes identified here (ERBB2, MDM2, CCND1) render the bladder cancers potentially sensitive to targeted therapy. Copy number profiling was completed for 80 urothelial carcinoma samples using the Affymetrix OncoScan(TM) FFPE Express platform.
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Project description:Interstitial cystitis (IC) and bladder pain syndrome are terms used to describe a heterogenous chronic pelvic and bladder pain disorder of unknown etiology. The goal of this pilot study was to determine if gene expression profiling of bladder biopsy tissue from patients experiencing symptoms could be used to separate the patients based on some clinical parameter.
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Project description:We sought to test the hypothesis that ascertainment of genome-wide copy number alterations in bladder cancer may have value for clinical management. We performed a genome wide analysis of 164 bladder cancer samples and 27 bladder cancer cell lines to identify genetic changes associated with disease characteristics. Multiplex inversion probe (MIP) analysis, a newly developed genomic technique, was used to study 80 bladder cancers to identify mutations and copy number changes. Selected amplification events were then analyzed in a validation cohort of 84 bladder cancers by multiplex ligation-dependent probe assay (MLPA). In the MIP analysis, 44 regions of significant copy number change were identified using GISTIC. Nine gene-containing regions of amplification were selected for validation in the second cohort by MLPA. Amplification events at these 9 genomic regions were found to correlate strongly with stage, being seen in only 2 of 23 (9%) Ta grade 1 or 1-2 cancers, in contrast to 31 of 61 (51%) Ta grade 3 and T2 grade 2 cancers, p < 0.001. These observations suggest that analysis of genomic amplification of these 9 regions might serve as a guide for clinical decision making, in terms of management decisions following transurethral resection of bladder cancers. This approach is facilitated by the capability of each of the MIP and MLPA methods to analyze formalin-fixed paraffin-embedded DNA, as done here. Furthermore several of the amplified genes identified here (ERBB2, MDM2, CCND1) render the bladder cancers potentially sensitive to targeted therapy.
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Project description:Bladder outlet obstruction (BOO) causes lower urinary tract symptoms and objectifiable urodynamic changes in bladder function. We carried out an integrated transcriptome and proteome analysis of bladder samples from male patients with BOO before and 3 months after de-obstruction surgery (transurethral resection of the prostate, TURP). mRNA and protein profiles were correlated with urodynamic findings, specifically voiding detrusor pressure (PdetQmax) before TURP. Patients with high PdetQmax showed less advanced remodeling and inflammatory changes than those with lower values. We oberved significant dysregulation of gene expression, which was reversed by de-obstruction in both patients’ groups. We propose a series of biomarker genes, indicative of BOO, and possibly contributing to the bladder changes. Our data sheds light on the stages of progressive obstruction-induced bladder decompensation, and might add selecting the operation point to avoid the loss of contractility.
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Project description:At diagnosis approximately 75% of bladder urothelial carcinomas are non muscle invasive bladder cancers (Ta, T1 and Tis), 20% are muscle invasive bladder cancer (T2-T4) and 5% are already metastatic. Non muscle invasive bladder cancers are characterized by tumor recurrence in 60% to 85% of cases and, therefore, long-term followup is needed. The current standard methods to detect and monitor bladder cancer are cystoscopy and cytology. Cystoscopy is an invasive method and cytology is hampered by low sensitivity, especially for low grade tumors. So there is need to develop reliable and noninvasive methods to detect and predict bladder cancer biological behavior. So we have performed high density oligonucleotide microarray for discovery of new molecular markers to diagnose and predict the outcome of bladder cancer. Under an ethical guideline of Chhatrapati Shahuji Maharaj Medical University, India histologically confirmed seven bladder cancer patients were recruited from Department of Urology, Chhatrapati Shahuji Maharaj Medical University, Lucknow, India. Total RNA was extracted from tumor biopsies and hybridized on affymetrix Human Gene ST 1.1 array to determine differentially expressed genes in urinary bladder cancer with muscle invasion in comparison of normal human urinary bladder.
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