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Dysregulation of EMT Drives the Progression to Clinically Aggressive Sarcomatoid Bladder Cancer [RT-PCR]

ABSTRACT: The progression of conventional urothelial carcinoma (UC) of the bladder to a tumor with a mesenchymal phenotype, referred to as sarcomatoid carcinoma (SARC), is signified by a high propensity for regional and distant metastasis resulting in shorter survival. We report a comprehensive retrospective analysis of 28 cases of SARCs and 84 cases of conventional UCs. A TCGA cohort of 408 muscle-invasive bladder cancers was used as a reference cohort. SARCs showed a distinct mutational landscape with enrichment of p53, PIK3CA, and RB1 mutations. They developed from basal precursor conventional UCs and could be divided into a basal subtype and the most aggressive mesenchymal subtype. Expression analysis showed that SARCs are driven by dysregulation of cell cycle and EMT regulatory networks and nearly half exhibited an immune infiltration phenotype with PDL1 upregulation. Our observations have important implications for prognostication and the development of more effective therapies for this highly lethal variant of bladder cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE128277 | GEO | 2019/03/14

REPOSITORIES: GEO

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Project description:Breast cancer is a profoundly heterogeneous disease with respect to biological and clinical behavior. Gene expression profiling has been used to dissect this complexity and stratify tumors into intrinsic gene expression subtypes associated with distinct biology, patient outcome and different genomic alterations. Additionally, breast tumors occurring in individuals with germline BRCA1 or BRCA2 mutations typically fall into distinct subtypes. We applied global DNA copy number and gene expression profiling in 359 breast tumors. All tumors were classified according to intrinsic gene expression subtypes and included cases from genetically predisposed women. The Genomic Identification of Significant Targets in Cancer (GISTIC) algorithm was used to identify significant DNA copy number aberrations and genomic subgroups of breast cancer. We identified 31 genomic regions that were highly amplified in >1% of the 359 breast tumors. Several amplicons were found to co-occur, the 8p12 and 11q13.3 regions being the most frequent combination besides amplicons on the same chromosomal arm. Unsupervised hierarchical clustering with 133 significant GISTIC regions (66 and 67 with DNA copy number gain and loss, respectively) revealed six genomic subtypes, termed: 17q12, basal-complex, luminal-simple, luminal-complex, amplifier and mixed subtype. Four of them had striking similarity to intrinsic gene expression subtypes and showed association to conventional tumor biomarkers and clinical outcome. However, luminal A-classified tumors were distributed in two main genomic subtypes, luminal-simple and luminal-complex, the former group having better prognosis while the latter group included also luminal B and the majority of BRCA2-mutated tumors. The basal-complex subtype displayed extensive genomic homogeneity and harbored the majority of BRCA1-mutated tumors. The 17q12 subtype comprised mostly HER2-amplified and HER2-enriched subtype tumors and had the worst prognosis. The amplifier and mixed subtypes contained tumors from all gene expression subtypes, the former being enriched for 8p12-amplified cases while the mixed subtype included many tumors with predominantly DNA copy number losses and poor prognosis. Genomic profiling of 359 breast tumors using tiling BAC aCGH. A number of cases were hybridized as replicates or replicate as dye-swaps. Gene expression profiling of 359 breast tumors using 55K oligonucleotide microarrays.

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Dysregulation of EMT Drives the Progression to Clinically Aggressive Sarcomatoid Bladder Cancer [RT-PCR]

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