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1.
Int J Mol Sci ; 22(21)2021 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-34768978

RESUMO

Histologically, bladder cancer is a heterogeneous group comprising urothelial carcinoma (UC), squamous cell carcinoma, adenocarcinomas (ACs), urachal carcinomas (UrCs), and small cell neuroendocrine carcinomas (SCCs). However, all bladder cancers have been treated so far uniformly, and targeted therapy options are still limited. Thus, we aimed to determine the protein expression/molecular status of commonly used cancer targets (programmed cell death 1 ligand 1 (PD-L1), mismatch repair (MMR), androgen and estrogen receptors (AR/ER), Nectin-4, tumor-associated calcium signal transducer 2 (Tacstd2, Trop-2), epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and fibroblast growth factor receptor 3 (FGFR3)) to give first insights into whether patients with SCC, AC/UrCs, and squamous-differentiated carcinomas (Sq-BLCA) of the bladder could be eligible for targeted therapies. In addition, for MMR-deficient tumors, microsatellite instability was analyzed. We completed our own data with molecular data from The Cancer Genome Atlas (TCGA). We present ratios for each drug and cumulative ratios for multiple therapeutic options for each nonurothelial subtype. For example, 58.9% of SCC patients, 33.5% of AC/UrCs patients, and 79.3% of Sq-BLCA patients would be eligible for at least one of the analyzed targets. In conclusion, our findings hold promise for targeted therapeutic approaches in selected patients in the future, as various drugs could be applied according to the biomarker status.


Assuntos
Terapia de Alvo Molecular/métodos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Idoso , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/metabolismo , Reparo de Erro de Pareamento de DNA , Feminino , Humanos , Imuno-Histoquímica , Masculino , Instabilidade de Microssatélites , Terapia de Alvo Molecular/tendências , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia
2.
Genes (Basel) ; 11(11)2020 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-33227989

RESUMO

Dysfunction of the SWI/SNF complex has been observed in various cancers including urothelial carcinomas. However, the clinical impact of the SWI/SNF complex in squamous-differentiated bladder cancers (sq-BLCA) remains unclear. Therefore, we aimed to analyze potential expression loss and genetic alterations of (putative) key components of the SWI/SNF complex considering the co-occurrence of genetic driver mutations and PD-L1 expression as indicators for therapeutic implications. Assessment of ARID1A, SMARCA2, SMARCA4, SMARCB1/INI1, SMARCC1, SMARCC2 and PBRM1 mutations in a TCGA data set of sq-BLCA (n = 45) revealed that ARID1A was the most frequently altered SWI/SNF gene (15%) while being associated with protein downregulation. Genetic alterations and loss of ARID1A were confirmed by Targeted Next Generation Sequencing (NGS) (3/6) and immunohistochemistry (6/116). Correlation with further mutational data and PD-L1 expression revealed co-occurrence of ARID1A loss and TP53 mutations, while positive correlations with other driver mutations such as PIK3CA were not observed. Finally, a rare number of sq-BLCA samples were characterized by both ARID1A protein loss and strong PD-L1 expression suggesting a putative benefit upon immune checkpoint inhibitor therapy. Hence, for the first time, our data revealed expression loss of SWI/SNF subunits in sq-BLCA, highlighting ARID1A as a putative target of a small subgroup of patients eligible for novel therapeutic strategies.


Assuntos
Carcinoma de Células Escamosas/genética , Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA/genética , Fatores de Transcrição/genética , Neoplasias da Bexiga Urinária/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Carcinoma de Células Escamosas/patologia , Proteínas Cromossômicas não Histona/metabolismo , DNA Helicases/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Proteína SMARCB1/genética , Análise Serial de Tecidos , Fatores de Transcrição/metabolismo , Neoplasias da Bexiga Urinária/patologia
3.
Virchows Arch ; 477(3): 445-454, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32198650

RESUMO

Primary glandular bladder tumours (bladder adenocarcinoma [BAC], urachal adenocarcinoma [UAC], urothelial carcinoma with glandular differentiation [UCg]) are rare malignancies with histological resemblance to colorectal adenocarcinoma (CORAD) in the majority of this subgroup. Definite case numbers are very low, molecular data are limited and the pathogenesis remains poorly understood. Therefore, this study was designed to complement current knowledge by in depth analysis of BAC (n = 12), UAC (n = 13), UCg (n = 11) and non-invasive glandular lesions (n = 19). In BAC, in addition to known alterations in TP53, Wnt, MAP kinase and MTOR pathway, mutations in SMAD4, ARID1A and BRAF were identified. Compared to published data on muscle invasive bladder cancer (BLCA) and CORAD, UCg exhibited frequent "urothelial" like alterations while BAC and UAC were characterised by a more "colorectal" like mutational pattern. Immunohistochemically, there was no evidence of DNA mismatch repair deficiency or PD-L1 tumour cell positivity in any sample. Depending on the used antibody 0-45% of BAC, 0-30% of UCg and 0% UAC cases exhibited PD-L1 expressing tumour associated immune cells. A single BAC (9%, 1/11) showed evidence of ARID1A protein loss, and two cases of UCg (20%, 2/10) showed loss of SMARCA1 and PBRM1, respectively. Taken together, our data suggest at least in part involvement of similar pathways driving tumourigenesis of adenocarcinomas like BAC, UAC and CORAD independent of their tissue origin. Alterations of TERT and FBXW7 in single cases of intestinal metaplasia further point towards a possible precancerous character in line with previous reports.


Assuntos
Neoplasias Epiteliais e Glandulares/genética , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/análise , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/análise , Feminino , Genômica/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias Epiteliais e Glandulares/patologia , Bexiga Urinária/patologia , Urotélio/patologia
4.
BMC Cancer ; 20(1): 230, 2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32188412

RESUMO

BACKGROUND: Immune checkpoint inhibitors (ICI) are an integral part of bladder cancer therapy, however, the relevance of ICI treatment for mixed and pure squamous cell carcinoma of the bladder remains poorly studied. Therefore, we analysed the expression of programmed death-ligand 1 (PD-L1) in urothelial carcinomas with squamous differentiation (UC/SCC) and pure squamous cell carcinoma (SCC) of the bladder and studied a UC/SCC patient with ICI therapy. METHODS: Tissue microarrays of 45 UC/SCC and 63 SCC samples were immunohistochemically stained with four anti-PD-L1 antibodies (28-8, 22C3, SP142 and SP263). PD-L1 expression was determined for tumour cells (TP-Score), immune cells (IC-Score) and combined (CPS, combined positive score). In addition, we present clinical and histological data of an UC/SCC patient with nivolumab therapy. RESULTS: Overall, positive PD-L1 staining ranged between 4.8 and 61.9% for IC and 0 and 51.2% for TC depending on the used antibody. There were no significant differences between UC/SCC and SCC. According to current FDA guidelines for example for first line therapy of urothelial cancer with pembrolizumab (CPS ≥ 10), a subset of SCC patients up to 20% would be eligible. Finally, our UC/SCC index patient revealed excellent therapy response regarding his lung metastasis. CONCLUSIONS: Our data reveal a PD-L1 expression in squamous differentiated carcinomas comparable with current data shown for urothelial tumours. In accordance with the encouraging clinical data of the index patient we suggest ICI treatment also for mixed and pure SCC of the urinary bladder.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Carcinoma de Células Escamosas/tratamento farmacológico , Nivolumabe/uso terapêutico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/análise , Antígeno B7-H1/metabolismo , Carcinoma de Células Escamosas/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Análise Serial de Tecidos , Neoplasias da Bexiga Urinária/metabolismo
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