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1.
Zhonghua Bing Li Xue Za Zhi ; 50(2): 103-107, 2021 Feb 08.
Artigo em Chinês | MEDLINE | ID: mdl-33535303

RESUMO

Objective: To investigate the clinicopathological features, differential diagnosis and molecular characteristics of clear cell renal cell carcinoma (ccRCC) with hemangioblastoma component (ccRCC-HBc). Methods: Two ccRCC-HBc cases diagnosed at Fujian Provincial Hospital in September 2015 and March 2016, respectively, were included. Their morphological, immunohistochemical and molecular features were analyzed, including fluorescence in situ hybridization (FISH) detection of TFE3, TFEB and VHL genes. Related literature was reviewed to reveal the characteristics of this tumor. Results: The two cases occurred in 2 women, aged 33 and 66 years, respectively. The maximum diameters of the tumors were 4.0 cm and 8.5 cm, respectively. Histologically, the ccRCC component, representing approximate 10%-20% of the neoplasm, while the tumor cells arranged in flaky, nested, and solid distribution. The tumor cells had conspicuous nucleoli, with rich thin-wall capillary network in the stroma. The hemangioblastoma-like component, representing approximate 60%-70% of the neoplasm, showed a rich capillary network of single-layered flat endothelial cells enclosing stromal cells. The latter cell type showed a pale or eosinophilic cytoplasm exhibiting occasional lipid droplets. Rare cell nuclei appeared enlarged, pleomorphic, or bizarre. The two components were intermingled with each other. Immunohistochemically, the tumor cells were positive for PAX8, CKpan, EMA, vimentin, CD10, RCC, CAⅨ, and P504s in ccRCC area; in another area, the tumor cells were positive for α-inhibin, CD34 and vimentin, while CD10 were weakly positive. Neither TFE3 or TFEB gene split signal was detected in the 2 cases (0/2), nor was VHL gene mutation in case 2 (0/1). Conclusion: ccRCC-HBc is an extremely rare entity of ccRCC. The diagnosis is mainly based on clinical and pathological characteristics, as well as immunohistochemistry. Molecular pathology is helpful for its differential diagnosis. The primary approach of treating ccRCC-HBc is complete surgical excision and chemotherapy. The targeted treatment is helpful if possible.


Assuntos
Carcinoma de Células Renais , Hemangioblastoma , Neoplasias Renais , Adulto , Idoso , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/genética , Diagnóstico Diferencial , Células Endoteliais , Feminino , Hemangioblastoma/diagnóstico , Hemangioblastoma/genética , Hemangioblastoma/cirurgia , Humanos , Hibridização in Situ Fluorescente , Neoplasias Renais/diagnóstico , Neoplasias Renais/genética , Pessoa de Meia-Idade
2.
Nat Commun ; 12(1): 808, 2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-33547292

RESUMO

Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD-L1 expression. Our findings build on prior work and shed light on the molecular drivers of aggressivity and responsiveness to ICI of S/R RCC.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Renais/imunologia , Regulação Neoplásica da Expressão Gênica , /imunologia , Neoplasias Renais/imunologia , Tumor Rabdoide/imunologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/mortalidade , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/imunologia , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Neoplasias Renais/mortalidade , Mutação , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/imunologia , Estudos Retrospectivos , Tumor Rabdoide/tratamento farmacológico , Tumor Rabdoide/genética , Tumor Rabdoide/mortalidade , Transdução de Sinais , Análise de Sobrevida , Transcrição Genética , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/imunologia , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/imunologia
3.
Am J Surg Pathol ; 45(1): 137-142, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33165095

RESUMO

Renal cell carcinoma (RCC) is a heterogenous disease composed of several different cancer types characterized by distinct histologies and genetic alterations, including mutation of the Krebs cycle enzyme genes for fumarate hydratase and succinate dehydrogenase (SDH). This report describes a patient with multifocal renal tumors that presented with a novel, biphasic histologic morphology with one component consisting of small cells growing in a diffuse pattern occasionally forming glandular and cystic structures, reminiscent of type 1 papillary RCC, and the other component having larger cells with abundant eosinophilic and clear cytoplasm and appearing in a solid pattern of growth. Genetic analysis of multiple tumors showed that all had a somatic mutation of the IDH2 gene that created the known pathogenic, gain-of-function p.R172M alteration that results in abnormal accumulation of the oncometabolite 2-hydroxyglutarate (2-HG). Analysis of multiple tumors demonstrated highly elevated levels of 2-HG and a CpG island methylator phenotype that is characteristic of 2-HG-related inhibition of the Ten-eleven translocation (TET) family of DNA demethylases. In combination with fumarate hydratase-deficient and succinate dehydrogenase-deficient RCCs that have increased levels of the fumarate and succinate oncometabolites, respectively, the mutation of isocitrate dehydrogenase 2 represents the third Krebs cycle enzyme alteration to be associated with oncometabolite-induced RCC tumorigenesis. This study associates the discovery of a new histologic presentation of RCC with the first report of an IDH2 gain-of-function mutation in RCC.


Assuntos
Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Isocitrato Desidrogenase/genética , Neoplasias Renais/genética , Neoplasias Renais/patologia , Adulto , Humanos , Masculino , Mutação
4.
Nat Commun ; 11(1): 5799, 2020 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-33199705

RESUMO

The extent and importance of functional heterogeneity and crosstalk between tumor cells is poorly understood. Here, we describe the generation of clonal populations from a patient-derived ovarian clear cell carcinoma model which forms malignant ascites and solid peritoneal tumors upon intraperitoneal transplantation in mice. The clonal populations are engineered with secreted Gaussia luciferase to monitor tumor growth dynamics and tagged with a unique DNA barcode to track their fate in multiclonal mixtures during tumor progression. Only one clone, CL31, grows robustly, generating exclusively malignant ascites. However, multiclonal mixtures form large solid peritoneal metastases, populated almost entirely by CL31, suggesting that transient cooperative interclonal interactions are sufficient to promote metastasis of CL31. CL31 uniquely harbors ERBB2 amplification, and its acquired metastatic activity in clonal mixtures is dependent on transient exposure to amphiregulin, which is exclusively secreted by non-tumorigenic clones. Amphiregulin enhances CL31 mesothelial clearance, a prerequisite for metastasis. These findings demonstrate that transient, ostensibly innocuous tumor subpopulations can promote metastases via "hit-and-run" commensal interactions.


Assuntos
Comunicação Celular , Células Clonais/patologia , Metástase Neoplásica/patologia , Anfirregulina/metabolismo , Animais , Ascite/patologia , Carcinogênese/patologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Proliferação de Células , Separação Celular , Estudos de Coortes , Variações do Número de Cópias de DNA/genética , Epitélio/patologia , Feminino , Amplificação de Genes , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Ligantes , Camundongos SCID , Modelos Biológicos , Neoplasias Peritoneais/secundário , Fenótipo , Receptor ErbB-2/genética , Fatores de Tempo
5.
Anticancer Res ; 40(11): 6337-6343, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33109571

RESUMO

BACKGROUND/AIM: Dysregulated expression of S100 protein family members, including S100A2, has been reported in various types of human malignant tumors; however, the functional role of S100A2 in renal cell carcinoma (RCC) remains unknown. The objective of this study was to assess the S100A2 expression pattern and its clinicopathological significance in RCC. MATERIALS AND METHODS: This study investigated the expression profiles of S100A2 mRNA, S100A2 protein and p53 mRNA in addition to S100A2 DNA methylation levels in 3 human RCC cell lines and 81 surgically resected RCC specimens. These findings were analyzed according to several clinicopathological parameters. RESULTS: In all RCC cell lines, both S100A2 mRNA and protein were barely detectable, and the S100A2 promoter was considered to be methylated. S100A2 mRNA expression levels in RCC tissues were markedly lower than those in normal kidney tissues. The rate in clear cell RCC (ccRCC) specimens with higher expression of S100A2 mRNA was significantly lower than that in non-ccRCC specimens (29.9 versus 71.4%, respectively). Furthermore, S100A2 expression in ccRCC specimens was significantly correlated with p53 mRNA expression, but not conventional clinicopathological parameters. CONCLUSION: These findings suggest limited roles of S100A2 in the progression of RCC, particularly ccRCC.


Assuntos
Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Fatores Quimiotáticos/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Neoplasias Renais/genética , Neoplasias Renais/patologia , Proteínas S100/genética , Linhagem Celular Tumoral , Fatores Quimiotáticos/metabolismo , Metilação de DNA/genética , Epigênese Genética , Humanos , Proteínas S100/metabolismo , Proteína Supressora de Tumor p53/metabolismo
6.
Anticancer Res ; 40(11): 6525-6530, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33109593

RESUMO

BACKGROUND/AIM: End-stage kidney disease is characterized by chronic inflammation and frequent development of cancer. The level of circulating vitamin D is generally low in patients with end-stage renal disease (ESRD). Experimental studies have implicated the role of dysfunctional vitamin D metabolism in tumorigenesis. PATIENTS AND METHODS: We analyzed the expression of vitamin D receptor (VDR), cytochrome P450 family 27 subfamily B member 1 (CYP27B1) and cytochrome P450 family 24 subfamily A member 1 (CYP24A1), the key genes involved in vitamin D signaling, in kidneys from patients with ESRD, tissue microarrays containing ESRD-associated renal cell tumors, as well as in their precursor lesions by immunohistochemistry. RESULTS: Kidneys from patients with ESRD showed strong structural rearrangement with only few tubules and epithelial cell groups embedded in fibrotic-inflammatory stroma. Only an estimated 1-3% of the epithelial cells showed positive staining with antibodies to VDR, CYP27B1 and CYP24A1, which contrasted with the 100%, 40-50% and 40-50% of positively stained cells, respectively, found in normal kidneys. Down-regulation of the vitamin D signaling proteins was found in patients with renal cancer, with the exception of tumors and their precursors occurring exclusively in ESRD. CONCLUSION: The significantly reduced activity of CYP27B1 in kidney from patients with ESRD explains the low level of circulating vitamin D. We suggest that the lack of anti-tumorigenic effect of vitamin D is a crucial factor in the frequent development of unique types of renal cell cancer in in patients with ESRD.


Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Carcinoma de Células Renais/genética , Falência Renal Crônica/genética , Receptores de Calcitriol/genética , Vitamina D3 24-Hidroxilase/genética , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/complicações , Carcinoma de Células Renais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Rim/metabolismo , Rim/patologia , Falência Renal Crônica/sangue , Falência Renal Crônica/complicações , Falência Renal Crônica/patologia , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Masculino , Redes e Vias Metabólicas/genética , Vitamina D/sangue
7.
Anticancer Res ; 40(10): 5667-5671, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988891

RESUMO

BACKGROUND: Renal cell carcinoma (RCC) is a common urological cancer, and its risk correlates with environmental factors such as obesity, smoking and hypertension. Microarray technology enables analysis of the expression pattern of the whole phosphatome, members of which are involved in many cellular pathways and may act as either tumour suppressors or oncogenes in cancers. MATERIALS AND METHODS: We analysed data for the expression level of 87 out of 107 known protein phosphatase genes included in the Hugo Gene Nomenclature Committee Website for 72 RCC tissues and paired healthy tissues obtained from the GEO Database. RESULTS: Our analysis revealed overexpression of DUSP1, DUSP4, PTP4A3, PTPRC and PTPRE genes at all examined stages of RCC. Moreover, we found overexpression of PTPN12 at stage 2, overexpression of CDKN3 at stages 3 and 4, and overexpression of DUSP10 and PTPN22 at stages 2, 3 and 4. Lower expression of DUSP9, PTPR9 and PTPRO was also observed at all stages. CONCLUSION: Significant changes in expression patterns of protein tyrosine phosphatase genes confirm the involvement of this group in crucial carcinogenesis pathways underlying RCC. Thus, we postulate that protein tyrosine phosphatases play an important role in RCC promotion and progression, and may be considered as potential therapeutic targets.


Assuntos
Carcinoma de Células Renais/genética , Proliferação de Células/genética , Oncogenes/genética , Proteínas Tirosina Fosfatases/genética , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Proteínas Inibidoras de Quinase Dependente de Ciclina/genética , Fosfatase 1 de Especificidade Dupla/genética , Fosfatases de Especificidade Dupla/genética , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Antígenos Comuns de Leucócito/genética , Masculino , Fosfatases da Proteína Quinase Ativada por Mitógeno/genética , Proteínas de Neoplasias/genética , Estadiamento de Neoplasias , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/genética , Proteínas Tirosina Fosfatases Classe 4 Semelhantes a Receptores/genética , Fatores de Risco , Transdução de Sinais/genética , Fumar/efeitos adversos
9.
PLoS One ; 15(9): e0238809, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32915890

RESUMO

Clear-cell renal cell carcinomas (ccRCC) can be divided into four transcriptomic subtypes, two of which have a favorable and two an unfavorable prognosis. To assess mechanisms driving these subtypes, we investigated their miRNA expression patterns. miRNAs are master regulators of mRNAs, that are widely deregulated in cancer. Unsupervised clustering in our dataset (n = 128) and The Cancer Genome Atlas (TCGA) validation set identified two distinct miRNA clusters that overlapped with the transcriptomic subtypes, underscoring the validity of these subtypes on a multi-omics level and suggesting a driving role for miRNAs. Discriminatory miRNAs for the favorable subtypes repressed epithelial-to-mesenchymal transition, based on gene set enrichment analysis and target-mRNA expression levels. Strikingly, throughout the entire dataset, miRNAs associated with favorable subtypes were also associated with longer overall survival after diagnosis, and miRNAs associated with unfavorable subtypes with shorter overall survival (Pearson r = -0.54, p<0.0001). These findings indicate a general shift in miRNA expression between more and less aggressive tumors. This adds to current literature, which usually suggests only a small subset of miRNAs as markers of aggressive disease. In conclusion, this study reveals distinct mRNA expression patterns underlying transcriptomic ccRCC-subtypes, whereby miRNAs associated with favorable subtypes counteract epithelial-to-mesenchymal transition. There is a general shift in miRNA expression in ccRCC, between more and less aggressive tumors.


Assuntos
Carcinoma de Células Renais/genética , Perfilação da Expressão Gênica , Neoplasias Renais/genética , MicroRNAs/genética , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Feminino , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , RNA Mensageiro/genética , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Sunitinibe/farmacologia , Sunitinibe/uso terapêutico , Análise de Sobrevida
10.
J Comput Assist Tomogr ; 44(5): 737-743, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32842065

RESUMO

PURPOSE: The aim of the study was to investigate associations between computed tomography (CT) imaging characteristics, DNA methylation subtyping, and overall survival in renal cell carcinomas. METHODS: Survival curves were calculated using the Kaplan-Meier analysis. The CT data from 212 patients generated with The Cancer Imaging Archive (TCIA) were reviewed. Identified were 70 (33.0%) M1 subtype, 17 (8.0%) M2 subtype, and 125 (59.0%) M3 subtype. Univariate and multivariate analyses were performed using the logistic regression model. RESULTS: Patients with M1 subtype had the shortest median overall survival (P < 0.001). On univariate analysis, long axis of 70 mm, intratumoral calcifications, enhancement, long axis > median, short axis > median, and intratumoral vascularity were associated with a significantly higher incidence of M1 subtype (P < 0.05). Short axis ≤ median, absence of necrosis, absence of intratumoral vascularity, and nodular enhancement were associated with M2 subtype (P < 0.05). Short axis ≤ median, long axis ≤ median, long axis of less than 70 mm, and necrosis were associated with a significantly higher incidence of M3 subtype (P < 0.05). On multivariate logistic regression analysis, long axis of greater than 70 mm (odds ratio [OR] = 2.452, P = 0.004; 95% confidence interval [CI] = 1.332-4.514) and necrosis (OR = 4.758, P = 0.041, 95% CI = 1.065-21.250) were associated with M1 subtype (area under the curve [AUC] = 0. 664). Necrosis (OR = 0.047, P < 0.001, 95% CI = 0.012-0.178) and enhancement (OR = 0.083, P = 0.024, 95% CI = 0.010-0.716) were associated with M2 subtype (AUC = 0.909). Long axis > median (OR = 0.303, P < 0.001, 95% CI = 0.164-0.561) and necrosis (OR = 3.256, P = 0.003, 95% CI = 1.617-10.303) were associated with M3 subtype (AUC = 0. 664). CONCLUSIONS: The shortest survival was observed in patients with M1 subtype. This preliminary radiogenomics analysis of renal cell carcinoma demonstrated associations between CT imaging characteristic and DNA methylation subtyping.


Assuntos
Carcinoma de Células Renais/diagnóstico por imagem , Carcinoma de Células Renais/genética , Metilação de DNA , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/genética , Carcinoma de Células Renais/mortalidade , Estudos de Coortes , Feminino , Genômica , Humanos , Neoplasias Renais/mortalidade , Modelos Logísticos , Masculino , Tomografia Computadorizada por Raios X
11.
J Clin Pathol ; 73(11): 691-694, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32820043

RESUMO

Transcription factor enhancer 3 (TFE3), on the short arm of chromosome Xp11.23 and its protein, belongs to the microphthalmia transcription family (MiTF) of transcription factors. It shares close homology with another member of the family, MiTF which is involved in melanocyte development. When a cell is stressed and/or starved, TFE3 protein translocates into the nucleus. TFE3 gene fusions with multiple different partner genes occur in several tumours with resultant nuclear expression of TFE3 protein. The main tumours associated with TFE3 gene fusions are: renal cell carcinoma, alveolar soft part sarcoma, a subset of epithelioid haemangioendotheliomas (EHE), some perivascular epithelioid cell tumours and rare examples of ossifying fibromyxoid tumour and malignant chondroid syringoma. TFE3 immunohistochemistry is of use in routine diagnostic practice with the aforementioned tumours harbouring TFE3 fusions leading to nuclear staining. In addition, there are tumours lacking TFE3 fusions but also display TFE3 nuclear immunolabeling, and these include: granular cell tumour, solid pseudopapillary neoplasm of the pancreas and ovarian sclerosing stromal tumour.


Assuntos
Adenoma Pleomorfo/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Carcinoma de Células Renais/genética , Hemangioendotelioma Epitelioide/genética , Neoplasias de Células Epitelioides Perivasculares/genética , Sarcoma Alveolar de Partes Moles/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Carcinoma de Células Renais/patologia , Núcleo Celular/metabolismo , Tumores do Estroma Endometrial/patologia , Feminino , Tumor de Células Granulares/patologia , Hemangioendotelioma Epitelioide/patologia , Humanos , Imuno-Histoquímica , Melanócitos/patologia , Fusão Oncogênica , Neoplasias de Células Epitelioides Perivasculares/patologia , Transporte Proteico , Sarcoma Alveolar de Partes Moles/patologia , Estresse Fisiológico , Translocação Genética
12.
Nat Commun ; 11(1): 4168, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32820162

RESUMO

There is conflicting data regarding the role of PBAF complex mutations and response to immune checkpoint blockade (ICB) therapy in clear cell renal cell carcinoma (ccRCC) and other solid tumors. We assess the prevalence of PBAF complex mutations from two large cohorts including the pan-cancer TCGA project (n = 10,359) and the MSK-IMPACT pan-cancer immunotherapy cohort (n = 3700). Across both cohorts, PBAF complex mutations, predominantly PBRM1 mutations, are most common in ccRCC. In multivariate models of ccRCC patients treated with ICB (n = 189), loss-of-function (LOF) mutations in PBRM1 are not associated with overall survival (OS) (HR = 1.24, p = 0.47) or time to treatment failure (HR = 0.85, p = 0.44). In a series of 11 solid tumors (n = 2936), LOF mutations are not associated with improved OS in a stratified multivariate model (HR = 0.9, p = 0.7). In a current series of solid tumors treated with ICB, we are unable to demonstrate favorable response to ICB in patients with PBAF complex mutations.


Assuntos
Carcinoma de Células Renais/terapia , Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA/genética , Imunoterapia/métodos , Neoplasias Renais/terapia , Mutação , Fatores de Transcrição/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Estudos de Coortes , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/genética , Neoplasias Renais/patologia , Pessoa de Meia-Idade
13.
Mol Carcinog ; 59(10): 1159-1173, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32794610

RESUMO

Sex-determining region Y box (SOXs) are expressed in various cells and control cell fate and differentiation in a multitude of physiologic processes. SOX6, a main representative of SOXs, is involved in the regulation of carcinogenesis in various human malignancies. However, the role of SOX6 in clear cell renal cell carcinoma (ccRCC) remains unclear. In this study, SOX6 expression in ccRCC and its clinical significance were investigated. In vitro and in vivo assays were used to explore the tumor-related function and the underlying molecular mechanism of SOX6 in ccRCC. We confirmed that SOX6 was frequently downregulated in ccRCC tissues and cell lines. Besides, downregulation of SOX6 was significantly associated with larger tumor sizes, advanced tumor stage, higher Fuhrman grades, and its expression could act as an independent prognostic factor for ccRCC (hazards ratio = 0.590, P = .026). Gain/loss-of-function experiments demonstrated that SOX6 could remarkably inhibit tumor cell growth and foci formation in vitro and xenograft tumorigenesis in vivo, respectively. Mechanistically, SOX6 could influence cell cycle by regulating the G1/the S phase transition and had an inhibitory effect on Wnt/ß-catenin signaling as well as its target genes, c-Myc and cyclin D1. Interesting, the tumor-suppressive function of SOX6 was proved to be dependent on its specific high-mobility-group (HMG) domain. In general, our findings indicated that SOX6 was a novel tumor suppressor and prognostic biomarker in ccRCC. SOX6 could inhibit tumor growth by negatively regulating the Wnt/ß-catenin signaling pathway in an HMG domain-dependent manner in ccRCC, which might provide a novel therapeutic approach for ccRCC.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/patologia , Domínios HMG-Box , Neoplasias Renais/patologia , Fatores de Transcrição SOXD/metabolismo , Proteína Wnt1/metabolismo , beta Catenina/metabolismo , Animais , Apoptose , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Proliferação de Células , Transformação Celular Neoplásica , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Prognóstico , Fatores de Transcrição SOXD/genética , Taxa de Sobrevida , Células Tumorais Cultivadas , Proteína Wnt1/genética , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina/genética
14.
Proc Natl Acad Sci U S A ; 117(35): 21441-21449, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32817424

RESUMO

Loss of the von Hippel-Lindau (VHL) tumor suppressor is a hallmark feature of renal clear cell carcinoma. VHL inactivation results in the constitutive activation of the hypoxia-inducible factors (HIFs) HIF-1 and HIF-2 and their downstream targets, including the proangiogenic factors VEGF and PDGF. However, antiangiogenic agents and HIF-2 inhibitors have limited efficacy in cancer therapy due to the development of resistance. Here we employed an innovative computational platform, Mining of Synthetic Lethals (MiSL), to identify synthetic lethal interactions with the loss of VHL through analysis of primary tumor genomic and transcriptomic data. Using this approach, we identified a synthetic lethal interaction between VHL and the m6A RNA demethylase FTO in renal cell carcinoma. MiSL identified FTO as a synthetic lethal partner of VHL because deletions of FTO are mutually exclusive with VHL loss in pan cancer datasets. Moreover, FTO expression is increased in VHL-deficient ccRCC tumors compared to normal adjacent tissue. Genetic inactivation of FTO using multiple orthogonal approaches revealed that FTO inhibition selectively reduces the growth and survival of VHL-deficient cells in vitro and in vivo. Notably, FTO inhibition reduced the survival of both HIF wild type and HIF-deficient tumors, identifying FTO as an HIF-independent vulnerability of VHL-deficient cancers. Integrated analysis of transcriptome-wide m6A-seq and mRNA-seq analysis identified the glutamine transporter SLC1A5 as an FTO target that promotes metabolic reprogramming and survival of VHL-deficient ccRCC cells. These findings identify FTO as a potential HIF-independent therapeutic target for the treatment of VHL-deficient renal cell carcinoma.


Assuntos
Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Mutações Sintéticas Letais , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Sistema ASC de Transporte de Aminoácidos/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinoma de Células Renais/metabolismo , Linhagem Celular Tumoral , Simulação por Computador , Humanos , Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Renais/metabolismo , Camundongos Knockout , Antígenos de Histocompatibilidade Menor/metabolismo
15.
Nat Commun ; 11(1): 4111, 2020 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-32807776

RESUMO

Mutational inactivation of VHL is the earliest genetic event in the majority of clear cell renal cell carcinomas (ccRCC), leading to accumulation of the HIF-1α and HIF-2α transcription factors. While correlative studies of human ccRCC and functional studies using human ccRCC cell lines have implicated HIF-1α as an inhibitor and HIF-2α as a promoter of aggressive tumour behaviours, their roles in tumour onset have not been functionally addressed. Herein we show using an autochthonous ccRCC model that Hif1a is essential for tumour formation whereas Hif2a deletion has only minor effects on tumour initiation and growth. Both HIF-1α and HIF-2α are required for the clear cell phenotype. Transcriptomic and proteomic analyses reveal that HIF-1α regulates glycolysis while HIF-2α regulates genes associated with lipoprotein metabolism, ribosome biogenesis and E2F and MYC transcriptional activities. HIF-2α-deficient tumours are characterised by increased antigen presentation, interferon signalling and CD8+ T cell infiltration and activation. Single copy loss of HIF1A or high levels of HIF2A mRNA expression correlate with altered immune microenvironments in human ccRCC. These studies reveal an oncogenic role of HIF-1α in ccRCC initiation and suggest that alterations in the balance of HIF-1α and HIF-2α activities can affect different aspects of ccRCC biology and disease aggressiveness.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Células 3T3 , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Western Blotting , Linfócitos T CD8-Positivos/metabolismo , Carcinoma de Células Renais/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Proliferação de Células/fisiologia , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Imuno-Histoquímica , Inflamação/genética , Inflamação/metabolismo , Neoplasias Renais/genética , Espectrometria de Massas , Camundongos , Proteômica/métodos , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de RNA , Microambiente Tumoral/genética , Microambiente Tumoral/fisiologia
16.
DNA Cell Biol ; 39(10): 1799-1812, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32716214

RESUMO

Clear cell renal cell carcinoma (ccRCC) is the most prevalent renal malignancy in adults with generally poor prognosis. This study aimed to establish a DNA methylation-driven gene-based prognostic model for ccRCC. We collected DNA methylation and gene expression profiles of over 1500 ccRCC samples from The Cancer Genome Atlas (TCGA) dataset, four Gene Expression Omnibus (GEO) datasets, the Genotype-Tissue Expression (GTEx) dataset, and cancer cell lines from Cancer Cell Line Encyclopedia database and performed comprehensive bioinformatics analysis. As a result, a total of 31 differentially expressed methylation-driven genes (DEMDGs) were identified. After univariate Cox regression, least absolute shrinkage and selection operator, and multivariate Cox regression analyses, four (NFE2L3, HHLA2, IFI16, and ZNF582) were finally selected to construct a risk score prognostic model. The high-risk group demonstrated significantly poor prognosis than the low-risk group did in TCGA training (hazard ratio [HR] = 3.533, p < 0.001), TCGA internal, and GEO external validation datasets. Furthermore, the nomogram, including the prognostic model and clinical factors, showed promising prognostic value (HR = 5.756, p < 0.001, and area under the curve at 1 year = 0.856). In addition, the model was found to be significantly associated with drug sensitivity of eight targeted agents. These findings provided a novel and reliable four DEMDG-based prognostic model for ccRCC.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Renais/genética , Metilação de DNA , Neoplasias Renais/genética , Idoso , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico
17.
Urol Clin North Am ; 47(3): 305-318, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32600533

RESUMO

In an era of several therapeutic options available, optimal treatment sequencing is crucial to providing patients the most effective therapy and promoting quality of life. In clear cell renal cell carcinoma, a combination approach with an immunotherapy backbone, such as nivolumab/ipilimumab or axitinib/pembrolizumab, has a key role in the first-line setting. Safety and activity data support the transition to single-agent targeted therapies in the second-line setting. Nivolumab monotherapy possesses clinical and mechanistic rationale as a second-line therapeutic option for patients treated with targeted therapies in the first-line setting. Gene expression models are being generated from large prospective clinical trial data sets.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Expressão Gênica , Humanos , Imunoterapia , Terapia de Alvo Molecular
18.
Zhonghua Bing Li Xue Za Zhi ; 49(7): 693-698, 2020 Jul 08.
Artigo em Chinês | MEDLINE | ID: mdl-32610380

RESUMO

Objective: To study clinical pathological characteristics, immunohistochemical, molecular genetical changes and prognosis in pediatric eosinophilic solid and cystic renal cell carcinoma (ESC RCC) with TSC2 gene mutations. Methods: The tissue samples were collected from two pediatric ESC RCC patients between 2017 and 2018. The tissues were subjected to histological examination and immunohistochemistry using EnVision system. The TFE3, TFEB gene rearrangements were tested using FISH and molecular genetic study. The paraffin sections were used for DNA extraction, PCR amplification and NGS sequencing. Results: The two patients with ESC RCC were both male, aged at 9 years and 8 months, and 13 years, respectively. The tumors were from the right kidney, 5 cm and 7 cm in size, respectively, with solid and cystic changes in cross section, and grey-reddish or grey-whitish fish meat appearance. Microscopic observation revealed the tumors had fibrous capsules, which were infiltrated by the tumor cells. The tumor cells were diffusely distributed, round-shaped, or polygon-shaped, and had voluminous cytoplasm, eosinophilic cytoplasm, various sizes of vacuoles and clear cell-like appearance. There were papillary structures in some areas, with visible fiber septa. The nuclei were round and vesicular, with multi-nucleated cells and megakaryocytes. The mitoses were not seen. A few cystic structures were visible in different sizes, and capsule walls were covered with a single layer of spike-like tumor cells. Thick-walled blood vessels were seen in the stroma, with focal lymphocytic infiltration, eosinophilic necrosis, calcifications and cholesterol crystals. Immunohistochemistry of the tumor cells was positive for PAX8 (diffuse), CK20 (focal), CKpan (focal), CK10 (1 focal, 1 diffuse), INI1, vimentin, CD68, and Ki-67 (5%~10%); the tumor cells were negative for HMB45, S-100, Melan A, p53, desmin, TFE3, CK7, CK19, EMA, CD56, CgA, Syn, CD30, CD117, WT1 and SMA. Molecular genetic study showed that TFE3 and TFEB gene rearrangements were not detected by FISH. NGS sequencing showed TSC2 p.Lys574Ter (0.198) was found in patient one and TSC2 p.Arg406Ter (0.355) in patient two. Conclusions: ESC RCC in children is a rare disease, and can be misdiagnosed easily. It has unique pathological characteristics, and immunohistochemical, molecular and genetic changes. The prognosis is relatively good.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Proteína 2 do Complexo Esclerose Tuberosa/genética , Adolescente , Biomarcadores Tumorais , Carcinoma de Células Renais/genética , Criança , Humanos , Imuno-Histoquímica , Neoplasias Renais/genética , Masculino , Mutação
19.
Bull Cancer ; 107(5S): S24-S34, 2020 Jun.
Artigo em Francês | MEDLINE | ID: mdl-32620204

RESUMO

The standard of care for metastatic clear cell renal cell carcinoma (mccRCC) has changed dramatically over the past decades thanks to the increasing number of treatments: anti-VEGFR tyrosine kinase inhibitors (TKI), mTOR inhibitors and immune checkpoint inhibitors (ICI): anti PD(L)-1 used as monotherapy or in combination with anti CTLA-4 or anti angiogenic therapies. In the face of rising therapeutic options, the question of the therapeutic sequences arises: which treatment for which patient? Actually, there is a lack of predictive biomarkers. A greater understanding of the cancer biology and its interaction with the microenvironment has allowed the development of genomic signatures which could perhaps be used as predictive biomarker. This review will give an insight on some robust genomic signatures assessed in mccRCC and will have a closer look at BIONIKK phase II trial, which is the first trial to adapt treatments according to the molecular characteristics of the tumor in the context of mccRCC.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Carcinoma de Células Renais/secundário , Tomada de Decisão Clínica , Humanos , Neoplasias Renais/patologia , Guias de Prática Clínica como Assunto
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