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1.
Braz. j. biol ; 84: e250575, 2024. tab, graf
Article in English | LILACS, VETINDEX | ID: biblio-1350309

ABSTRACT

Abstract Cancer is a fatal malignancy and its increasing worldwide prevalence demands the discovery of more sensitive and reliable molecular biomarkers. To investigate the GINS1 expression level and its prognostic value in distinct human cancers using a series of multi-layered in silico approach may help to establish it as a potential shared diagnostic and prognostic biomarker of different cancer subtypes. The GINS1 mRNA, protein expression, and promoter methylation were analyzed using UALCAN and Human Protein Atlas (HPA), while mRNA expression was further validated via GENT2. The potential prognostic values of GINS1 were evaluated through KM plotter. Then, cBioPortal was utilized to examine the GINS1-related genetic mutations and copy number variations (CNVs), while pathway enrichment analysis was performed using DAVID. Moreover, a correlational analysis between GINS1 expression and CD8+ T immune cells and a the construction of gene-drug interaction network was performed using TIMER, CDT, and Cytoscape. The GINS1 was found down-regulated in a single subtypes of human cancer while commonly up-regulated in 23 different other subtypes. The up-regulation of GINS1 was significantly correlated with the poor overall survival (OS) of Liver Hepatocellular Carcinoma (LIHC), Lung Adenocarcinoma (LUAD), and Kidney renal clear cell carcinoma (KIRC). The GINS1 was also found up-regulated in LIHC, LUAD, and KIRC patients of different clinicopathological features. Pathways enrichment analysis revealed the involvement of GINS1 in two diverse pathways, while few interesting correlations were also documented between GINS1 expression and its promoter methylation level, CD8+ T immune cells level, and CNVs. Moreover, we also predicted few drugs that could be used in the treatment of LIHC, LUAD, and KIRC by regulating the GINS1 expression. The expression profiling of GINS1 in the current study has suggested it a novel shared diagnostic and prognostic biomarker of LIHC, LUAD, and KIRC.


Resumo O câncer é uma doença maligna fatal e sua crescente prevalência mundial exige a descoberta de biomarcadores moleculares mais sensíveis e confiáveis. Investigar o nível de expressão de GINS1 e seu valor prognóstico em cânceres humanos distintos, usando uma série de abordagens in silico em várias camadas, pode ajudar a estabelecê-lo como um potencial biomarcador de diagnóstico e prognóstico compartilhado de diferentes subtipos de câncer. O mRNA de GINS1, a expressão da proteína e a metilação do promotor foram analisados ​​usando UALCAN e Human Protein Atlas (HPA), enquanto a expressão de mRNA foi posteriormente validada via GENT2. Os valores prognósticos potenciais de GINS1 foram avaliados por meio do plotter KM. Em seguida, o cBioPortal foi utilizado para examinar as mutações genéticas relacionadas ao GINS1 e as variações do número de cópias (CNVs), enquanto a análise de enriquecimento da via foi realizada usando DAVID. Além disso, uma análise correlacional entre a expressão de GINS1 e células imunes T CD8 + e a construção de uma rede de interação gene-droga foi realizada usando TIMER, CDT e Cytoscape. O GINS1 foi encontrado regulado negativamente em um único subtipo de câncer humano, enquanto comumente regulado positivamente em 23 outros subtipos diferentes. A regulação positiva de GINS1 foi significativamente correlacionada com a sobrevida global pobre (OS) de Carcinoma Hepatocelular de Fígado (LIHC), Adenocarcinoma de Pulmão (LUAD) e Carcinoma de Células Claras Renais de Rim (KIRC). O GINS1 também foi encontrado regulado positivamente em pacientes LIHC, LUAD e KIRC de diferentes características clínico-patológicas. A análise de enriquecimento de vias revelou o envolvimento de GINS1 em duas vias diversas, enquanto poucas correlações interessantes também foram documentadas entre a expressão de GINS1 e seu nível de metilação do promotor, nível de células imunes T CD8 + e CNVs. Além disso, também previmos poucos medicamentos que poderiam ser usados ​​no tratamento de LIHC, LUAD e KIRC, regulando a expressão de GINS1. O perfil de expressão de GINS1 no estudo atual sugeriu que é um novo biomarcador de diagnóstico e prognóstico compartilhado de LIHC, LUAD e KIRC.


Subject(s)
Humans , Carcinoma, Renal Cell/genetics , Kidney Neoplasms/genetics , Liver Neoplasms , Prognosis , Biomarkers, Tumor/genetics , Gene Expression Regulation, Neoplastic , Up-Regulation , DNA-Binding Proteins , DNA Copy Number Variations
2.
Int. j. morphol ; 41(6): 1789-1801, dic. 2023. ilus, tab, graf
Article in English | LILACS | ID: biblio-1528808

ABSTRACT

SUMMARY: We investigated the expression and clinical significance of miR-15b-5p in clear cell renal cell carcinoma (RCC) through bioinformatics analysis and experimental verification. The differentially expressed miRNAs were screened in the GEO database. Venn diagram showed that there were 5 up-regulated miRNAs (has-miR-210, has-miR-142-3p, has-miR-142-5p, has-miR-15b-5p, and has-miR-193a-3p) and only 1 down-regulated miRNA (has-miR-532-3p) that were commonly expressed between GSE189331 and GSE16441 datasets. This was further confirmed in TCGA. Further analysis showed that the has-miR-193a-3p, has-miR-142-3p, has- miR-142-5p, and has-miR-15b-5p were closely related to tumor invasion, distant metastasis and survival probability. The expression of miR-15b-5p in ccRCC tissues was significantly higher than that in adjacent normal kidney tissues (P0.05). Following inhibition of miR-15b-5p expression, RCC cells had attenuated proliferation, increased apoptosis, and attenuated migration and invasion. has-miR-15b-5p-WEE1, has-miR-15b-5p-EIF4E, has-miR-15b-5p-PPP2R1B may be three potential regulatory pathways in ccRCC. miR-15b-5p is highly expressed in cancer tissues of ccRCC patients. It may promote proliferation, inhibit apoptosis and enhance cell migration and invasion of RCC cells. The has-miR-15b-5p-WEE1, has-miR-15b-5p-EIF4E, and has-miR-15b-5p-PPP2R1B may be three potential regulatory pathways in ccRCC.


Investigamos la expresión y la importancia clínica de miR-15b-5p en el carcinoma de células renales (CCR) de células claras mediante análisis bioinformático y verificación experimental. Los miARN expresados diferencialmente se examinaron en la base de datos GEO. El diagrama de Venn mostró que había 5 miARN regulados positivamente (has-miR-210, has-miR-142-3p, has-miR-142-5p, has-miR-15b-5p y has-miR-193a-3p). ) y solo 1 miARN regulado negativamente (has-miR-532-3p) que se expresaron comúnmente entre los conjuntos de datos GSE189331 y GSE16441. Esto fue confirmado aún más en TCGA. Un análisis más detallado mostró que has-miR-193a-3p, has-miR-142-3p, has- miR-142-5p y has-miR-15b-5p estaban estrechamente relacionados con la invasión tumoral, la metástasis a distancia y la probabilidad de supervivencia. La expresión de miR-15b-5p en tejidos ccRCC fue significativamente mayor que la de los tejidos renales normales adyacentes (P 0,05). Tras la inhibición de la expresión de miR-15b-5p, las células RCC tuvieron una proliferación atenuada, un aumento de la apoptosis y una migración e invasión atenuadas. has-miR-15b-5p-WEE1, has- miR-15b-5p-EIF4E, has-miR-15b-5p-PPP2R1B pueden ser tres posibles vías reguladoras en ccRCC. miR-15b-5p se expresa altamente en tejidos cancerosos de pacientes con ccRCC. Puede promover la proliferación, inhibir la apoptosis y mejorar la migración celular y la invasión de células RCC. has-miR-15b-5p-WEE1, has- miR-15b-5p-EIF4E y has-miR-15b-5p-PPP2R1B pueden ser tres posibles vías reguladoras en ccRCC.


Subject(s)
Humans , Male , Female , Carcinoma, Renal Cell/pathology , MicroRNAs , Kidney Neoplasms/pathology , Carcinoma, Renal Cell/genetics , Survival Analysis , Cell Movement , Computational Biology , Real-Time Polymerase Chain Reaction , Kidney Neoplasms/genetics , Neoplasm Invasiveness , Neoplasm Metastasis
3.
Chinese Medical Sciences Journal ; (4): 191-205, 2023.
Article in English | WPRIM | ID: wpr-1008987

ABSTRACT

Background Kidney renal clear cell carcinoma (KIRC) is one of the most common renal malignancies with a high mortality rate. Cuproptosis, a novel form of cell death, is strongly linked to mitochondrial metabolism and is mediated by protein lipoylation, leading to a proteotoxic stress response and cell death. To date, few studies have ellucidated the holistic role of cuproptosis-related genes (CRGs) in the pathogenesis of KIRC.Methods We comprehensively and completely analyzed the RNA sequencing data and corresponding clinical information from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. We screened for differentially expressed CRGs and constructed a prognostic risk model using univariate and multivariate Cox proportional regression analyses. Kaplan-Meier analysis was performed and receiver operating characteristic (ROC) curves were plotted to predict the prognosis of KIRC patients. Functional enrichment analysis was utilized to explore the internal mechanisms. Immune-related functions were analyzed using single-sample gene set enrichment analysis (ssGSEA), tumour immune dysfunction and exclusion (TIDE) scores, and drug sensitivity analysis.Results We established a concise prognostic risk model consisting of four CRGs (DBT, DLAT, LIAS and PDHB) to predict the overall survival (OS) in KIRC patients. The results of the survival analysis indicated a significantly lower OS in the high-risk group as compared to the patients in the low-risk group. The area under the time-dependent ROC curve (AUC) at 1, 3, and 5 year was 0.691, 0.618, and 0.614 in KIRC. Functional enrichment analysis demonstrated that CRGs were significantly enriched in tricarboxylic acid (TCA) cycle-related processes and metabolism-related pathways. Sorafenib, doxorubicin, embelin, and vinorelbine were more sensitive in the high-risk group.Conclusions We constructed a concise CRGs risk model to evaluate the prognosis of KIRC patients and this may be a new direction for the diagnosis and treatment of KIRC.


Subject(s)
Humans , Carcinoma, Renal Cell/genetics , Immunotherapy , Kidney , Kidney Neoplasms/genetics , Prognosis , Copper , Apoptosis
4.
Frontiers of Medicine ; (4): 503-517, 2023.
Article in English | WPRIM | ID: wpr-982571

ABSTRACT

Aldolase B (ALDOB), a glycolytic enzyme, is uniformly depleted in clear cell renal cell carcinoma (ccRCC) tissues. We previously showed that ALDOB inhibited proliferation through a mechanism independent of its enzymatic activity in ccRCC, but the mechanism was not unequivocally identified. We showed that the corepressor C-terminal-binding protein 2 (CtBP2) is a novel ALDOB-interacting protein in ccRCC. The CtBP2-to-ALDOB expression ratio in clinical samples was correlated with the expression of CtBP2 target genes and was associated with shorter survival. ALDOB inhibited CtBP2-mediated repression of multiple cell cycle inhibitor, proapoptotic, and epithelial marker genes. Furthermore, ALDOB overexpression decreased the proliferation and migration of ccRCC cells in an ALDOB-CtBP2 interaction-dependent manner. Mechanistically, our findings showed that ALDOB recruited acireductone dioxygenase 1, which catalyzes the synthesis of an endogenous inhibitor of CtBP2, 4-methylthio 2-oxobutyric acid. ALDOB functions as a scaffold to bring acireductone dioxygenase and CtBP2 in close proximity to potentiate acireductone dioxygenase-mediated inhibition of CtBP2, and this scaffolding effect was independent of ALDOB enzymatic activity. Moreover, increased ALDOB expression inhibited tumor growth in a xenograft model and decreased lung metastasis in vivo. Our findings reveal that ALDOB is a negative regulator of CtBP2 and inhibits tumor growth and metastasis in ccRCC.


Subject(s)
Humans , Carcinoma, Renal Cell/genetics , Fructose-Bisphosphate Aldolase/metabolism , Co-Repressor Proteins/metabolism , Transcription Factors/genetics , Kidney Neoplasms/genetics , Cell Line, Tumor , Cell Proliferation/genetics , Gene Expression Regulation, Neoplastic
5.
Chinese Journal of Medical Genetics ; (6): 494-498, 2022.
Article in Chinese | WPRIM | ID: wpr-928444

ABSTRACT

OBJECTIVE@#To analyze clinical phenotype and genetic variants in a Chinese pedigree of hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome.@*METHODS@#Whole exome sequencing was carried out for the proband from the pedigree. Suspected FH gene variants were validated by Sanger sequencing. Clinical manifestation and histopathological examination were used to analyze the pedigree comprehensively.@*RESULTS@#The pedigree met the clinical diagnostic criteria for HLRCC syndrome. The whole exome sequencing showed that the FH gene of the proband had a heterozygous missense variant of c.1490T>C (p.F497S), which was consistent with the Sanger sequencing. The mother, daughter and son of the proband all had the heterozygous missense variant of c.1490T>C (p.F497S). According to the American Society of Medical Genetics and Genomics Classification Standards and Guidelines for Genetic Variations, c.1490T>C (p.F497S) (PM2+PP1-M+PP3+PP4) was a possible pathogenic variant. Based on our literature search, this variant was a new variant that had not been reported.@*CONCLUSION@#The FH gene missense variant of c.1490T>C (p.F497S) may be the cause of the HLRCC syndrome pedigree, which provides a basis for the genetic diagnosis and genetic counseling of the HLRCC syndrome.


Subject(s)
Humans , Carcinoma, Renal Cell/genetics , Kidney Neoplasms/genetics , Leiomyomatosis/pathology , Mutation , Neoplastic Syndromes, Hereditary , Pedigree , Phenotype , Skin Neoplasms , Uterine Neoplasms
6.
Chinese Journal of Pathology ; (12): 28-32, 2022.
Article in Chinese | WPRIM | ID: wpr-935466

ABSTRACT

Objective: To investigate the clinicopathological features, molecular characteristics, differential diagnosis and prognosis of anaplastic lymphoma kinase (ALK)-translocation renal cell carcinoma. Methods: Two cases of ALK-translocation renal cell carcinoma diagnosed from January 2011 to December 2020 were retrospectively analyzed to characterize their morphological features, immunohistochemical expression and prognosis. Multiple molecular studies including fluorescence in situ hybridization (FISH), reverse transcriptase-polymerase chain reaction (RT-PCR), and next-generation sequencing were performed to characterize the genetic alterations. Results: Two patients included one male and one female, with 59 and 57 years old, respectively. Morphologically, case 1 resembled collecting duct carcinoma or renal medullary carcinoma, which demonstrated tubular, microcapsule and reticular structures, with a remarkable myxoid background and lymphocytes infiltration; case 2 resembled Xp11.2 translocation renal cell carcinoma or type 2 papillary renal cell carcinoma, which demonstrated tubular papillary and focal solid structures, with flocculent cytoplasm and many foamy histiocytes, but without myxoid background and lymphocytes infiltration. Immunohistochemistry showed strongly positive expression of ALK. CK7, E-cadherin, vimentin, PAX8 and CD10 showed various degrees of expression, and other antibodies were nonreactive. A variety of molecular assays showed definite ALK gene translocation, with rare VCL-ALK gene fusion (VCL exon and 16-ALK exon 20) in case 1, and EML4-ALK gene fusion (EML4 exon and 2-ALK exon 20) in case 2. Conclusions: ALK-translocation renal cell carcinoma is rare with various morphological features, and is easy to miss and misdiagnose. The characteristic ALK expression and molecular detection of ALK translocation are helpful for diagnosing this type of renal cell carcinoma.


Subject(s)
Female , Humans , Male , Anaplastic Lymphoma Kinase/genetics , Carcinoma, Renal Cell/genetics , In Situ Hybridization, Fluorescence , Kidney Neoplasms/genetics , Lung Neoplasms , Oncogene Proteins, Fusion/genetics , Retrospective Studies
7.
Chinese Journal of Pathology ; (12): 23-27, 2022.
Article in Chinese | WPRIM | ID: wpr-935465

ABSTRACT

Objective: To study the clinical pathological characteristics, immunophenotype, molecular changes and prognosis of the papillary renal neoplasm with reverse polarity (PRNRP). Methods: Nine cases of PRNRP, diagnosed from 2013 to 2019, were retrieved from the Department of Pathology of Nanjing Jinling Hospital, Nanjing University School of Medicine. Histomorphology, immunophenotype and molecular genetics were analyzed with review of the literatures. Results: There were five male and four female patients, aged from 49 to 70 years, with an average age of 60.1 years. During a mean follow-up of 29 months, one patient died for other cause, and the others survived without disease. Microscopically, the tumor cells arranged in papillary structure with a fibrovascular core, the surface of which was covered with a single layer of cuboidal or columnar cells. The most prominent feature was that the tumor nuclei located at the top of the cytoplasm far from the basement membrane, and they were monotonous in size and arranged neatly with no or few nucleoli. Immunohistochemically, all nine cases of PRNRP showed diffuse positive expression of CK7 and E-cadherin, various degrees of P504s expression, and no expression of CD10 and CD117, with a Ki-67 index of 1%-3%. Unlike other papillary renal cell carcinoma, the nine cases of PRNRP all showed characteristic positive expression of GATA3. The fluorescence in situ hybridization assay showed that the majority of PRNRPs (8/9) did not have triploids on chromosomes 7 and 17. The sequencing of the KRAS gene confirmed the presence of a nonsense KRAS mutation in 8 of the 9 cases. Conclusions: PRNRP is a subtype of papillary renal cell carcinoma with characteristic morphological, immunophenotypic and molecular features, and indolent behaviors. More data are needed to define PRNRP as "carcinoma", and a definitive diagnosis of PRNRP is of great significance for proper treatment choice and accurate prognostication.


Subject(s)
Female , Humans , Male , Middle Aged , Biomarkers, Tumor , Carcinoma, Renal Cell/genetics , In Situ Hybridization, Fluorescence , Kidney , Kidney Neoplasms/genetics , Prognosis
8.
Chinese Journal of Pathology ; (12): 12-16, 2022.
Article in Chinese | WPRIM | ID: wpr-935463

ABSTRACT

Objective: To investigate the clinicopathological features, immunophenotype, ultrastructure, genetic alterations and prognosis of succinate dehydrogenase-deficient renal cell carcinoma (SDH RCC). Methods: A total of 11 SDH RCCs, diagnosed from 2010 to 2019, were selected from the Department of Pathology of Nanjing Jingling Hospital, Nanjing University School of Medicine for clinicopathologic, immunohistochemical (IHC), ultrastructural investigation and follow-up. The molecular features of seven cases were analyzed by the panel-targeted DNA next generation sequencing (NGS). Results: There were seven males and four females, with ages ranging from 24 to 62 years (mean 41.4 years, median 41 years). Microscopically, SDH RCC was mainly composed of solid and tubular structures with local cystic change. Four cases showed nested or trabecular structure distributed in a loose hypocellular connective tissue or around scar, similar to oncocytoma. The neoplastic cells demonstrated flocculent eosinophilic cytoplasm with typical intracytoplasmic vacuoles. Immunohistochemically, eight cases were negative for SDHB; three cases showed focal and weak expression, whereas normal renal tubular and vascular endothelial cells demonstrated strong cytoplasmic staining. NGS of DNA targeted-panel detected pathogenic mutations of SDHB gene in seven cases (including three cases with equivocal IHC expression of SDHB), without any mutations in other SDH related genes. There were four cases of SDHB missense mutation, one case of frameshift mutation, one case of splicing mutation, and one case of acquired stop codon mutation. Conclusions: SDH RCC is a distinct variant of RCCs with genetic tendency or with hereditary cancer syndrome. NGS is recommended to detect the related gene mutations for a definitive diagnosis. The patients should be closely followed up.


Subject(s)
Adult , Female , Humans , Male , Middle Aged , Young Adult , Carcinoma, Renal Cell/genetics , Endothelial Cells , Kidney Neoplasms/genetics , Prognosis , Succinate Dehydrogenase/genetics
9.
São Paulo; s.n; 2022. 138 p. ilus, tab.
Thesis in Portuguese | LILACS, Inca | ID: biblio-1378924

ABSTRACT

O carcinoma renal de células claras (CRCC) é o tipo de neoplasia renal com maior incidência, cerca de 80%. A maioria dos casos são curados após cirurgia, porém, cerca de um terço dos pacientes apresentam recidiva da doença com metástase à distância. O tratamento para este tumor evoluiu muito nas últimas duas décadas, entretanto, pacientes metastáticos ainda apresentam baixas taxas de resposta aos tratamentos devido a resistência adquirida pelo tumor para escapar da terapia alvo. Identificar os mecanismos moleculares associados à carcinogênese do CRCC é essencial para entender as características tumorais que estão associadas a progressão da doença e resistência aos tratamentos. Entre as alterações mais frequentes no CRCC está a perda do gene VHL, um supressor tumoral e principal regulador da resposta à hipóxia. VHL tem dois principais alvos, o fator induzido por hipóxia 1α (HIF-1α) e o fator induzido por hipóxia α (HIF-2α). Em normóxia, VHL é responsável pela degradação das subunidades de HIF. Em hipóxia, VHL deixa de reconhecer e marcar HIF-1α e HIF-2α para degradação e, uma vez estabilizadas, ativam vias de sinalização associadas a sobrevivência celular. As informações sobre alterações encontradas em tumores normalmente são estudadas a partir do sequenciamento da população total de mRNAs, oferecendo uma visão do transcriptoma. Nossa abordagem metodológica coleta e analisa apenas a população de mRNAs ativamente traduzidos, oferecendo uma visão mais próxima da expressão proteica final. A via de mTOR regula o início da tradução de mRNAs e está frequentemente mutada em CRCC. A hipóxia afeta a expressão de genes tanto via transcrição quanto via tradução. Alterações no controle traducional em CRCC afetam a expressão gênica contribuindo para a formação do tumor e progressão da doença. Assim, nosso objetivo principal foi identificar o perfil de genes diferencialmente traduzidos dependendo do status de VHL e da via de mTOR. Para isso utilizamos um modelo celular de CRCC deficiente em VHL e sua contraparte onde VHL foi restituído. Realizamos o perfil polissomal em modelos celulares de CRCC para separar e coletar a população de mRNAs ativamente traduzidos que foram posteriormente sequenciados. Nossos dados mostraram perfis distintos de tradução entre as células VHL- deficientes e VHL-proficientes. Além disso, após a inibição de mTOR, ambas as células também apresentaram respostas diferentes ao tratamento. Além disso, observamos alterações na resposta imune e aumento do ciclo celular na ausência de VHL, que podem contribuir para a progressão tumoral. Em modelo com tecido tumoral congelado, nossos resultados parciais indicam que alterações na tradução global podem interferir principalmente no estadiamento clínico de pacientes com CRCC. Por fim, também analisamos a expressão de HIF-2α, um dos alvos de VHL, em tecidos de pacientes com CRCC. Nossos resultados mostram que HIF-2α pode ser utilizado na estratificação de pacientes com maior risco de recidiva, dependendo do estadiamento clínico.


Clear cell renal cell carcinoma (ccRCC) is the most common type of renal neoplasia with 80% of incidence. Most cases are cured after surgery, however, one third of all patients will have disease recurrence with distant metastasis. ccRCC treatment had evolved in the past two decades, however, metastatic patients still have low response rates due to tumor resistance. The identification of molecular mechanisms associated with ccRCC carcinogenesis is essential to understand the characteristics associated with disease progression and treatment resistance. The most frequent alteration in ccRCC is the loss of VHL gene, a tumor suppressor and the main regulator in response to hypoxia. VHL has two main target, hypoxia-induced factor 1 α (HIF-1 α) and hypoxia-induced factor α (HIF-2 α). In normoxic conditions, VHL can lead HIF subunits to degradation. In hypoxia, HIF-1α and HIF-2α stabilize and activate cell survival associated signaling pathways. Studies about tumor alterations usually provides a view of the transcriptome. Our approach is based on the actively translated mRNAs collection and analysis, which provides a closer view from protein expression. mTOR pathway regulates translation initiation and is frequently mutated in ccRCC. Hypoxia affects gene expression in both transcriptional and translational regulation. Alteration in translational control in ccRCC affect gene expression which contributes to tumor progression. Our main objective was to identify the differentially translated gene profile depending on VHL status and mTOR pathway activation. To assess this, we used a VHL-deficient and a VHL-proficient ccRCC cell line. We used the polysome profiling technique to separate and collect the population of mRNAs actively translated that were subsequently sequenced. Our data showed distinct translation profiles between VHL-deficient and VHL-proficient cells. In addition, after mTOR inhibition, both cells showed different responses to treatment. We observed changes in immune response and increased cell cycle pathways in VHL deficient cells, which may contribute to tumor progression. In tumor tissue, our polysome profiling analysis indicate that changes in global translation may interfere in clinical staging of ccRCC patients. Finally, we analyzed the expression of HIF-2α, a VHL target, in ccRCC patient's tissues. Our results showed that HIF-2α can distinct patients at higher recurrence risk depending on clinical staging.


Subject(s)
Humans , RNA, Messenger/genetics , Carcinoma, Renal Cell/genetics , Gene Expression Profiling , Von Hippel-Lindau Tumor Suppressor Protein , Kidney Neoplasms/genetics , Signal Transduction , Gene Expression Regulation, Neoplastic
10.
Int. j. morphol ; 39(6): 1719-1726, dic. 2021. ilus, tab
Article in English | LILACS | ID: biblio-1385523

ABSTRACT

SUMMARY: The group of primary renal tumours with granular-oncocytic cytoplasm is a very heterogeneous group, in its histological origin and biological behavior resulting in many diagnostic problems. In this study 57 renal epithelial tumours with granular oncocytic cells were analyzed using fluorescence in situ hybridisation (FISH), array comparative genomic hybridisation (aCGH) and polymerase chain reaction (PCR). The results of analysis in renal oncocytoma (RO) did not indicate the presence of the gene mutations or chromosomal abnormalities. Sporadic renal hybrid oncocytic/chromophobe tumours (HOCT) had multiple numerical aberrations of chromosomes 1, 2, 6, 9, 10, 13, 17, 20, 21 and 22. This type of tumour had no mutations in the VHL, c-kit, PDGFRA, and FLCN genes. Oncocytic papillary renal cell carcinoma (O-PRCC) had numerical abnormalities of chromosomes 7 and 17 and the loss of the Y chromosome. Cytogenetic analysis of 20 pigmented microcystic chromophobe renal cell carcinomas (PMChRCC) showed monosomy as the most frequent aberration in all analyzed chromosomes 1, 2, 5, 10, 13, 17 and 21. One case of chromophobe renal cell carcinoma (ChRCC) with hyaline globules had a mutation in the distal part of exon 3 of the VHL gene. Absence of genetic disorders in usual RO is common result, but we have established absence of genetic disorders even in rare variants. Variety of genetic alterations detected in sporadic renal HOCT proves it to be a separate entity, not a variant of ChRCC, while PMChRCC is an uncommon variant of ChRCC. O-PRCC is a subtype of papillary renal cell carcinoma.


RESUMEN: El grupo de tumores renales primarios con citoplasma granular-oncocítico es un grupo muy heterogéneo, en su origen histológico y comportamiento biológico, resultando en problemas de diagnóstico. En el estudio se analizaron 57 tumores epiteliales renales con citoplasma oncocítico granular mediante hibridación fluorescente in situ (FISH), hibridación genómica comparativa de matriz (aCGH) y reacción en cadena de la polimerasa (PCR). Los resultados del análisis en oncocitoma renal (RO) no indicaron la presencia de mutaciones genéticas ni anomalías cromosómicas. Los tumores oncocíticos / cromófobos híbridos renales esporádicos (HOCT) tenían múltiples aberraciones numéricas de los cromosomas 1, 2, 6, 9, 10, 13, 17, 20, 21 y 22. No se observaron mutaciones en este tipo de tumor en el VHL, c-kit, PDGFRA y genes FLCN. El carcinoma de células renales papilar oncocítico (O-PRCC) tenía anomalías numéricas de los cromosomas 7 y 17 y la pérdida del cromosoma Y. El análisis citogenético de 20 carcinomas de células renales cromófobos microquísticos pigmentados (PMChRCC) mostró que la monosomía era la aberración más frecuente en todos los cromosomas analizados 1, 2, 5, 10, 13, 17 y 21. Un caso de carcinoma de células renales cromófobo (CCRc) hialino tenía una mutación en la parte distal del exón 3 del gen VHL. La ausencia de trastornos genéticos en la OI habitual es un resultado común, pero hemos establecido la ausencia de trastornos genéticos incluso en variantes raras. Varias alteraciones genéticas detectadas en esporádica HOCT renal demuestran que es una entidad separada, no una variante de ChRCC, mientras que PMChRCC es una variante poco común de ChRCC. O-PRCC es un subtipo de carcinoma papilar de células renales.


Subject(s)
Humans , Carcinoma, Renal Cell/genetics , Adenoma, Oxyphilic/genetics , Neoplasms, Glandular and Epithelial/genetics , Kidney Neoplasms/genetics , Polymerase Chain Reaction , Retrospective Studies , In Situ Hybridization, Fluorescence
11.
Chinese Journal of Medical Genetics ; (6): 652-655, 2021.
Article in Chinese | WPRIM | ID: wpr-888367

ABSTRACT

OBJECTIVE@#To analyze the expression of microRNA-106a(miR-106a) in renal cell carcinoma (RCC) and its correlation with clinicopathological characteristics and prognosis of patients.@*METHODS@#Serum samples of 64 patients with newly diagnosed RCC were collected as the study group, and serum samples of 40 healthy individuals were used as the control group. Real-time fluorescence quantitative PCR was used to determine the expression level of miR-106a in each group. The correlation between miR-106a expression and clinicopathological characteristics of the patients was studied with single factor analysis and multiple Logistic regression model. Kaplan-Meier survival curve was used to analyze its correlation with the prognosis of patients.@*RESULTS@#Before surgery, compared with the control group (1.17± 0.58), RCC patients with high- (9.15± 0.96) and low-expression(3.45± 0.37) had increased expression of miR-106a. Postoperatively, the expression level of miR-106a in both groups of patients decreased to 1.53± 0.18 and 1.75± 0.21, respectively. The area under the curve (AUC) of the diagnostic value of serum miR-106a for RCC was 0.782 (95% CI: 0.661-0.902). With an optimal cutoff value of 0.531, the sensitivity was 78.10% and the specificity was 75.00%. Serum miR-106a level of RCC patients with TNM stage T3 or T4, clinical stage II or III, lymph node metastasis, and recurrence were significantly increased. The high expression of serum miR-106a in RCC patients has an independent relationship with the tumor TNM stage and lymph node metastasis. Of the 64 follow-up patients, 4 were lost and 30 had died. Among them, the median survival time of patients in the miR-106a high expression group was 30 months, which was significantly shorter than that of the low expression group (52 months).@*CONCLUSION@#The serum level of miR-106a is elevated in RCC patients, and may be used as a molecular marker for the diagnosis of RCC. High serum expression of miR-106a is an independent predictor for tumor TNM stage and lymph node metastasis, as well as an independent predictor for poor prognosis of RCC patients.


Subject(s)
Humans , Biomarkers, Tumor/genetics , Carcinoma, Renal Cell/genetics , Gene Expression Regulation, Neoplastic , Kidney Neoplasms/genetics , MicroRNAs/genetics , Neoplasm Recurrence, Local , Prognosis
12.
Journal of Peking University(Health Sciences) ; (6): 640-646, 2021.
Article in Chinese | WPRIM | ID: wpr-942229

ABSTRACT

OBJECTIVE@#To investigate the clinicopathological features and prognosis of fumarate hydratase deficient renal cell carcinoma (FH-RCC).@*METHODS@#Immunohistochemical (IHC) staining was used to detect the expression of fumarate hydratase (FH) in tumor tissues of 109 different types of renal cell carcinoma (RCC) patients aged 60 years and younger from the Department of Urology of Peking University First Hospital from January 2013 to December 2019. The clinicopathological data and prognosis of FH-RCC were collected and analyzed.@*RESULTS@#There were eleven patients with FH-negative expression. Seven were males and four females. The age of onset ranged 16-53 years (mean age: 36.7 years), and four female patients all had a history of uterine leiomyoma. Only one first-degree relative of one patient had renal cancer, and none of the patients had a history or family history of cutaneous leiomyomas. The diameter of the tumor was 2.1-12.0 cm (mean: 8.83 cm). Renal sinus or perirenal fat invasion was seen in nine cases, tumor thrombus in renal vein or inferior vena cava in six cases, lymph node metastasis in seven cases, adrenal gland invasion in four cases and splenic capsule invasion in one case. The cases were initially diagnosed as type Ⅱ papillary RCC (7/49, 14.3%), collecting duct carcinoma (2/9, 22.2%) and unclassified RCC (2/51, 3.9%). Tumor histopathology mostly showed a mixture of different structures, such as papillary, tubular cystic, solid, and so on. The most common histological structures were papillary (9/11, 81.8%) and tubular (8/11, 72.7%). Three cases had sarcomatoid areas. At least focal eosinophilic nucleolus (WHO/grades Ⅲ-Ⅳ) and perinuclear halo could be seen in all cases. Immunohistochemical (IHC) stains of most tumors were negative for CA9, CD10 and CK7. The results of fluorescence in situ hybridization (FISH) showed that there was no translocation or amplification of TFE3 gene in two cases with TFE3 IHC expression. All the patients were followed up for 11-82 months. Mean survival was 24 months. Five cases died of distant metastasis 9-31 months after operation (mean: 19 months), and five of the six patients alive had became metastatic.@*CONCLUSION@#Morphologically, FH-RCC overlaps with many types cell RCC. A mixture of papillary and tubular cystic arrangement is the most common growth pattern of FH-RCC. At least focally large and obvious eosinophilic nucleoli are an important histological feature of this tumor. The negative expression of FH can help to confirm the diagnosis. Young female RCC patients with uterine leiomyomas should be suspected of FH-RCC. Some FH-RCC cases lack clinical evidence. The suspicion raised by pathologists based on histological characteristics is often the key step to further genetic testing and the final diagnosis of the tumor.


Subject(s)
Adolescent , Adult , Female , Humans , Male , Middle Aged , Young Adult , Biomarkers, Tumor , Carcinoma, Renal Cell/genetics , Fumarate Hydratase/genetics , In Situ Hybridization, Fluorescence , Kidney Neoplasms/genetics , Prognosis
13.
Int. braz. j. urol ; 43(2): 192-201, Mar.-Apr. 2017. tab, graf
Article in English | LILACS | ID: biblio-840816

ABSTRACT

ABSTRACT Cancer related to hereditary syndromes corresponds to approximately 5-10% of all tumors. Among those from the genitourinary system, many tumors had been identified to be related to genetic syndromes in the last years with the advent of new molecular genetic tests. New entities were described or better characterized, especially in kidney cancer such as hereditary leiomyomatosis renal cell carcinoma (HLRCC), succinate dehydrogenase kidney cancer (SDH-RCC), and more recently BAP1 germline mutation related RCC. Among tumors from the bladder or renal pelvis, some studies had reinforced the role of germline mutations in mismatch repair (MMR) genes, especially in young patients. In prostate adenocarcinoma, besides mutations in BRCA1 and BRCA2 genes that are known to increase the incidence of high-risk cancer in young patients, new studies have shown mutation in other gene such as HOXB13 and also polymorphisms in MYC, MSMB, KLK2 and KLK3 that can be related to hereditary prostate cancer. Finally, tumors from testis that showed an increased in 8 - 10-fold in siblings and 4 - 6-fold in sons of germ cell tumors (TGCT) patients, have been related to alteration in X chromosome. Also genome wide association studies GWAS pointed new genes that can also be related to increase of this susceptibility.


Subject(s)
Humans , Male , Female , Neoplastic Syndromes, Hereditary/genetics , Urologic Neoplasms/genetics , Carcinoma, Renal Cell/genetics , Risk Factors , Germ-Line Mutation , Genetic Predisposition to Disease , Kidney Neoplasms/genetics
14.
Rev. bras. parasitol. vet ; 23(4): 509-515, Oct-Dec/2014. tab, graf
Article in English | LILACS | ID: lil-731257

ABSTRACT

Different parasites that commonly occur concomitantly can influence one another, sometimes with unpredictable effects. We evaluated pathological aspects of dogs naturally co-infected with Leishmania infantum and Ehrlichia canis. The health status of the dogs was investigated based on histopathological, hematological and biochemical analyses of 21 animals infected solely with L. infantum and 22 dogs co- infected with L. infantum and E. canis. The skin of both groups showed chronic, predominantly lymphohistioplasmacytic inflammatory reaction. The plasmacytosis in the lymphoid tissues was likely related with the hypergammaglobulinemia detected in all the dogs. The disorganization of extracellular matrix found in the reticular dermis of the inguinal region and ear, characterized by the substitution of thick collagen fibers for thin fibers, was attributed to the degree of inflammatory reaction, irrespective of the presence of parasites. In addition, the histopathological analysis revealed that twice as many dogs in the co-infected group presented Leishmania amastigotes in the ear skin than those infected solely with Leishmania, increasing the possibility of becoming infected through sand fly vectors. Our findings highlight the fact that the health of dogs infected concomitantly with L. infantum and E. canis is severely compromised due to their high levels of total plasma protein, globulins, alkaline phosphatase and creatine kinase, and severe anemia.


A infecção simultânea por parasitas de diferentes espécies pode resultar em alterações imprevisíveis. O presente estudo avaliou a patologia de cães naturalmente coinfectados por Leishmania infantum e Ehrlichia canis. A saúde dos cães foi investigada pelas análises histopatológicas, hematológicas e bioquímicas de 21 cães infectados somente por L. infantum e 22 cães coinfectados por L. infantum e E. canis. Observou-se uma reação inflamatória crônica, predominantemente linfohistioplasmocítica, na pele dos dois grupos. A plasmocitose, encontrada nos tecidos linfóides, provavelmente estava relacionada com a hipergamaglobulinemia observada em todos os cães amostrados. A desorganização da matriz extracelular da derme da região inguinal e da orelha, demonstrada pela substituição das fibras de colágeno espessas por fibras finas, foi relacionada com o grau de reação inflamatória, independente da presença de parasitas. Ainda, observamos duas vezes mais animais do grupo coinfectado apresentando formas amastigotas na pele de orelha pela histopatologia comparado ao número de cães infectados apenas por Leishmania, tornando-os desta forma mais infectivos aos vetores. Nossos resultados ressaltam que a saúde de cães coinfectados estava severamente comprometida devido aos altos níveis de proteína plasmática total, globulinas, fosfatase alcalina, creatina quinase e anemia acentuada.


Subject(s)
Humans , Cyclin D1/genetics , Genes, Tumor Suppressor , Ligases/genetics , Tumor Suppressor Proteins , Ubiquitin-Protein Ligases , von Hippel-Lindau Disease/genetics , Blotting, Northern , Carcinoma, Renal Cell/genetics , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Kidney Neoplasms/genetics , Oligonucleotide Array Sequence Analysis , Oxygen/pharmacology , Transfection , Tumor Cells, Cultured , Von Hippel-Lindau Tumor Suppressor Protein
15.
An. bras. dermatol ; 88(6,supl.1): 124-127, Nov-Dec/2013. graf
Article in English | LILACS | ID: lil-696802

ABSTRACT

A 34-year-old woman with no known medical history was evaluated for multiple painful brown nodules and papules on the anterior aspect of the trunk. She mentioned a history of similar cutaneous findings on her mother. Biopsies of three lesions revealed piloleiomyomata. Renal and adrenal ultrasound revealed an isolated simple cortical cyst, and pelvic and endovaginal ultrasound revealed two uterine myomata. The clinical diagnosis of hereditary leiomyomatosis and renal cell cancer was corroborated by the identification of a heterozygous variant on exon 5 of the fumarate hydratase gene (c.578C>T p.T193I). Identification of the tumor piloleiomyoma should alert the dermatologist to this rare genodermatosis, which is associated with an increased risk of renal cell tumors, demanding multidisciplinary follow-up, and personal and family counseling.


Uma mulher de 34 anos sem antecedentes patológicos conhecidos foi avaliada por apresentar múltiplos nódulos e pápulas castanhos, dolorosos, na face anterior do tronco. Referia história de achados cutâneos semelhantes na sua mãe. As biópsias de três lesões revelaram piloleiomiomas. As ecografias renal e suprarenal identificaram apenas cisto renal cortical simples, e as ecografias endovaginal e pélvica, dois miomas uterinos. O diagnóstico clínico de leiomiomatose herediária e câncer de células renais foi corroborado pela identificação de variante heterozigota no exon 5 do gene da Fumarato hidratase (c.578C>T p.T193I). O piloleimomioma é um tumor cuja identificação deve alertar o dermatologista para esta rara genodermatose, associada a um risco aumentado de tumores de células renais, exigindo seguimento multidisciplinar e aconselhamento pessoal e familiar.


Subject(s)
Adult , Female , Humans , Middle Aged , Carcinoma, Renal Cell/pathology , Kidney Neoplasms/pathology , Leiomyomatosis/pathology , Skin Neoplasms/pathology , Skin/pathology , Uterine Neoplasms/pathology , Biopsy , Carcinoma, Renal Cell/genetics , Fumarate Hydratase/genetics , Genetic Predisposition to Disease , Kidney Neoplasms/genetics , Leiomyomatosis/genetics , Skin Neoplasms/genetics , Uterine Neoplasms/genetics
16.
Rev. Col. Bras. Cir ; 40(6): 471-475, nov.-dez. 2013. ilus, graf, tab
Article in Portuguese | LILACS | ID: lil-702656

ABSTRACT

OBJETIVO: avaliar a frequência de deleção do gene PTEN no carcinoma de células renais e o impacto da deleção nas taxas de sobrevida global e livre de doença. MÉTODOS: foram analisados 110 pacientes portadores de carcinoma de células renais submetidos à nefrectomia radical ou parcial entre os anos de 1980 e 2007. Em 53 casos foi possível a análise do gene PTEN pelo método de hibridização in situ fluorescente através da técnica de "tissue microarray". Para a análise estatística, os pacientes foram classificados em dois grupos, de acordo com a presença ou ausência de deleção. RESULTADOS: o tempo médio de seguimento foi de 41,9 meses. Deleção hemizigótica foi identificada em 18 pacientes (33,9%), ao passo que deleção homozigótica esteve presente em três (5,6%). Em aproximadamente 40% dos casos analisados havia deleção. Monossomia e trissomia foram detectadas, respectivamente, em nove (17%) e dois pacientes (3,8%). Em 21 pacientes (39,6%), a análise por hibridização in situ do gene PTEN foi normal. Não houve diferenças estatisticamente significativas nas taxas de sobrevida global (p=0,468) e livre de doença (p=0,344) entre os pacientes portadores ou não de deleção. Foram fatores independentes para a sobrevida global: estádio clínico TNM, sintomatologia ao diagnóstico, alto grau de Fuhrmann performance status (Ecog) e recorrência tumoral. A livre de doença foi influenciada unicamente pelo estádio clínico TNM. CONCLUSÃO: deleção do gene PTEN no CCR foi detectada com frequência de aproximadamente 40% e sua presença não foi determinante de menores taxas de sobrevida, permanecendo os fatores prognósticos tradicionais como determinantes da evolução dos pacientes.


OBJECTIVE: To evaluate the frequency of deletion of the PTEN gene in renal cell carcinoma (RCC) and its impact on the rates of overall and disease-free survival. METHODS: We analyzed 110 patients with renal cell carcinoma who underwent radical or partial nephrectomy between 1980 and 2007. In 53 cases it was possible to analyse the PTEN gene by the method of fluorescent in situ hybridization using the technique of tissue microarray. For statistical analysis, patients were classified in two groups according to the presence or absence of the deletion. RESULTS: The mean follow-up time was 41.9 months. Hemizygous deletion was detected in 18 patients (33.9%), while the homozygous one was present in three (5.6%). Deletion was present in approximately 40% of the analyzed cases. Monosomy and trisomy were detected in nine (17%) and two patients (3.8%), respectively. In 21 patients (39.6%) the analysis of the PTEN gene by in situ hybridization was normal. There were no statistically significant differences in overall (p = 0.468) and disease-free (p = 0.344) survival rates between patients with or without deletion. Factors which were independent for overall survival: TNM clinical stage, symptoms at diagnosis, high Fuhrmann grade, performance status (ECoG) and tumor recurrence. Disease-free survival was influenced only by the clinical TNM stage. CONCLUSION: Deletion of the PTEN gene in RCC was detected with a frequency of approximately 40% and its presence was not determinant of lower survival rates, the traditional prognostic factors remaining as determinants of outcome.


Subject(s)
Female , Humans , Male , Middle Aged , Carcinoma, Renal Cell/genetics , Gene Deletion , Kidney Neoplasms/genetics , PTEN Phosphohydrolase/genetics , Carcinoma, Renal Cell/mortality , Disease-Free Survival , In Situ Hybridization, Fluorescence , Kidney Neoplasms/mortality , Retrospective Studies , Survival Rate , Tissue Array Analysis
17.
Clinics ; 68(6): 825-833, jun. 2013. graf
Article in English | LILACS | ID: lil-676926

ABSTRACT

OBJECTIVES: MiRNAs are intrinsic RNAs that interfere with protein translation. Few studies on the synergistic effects of miRNAs have been reported. Both miR-424 and miR-381 have been individually reported to be involved in carcinogenesis. They share a common putative target, WEE1, which is described as an inhibitor of G2/M progression. Here, we studied the synergistic effects of miR-424 and miR-381 on renal cancer cells. METHODS: The viability of 786-O cells was analyzed after transfection with either a combination of miR-424 and miR-381 or each miRNA alone. We investigated cell cycle progression and apoptosis with flow cytometry. To confirm apoptosis and the abrogation of G2/M arrest, we determined the level of pHH3, which is an indicator of mitosis, and caspase-3/7 activity. The expression levels of WEE1, Cdc25, γH2AX, and Cdc2 were manipulated to investigate the roles of these proteins in the miRNA-induced anti-tumor effects. To verify that WEE1 was a direct target of both miR-424 and miR-381, we performed a dual luciferase reporter assay. RESULTS: We showed that the combination of these miRNAs synergistically inhibited proliferation, abrogated G2/M arrest, and induced apoptosis. This combination led to Cdc2 activation through WEE1 inhibition. This regulation was more effective when cells were treated with both miRNAs than with either miRNA alone, indicating synergy between these miRNAs. WEE1 was verified to be a direct target of each miRNA according to the luciferase reporter assay. CONCLUSIONS: These data clearly demonstrate that these two miRNAs might synergistically act as novel modulators of tumorigenesis by down-regulating WEE1 expression in renal cell cancer cells. .


Subject(s)
Humans , Carcinoma, Renal Cell/genetics , Cell Cycle Proteins/metabolism , Cyclin B/metabolism , Kidney Neoplasms/genetics , MicroRNAs/pharmacology , Nuclear Proteins/metabolism , Protein-Tyrosine Kinases/metabolism , Blotting, Western , Cell Line, Tumor , Cell Physiological Phenomena , Cell Transformation, Neoplastic , Down-Regulation , Flow Cytometry , Gene Expression Regulation, Neoplastic , MicroRNAs/metabolism , Real-Time Polymerase Chain Reaction , Time Factors , Up-Regulation
18.
São Paulo; s.n; 2013. 101 p. ilus, tab.
Thesis in Portuguese | LILACS, Inca | ID: lil-751064

ABSTRACT

O objetivo deste estudo foi avaliar o papel prognóstico das expressões proteica e gênica do PBRM1 e demais variáveis clínicas e anátomo-patológicas em pacientes portadores de carcinoma de células renais (CCR). Os prontuários de 220 pacientes tratados no Núcleo de Urologia do A.C. Camargo Cancer Center foram revisados. Todos os pacientes foram submetidos a tratamento cirúrgico de 1992 a 2009. Dois artigos foram formulados e aceitos para publicação. O primeiro avaliou o impacto prognóstico da presença de invasão de veia renal e invasão de gordura perirrenal em 46 pacientes de diversos tipos histológicos em estádio pT3a. Pacientes com presença concomitante de ambos os parâmetros apresentaram maior probabilidade de morte por câncer (RR=2,6; p = 0,04) e progressão da doença (RR=2,5; p = 0,04) do que aqueles com qualquer um deles isoladamente. O segundo artigo avaliou a expressão tecidual de PBRM1 em 112 portadores de CCR do tipo células claras (CCRCC) através de imuno-histoquímica (IHQ) em lâmina de tissue microarray (TMA) e real-time reverse transcriptase polymerase chain reaction (qRT-PCR). A análise IHQ mostrou que 34 (30,4%) pacientes não apresentaram expressão de PBRM1 enquanto 78 (69,6%) pacientes mostraram expressão positiva do marcador. A expressão proteica de PBRM1 se associou ao estádio clínico (p <0,001), estádio patológico (p < 0,001), metástase linfonodal (p = 0,035) e diâmetro tumoral (p = 0,002). O padrão de expressão transcricional foi avaliado em tecido congelado de 44 pacientes através de qRT-PCR. Houve associação com o estádio clínico (p = 0,023), invasão de gordura perirrenal (p = 0,008) e invasão linfo-vascular (p = 0,042). O padrão de expressão de PBRM1 influenciou as taxas de recorrência tumoral e morte específica na análise univariada. As taxas de sobrevida câncer específica e de sobrevida livre de recorrência em pacientes com expressão positiva e negativa de PBRM1 foram 89,7% vs. 70,6% (p = 0,017) e 87,3% vs. 66,7% (p = 0,048)...


The aim of this study was to evaluate the prognostic role of gene and protein expression of PBRM1 and other clinical and pathological parameters in patients with renal cell carcinoma (RCC). The charts of 220 patients treated at the Department of Urology of the AC Camargo Cancer Center were reviewed. All patients underwent surgical treatment from 1992 to 2009. Two studies were formulated and accepted for publication. The first study assessed the prognostic impact of the presence of renal vein invasion and fat invasion in 46 patients of different histological types in pT3a stage. Patients with concomitant presence of both parameters showed a higher probability of cancer death (HR = 2.6, p = 0.04) and disease progression (HR = 2.5, p = 0.04) than those with any one of them alone. The second study evaluated PBRM1 tissue expression in 112 patients with clear cell renal cell carcinoma (CCRCC). A single pathologist reviewed all cases to effect a uniform reclassification and determined the most representative tumor areas for construction of a tissue microarray. In addition, mRNA expression of PBRM1 was analyzed by qRT-PCR. The protein expression of PBRM1 was associated with tumor stage (p<0.001), clinical stage (p<0.001), pN stage (p=0.035) and tumor size (p=0.002). PBRM1 mRNA expression was associated with clinical stage (p=0.023), perinephric fat invasion (p=0.008) and lymphovascular invasion (p=0.042). PBRM1 significantly influenced tumor recurrence and tumor related death. Disease specific survival (DSS) rates for patients whose specimens showed positive and negative PBRM1 expression was 89.7% and 70.6%, respectively (p=0.017). Recurrence free survival (RFS) rates in patients with positive and negative expression of PBRM1 were 87.3% and 66.7%, respectively (p=0.048). However, the expression pattern of PBRM1 did not remain as an independent predictor of neither DSS nor RFS in multivariate analysis...


Subject(s)
Humans , Male , Carcinoma, Renal Cell/diagnosis , Carcinoma, Renal Cell/genetics , Gene Expression , Genes, Tumor Suppressor , Kidney Neoplasms , Prognosis
19.
Int. braz. j. urol ; 36(4): 410-419, July-Aug. 2010. graf, tab
Article in English | LILACS | ID: lil-562107

ABSTRACT

PURPOSE: The determination of prognosis in patients with renal cell carcinoma (RCC) is based, classically, on stage and histopathological aspects. The metastatic disease develops in one third of patients after surgery, even in localized tumors. There are few options for treating those patients, and even the new target designed drugs have shown low rates of success in controlling disease progression. Few studies used high throughput genomic analysis in renal cell carcinoma for determination of prognosis. This study is focused on the identification of gene expression signatures in tissues of low-risk, high-risk and metastatic RCC clear cell type (RCC-CCT). MATERIALS AND METHODS: We analyzed the expression of approximately 55,000 distinct transcripts using the Whole Genome microarray platform hybridized with RNA extracted from 19 patients submitted to surgery to treat RCC-CCT with different clinical outcomes. They were divided into three groups (1) low risk, characterized by pT1, Fuhrman grade 1 or 2, no microvascular invasion RCC; (2) high risk, pT2-3, Fuhrman grade 3 or 4 with, necrosis and microvascular invasion present and (3) metastatic RCC-CCT. Normal renal tissue was used as control. RESULTS: After comparison of differentially expressed genes among low-risk, high-risk and metastatic groups, we identified a group of common genes characterizing metastatic disease. Among them Interleukin-8 and Heat shock protein 70 were over-expressed in metastasis and validated by real-time polymerase chain reaction. CONCLUSION: These findings can be used as a starting point to generate molecular markers of RCC-CCT as well as a target for the development of innovative therapies.


Subject(s)
Adult , Aged , Female , Humans , Male , Middle Aged , Carcinoma, Renal Cell/genetics , Gene Expression Profiling , Gene Expression Regulation, Neoplastic/genetics , Kidney Neoplasms/genetics , Carcinoma, Renal Cell/pathology , Disease Progression , Heat-Shock Proteins , Kidney Neoplasms/pathology , Microarray Analysis , Neoplasm Staging , Biomarkers, Tumor/genetics
20.
Int. braz. j. urol ; 34(4): 492-502, July-Aug. 2008. ilus, graf
Article in English | LILACS | ID: lil-493670

ABSTRACT

PURPOSE: Renal cell carcinoma (RCC) is the most lethal among the common urologic malignancies, comprising 3 percent of all human neoplasias; approximately 40 percent of patients eventually die of cancer progression. One third of patients who present with metastatic disease and up to 40 percent treated for localized disease generally experience recurrence. RCCs are characterized by high resistance to chemo-, radio- and immunotherapy. We recently discovered an endogenous enzymatic activity, which is particularly expressed in tumorigenic cell, endogenous non-telomerase reverse transcriptase (RT) of retrotrasposon / retroviral origin, as a specific target to induce proliferation arrest in a number of human carcinogenesis in vitro culture cell lines. METHODS: To address this possibility, we have employed RCC primary cell culture testing pharmacological inhibition, in vitro, by two characterized non nucleosidic RT inhibitors, nevirapine and efavirenz; next, we assessed morphological effects and analyzed putative modulation on gene expression profile. RESULTS: Both treatments reduced cell proliferation rate and induced morphological differentiation and gene expression reprogramming in different RCC analyzed tumor biomarkers. CONCLUSION: In this study we describe a new potential therapeutic approach to obtain considerable future benefits in renal carcinoma cure and attempt to establish a new possible pharmacological therapy based on oral drugs administration in renal RCC treatment.


Subject(s)
Humans , Antineoplastic Agents/therapeutic use , Benzoxazines/therapeutic use , Carcinoma, Renal Cell/drug therapy , Kidney Neoplasms/drug therapy , Nevirapine/therapeutic use , Reverse Transcriptase Inhibitors/therapeutic use , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/pathology , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor/methods , Gene Expression Regulation, Neoplastic/drug effects , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Reverse Transcriptase Polymerase Chain Reaction , RNA , Tumor Cells, Cultured
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