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1.
N Engl J Med ; 382(9): 835-844, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-32101665

RESUMO

Mutations in VHL, which encodes von Hippel-Lindau tumor suppressor (VHL), are associated with divergent diseases. We describe a patient with marked erythrocytosis and prominent mitochondrial alterations associated with a severe germline VHL deficiency due to homozygosity for a novel synonymous mutation (c.222C→A, p.V74V). The condition is characterized by early systemic onset and differs from Chuvash polycythemia (c.598C→T) in that it is associated with a strongly reduced growth rate, persistent hypoglycemia, and limited exercise capacity. We report changes in gene expression that reprogram carbohydrate and lipid metabolism, impair muscle mitochondrial respiratory function, and uncouple oxygen consumption from ATP production. Moreover, we identified unusual intermitochondrial connecting ducts. Our findings add unexpected information on the importance of the VHL-hypoxia-inducible factor (HIF) axis to human phenotypes. (Funded by Associazione Italiana Ricerca sul Cancro and others.).


Assuntos
Mutação em Linhagem Germinativa , Transtornos do Crescimento/genética , Hipoglicemia/genética , Fator 1 Induzível por Hipóxia/deficiência , Mitocôndrias/metabolismo , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Expressão Gênica , Crescimento/genética , Humanos , Masculino , Metaboloma/genética , Metaboloma/fisiologia , Síndrome , Adulto Jovem
2.
Nat Med ; 25(12): 1938-1947, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31792461

RESUMO

B-cell lymphoma extra large (BCL-XL) is a well-validated cancer target. However, the on-target and dose-limiting thrombocytopenia limits the use of BCL-XL inhibitors, such as ABT263, as safe and effective anticancer agents. To reduce the toxicity of ABT263, we converted it into DT2216, a BCL-XL proteolysis-targeting chimera (PROTAC), that targets BCL-XL to the Von Hippel-Lindau (VHL) E3 ligase for degradation. We found that DT2216 was more potent against various BCL-XL-dependent leukemia and cancer cells but considerably less toxic to platelets than ABT263 in vitro because VHL is poorly expressed in platelets. In vivo, DT2216 effectively inhibits the growth of several xenograft tumors as a single agent or in combination with other chemotherapeutic agents, without causing appreciable thrombocytopenia. These findings demonstrate the potential to use PROTAC technology to reduce on-target drug toxicities and rescue the therapeutic potential of previously undruggable targets. Furthermore, DT2216 may be developed as a safe first-in-class anticancer agent targeting BCL-XL.


Assuntos
Compostos de Anilina/farmacologia , Sulfonamidas/farmacologia , Trombocitopenia/tratamento farmacológico , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Proteína bcl-X/genética , Compostos de Anilina/química , Animais , Antineoplásicos/farmacologia , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Xenoenxertos , Humanos , Camundongos , Proteólise , Sulfonamidas/química , Trombocitopenia/genética , Trombocitopenia/patologia , Proteína bcl-X/antagonistas & inibidores
3.
BMC Med Genet ; 20(1): 194, 2019 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-31823746

RESUMO

BACKGROUND: Von Hippel-Lindau (VHL) syndrome is a familial autosomal dominant hereditary neoplastic disease caused by mutations in the VHL gene. Approximately 503 kinds of VHL gene mutations have been reported. Different types of mutations manifest various clinical phenotypes, from benign to malignant tumours or coexisting cysts. Thus, a gene mutation test is essential in the diagnosis of VHL syndrome. CASE PRESENTATION: We reported two cases in which a novel mutation site in the c530-536delGACTGGA region in exon 3 of the VHL gene resulted in the development of VHL syndrome. According to the ACMG guidelines, this variation is pathogenic and consistent with autosomal dominant inheritance. This variation has not been reported anywhere in the databases or literature. CONCLUSION: This report will add a new mutation site to VHL gene databases. The newly added gene mutation and its associated clinical phenotypes will help improve the accuracy of VHL diagnosis and benefit the community of VHL gene mutation carriers.


Assuntos
Mutação , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Doença de von Hippel-Lindau/genética , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
4.
Exp Suppl ; 111: 129-147, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31588531

RESUMO

Pheochromocytomas (Pheo) and paragangliomas (PGL) are rare tumors originating from catecholamine-producing chromaffin cells. They occur approximately in 0.1% of patients affected with hypertonia. Pheo/PGL may manifest itself at any age; in 10% of the patients, the disease is bilateral, and also in 10% it occurs outside of the adrenal medulla. From a genetic aspect, a considerable proportion of these tumors represents a prototype for an autosomal dominantly inherited syndrome with incomplete penetrance. In addition, to date more than 15 genes have been identified representing genetic susceptibility for Pheo/PGL and accounting for 40% of all cases. In general, in familiar cases, the tumor manifests at younger age, and they are often occurring as multiplex tumors. Permanent recovery can be achieved with an early diagnosis and with a successful surgical removal of the tumor tissue. On the other hand, undiagnosed, hormonally active Pheos may lead to severe, or even lethal, consequences. This chapter will summarize our recent knowledge about the genetics of Pheo/PGL, focusing on tumor syndromes where Pheo/PGLs are among the main manifestations.


Assuntos
Neurofibromina 1/genética , Feocromocitoma/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Neoplasias das Glândulas Suprarrenais/genética , Catecolaminas , Humanos , Paraganglioma/genética
6.
Int J Oncol ; 55(2): 371-390, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31268155

RESUMO

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell cancer, characterized by the highest mortality rate among other RCC subtypes due to the occurrence of metastasis and drug resistance following surgery. The Von Hippel­Lindau tumor suppressor (VHL)­hypoxia­inducible factor 1 subunit α (HIF1A)/hypoxia­inducible factor 2α (HIF2A)­vascular endothelial growth factor A (VEGFA) protein axis is involved in the development and progression of ccRCC, whereas sunitinib, a tyrosine kinase inhibitor, blocks the binding of VEGFA to its receptor. The aim of the present study was to examine the possible association of the gene expression of VHL, HIF1A, HIF2A, VEGFA and tumor protein P53 (P53) in cancer tissue with the outcome of ccRCC patients who were treated with sunitinib as first­line therapy following nephrectomy. A total of 36 ccRCC patients were enrolled, 11 of whom were administered sunitinib post­operatively. Tumor and control samples were collected, and mRNA and protein levels were assessed by reverse transcription­quantitative polymerase chain reaction and western blot analysis, respectively. High mRNA and protein expression levels of HIF2A and VEGFA were found to be associated with shorter overall survival (OS) and progression­free survival (PFS) rates, as well as with unfavorable risk factors of cancer recurrence and mortality. Resistance to sunitinib was also observed; the OS and PFS rates were shorter (median OS and PFS: 12 and 6 months, respectively, vs. undetermined). Sunitinib resistance was associated with high HIF2A and VEGFA protein levels (b=0.57 and b=0.69 for OS and PFS, respectively; P<0.001). Taken together, the findings of this study suggest that the protein levels of HIF2A and VEGFA in tumor tissue may serve as independent prognostic factors in ccRCC. ccRCC patients with increased intratumoral HIF2A and VEGFA protein levels, and unaltered VHL protein levels, are not likely to benefit from sunitinib treatment following nephrectomy; however, this hypothesis requires verification by large­scale replication studies.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinoma de Células Renais/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Sunitinibe/uso terapêutico , Proteína Supressora de Tumor p53/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/metabolismo , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Taxa de Sobrevida , Proteína Supressora de Tumor p53/genética , Fator A de Crescimento do Endotélio Vascular/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genética
7.
Nat Commun ; 10(1): 3293, 2019 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-31337753

RESUMO

Duplication of ancestral hypoxia-inducible factor (HIF)α coincided with the evolution of vertebrate species. Paralogs HIF1α and HIF2α are the most well-known factors for modulating the cellular transcriptional profile following hypoxia. However, how the processes of natural selection acted upon the coding region of these two genes to optimize the cellular response to hypoxia during evolution remains unclear. A key negative regulator of HIFα is von Hippel-Lindau (VHL) tumour suppressor protein. Here we show that evolutionarily-relevant substitutions can modulate a secondary contact between HIF1α Met561 and VHL Phe91. Notably, HIF1α binds more tightly than HIF2α to VHL due to a conserved Met to Thr substitution observed in the vertebrate lineage. Similarly, substitution of VHL Phe91 with Tyr, as seen in invertebrate species, decreases VHL affinity for both HIF1α and HIF2α. We propose that vertebrate evolution involved a more complex hypoxia response with fine-tuned divergence of VHL affinity for HIF1α and HIF2α.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/química , Evolução Biológica , Duplicação Gênica , Subunidade alfa do Fator 1 Induzível por Hipóxia/química , Proteína Supressora de Tumor Von Hippel-Lindau/química , Substituição de Aminoácidos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Evolução Molecular , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Metionina/metabolismo , Oxirredução , Oxigênio/metabolismo , Seleção Genética , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo
8.
BMC Cancer ; 19(1): 619, 2019 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-31234811

RESUMO

BACKGROUND: Succinate dehydrogenase (SDH) loss and mastermind-like 3 (MAML3) translocation are two clinically important genetic alterations that correlate with increased rates of metastasis in subtypes of human paraganglioma and pheochromocytoma (PPGL) neuroendocrine tumors. Although hypotheses propose that succinate accumulation after SDH loss poisons dioxygenases and activates pseudohypoxia and epigenomic hypermethylation, it remains unclear whether these mechanisms account for oncogenic transcriptional patterns. Additionally, MAML3 translocation has recently been identified as a genetic alteration in PPGL, but is poorly understood. We hypothesize that a key to understanding tumorigenesis driven by these genetic alterations is identification of the transcription factors responsible for the observed oncogenic transcriptional changes. METHODS: We leverage publicly-available human tumor gene expression profiling experiments (N = 179) to reconstruct a PPGL tumor-specific transcriptional network. We subsequently use the inferred transcriptional network to perform master regulator analyses nominating transcription factors predicted to control oncogenic transcription in specific PPGL molecular subtypes. Results are validated by analysis of an independent collection of PPGL tumor specimens (N = 188). We then perform a similar master regulator analysis in SDH-loss mouse embryonic fibroblasts (MEFs) to infer aspects of SDH loss master regulator response conserved across species and tissue types. RESULTS: A small number of master regulator transcription factors are predicted to drive the observed subtype-specific gene expression patterns in SDH loss and MAML3 translocation-positive PPGL. Interestingly, although EPAS1 perturbation is detectible in SDH-loss and VHL-loss tumors, it is by no means the most potent factor driving observed patterns of transcriptional dysregulation. Analysis of conserved SDH-loss master regulators in human tumors and MEFs implicated ZNF423, a known modulator of retinoic acid response in neuroblastoma. Subsequent functional analysis revealed a blunted cell death response to retinoic acid in SDH-loss MEFs and blunted differentiation response in SDH-inhibited SH-SY5Y neuroblastoma cells. CONCLUSIONS: The unbiased analyses presented here nominate specific transcription factors that are likely drivers of oncogenic transcription in PPGL tumors. This information has the potential to be exploited for targeted therapy. Additionally, the observation that SDH loss or inhibition results in blunted retinoic acid response suggests a potential developmental etiology for this tumor subtype.


Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Proteínas de Ligação a DNA/genética , Proteínas de Membrana/genética , Feocromocitoma/genética , Succinato Desidrogenase/genética , Fatores de Transcrição/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Algoritmos , Animais , Células Cultivadas , Proteínas de Ligação a DNA/metabolismo , Bases de Dados Genéticas , Fibroblastos , Humanos , Camundongos/embriologia , Mutação , Fatores de Transcrição/metabolismo , Transcriptoma , Translocação Genética , Tretinoína/metabolismo
9.
Exp Eye Res ; 185: 107690, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31181196

RESUMO

Reduced oxygenation of the outer retina in the aging eye may activate a chronic hypoxic response in RPE and photoreceptor cells and is considered as a risk factor for the development of age-related macular degeneration (AMD). In mice, a chronically active hypoxic response in the retinal pigment epithelium (RPE) or photoreceptors leads to age-dependent retinal degeneration. To identify proteins that may serve as accessible markers for a chronic hypoxic insult to photoreceptors, we used proteomics to determine the protein composition of the vitreous humor in genetically engineered mice that lack the von Hippel-Lindau tumor suppressor (Vhl) specifically in rods (rodΔVhl) or cones (all-coneΔVhl). Absence of VHL leads to constitutively active hypoxia-inducible transcription factors (HIFs) and thus to a molecular response to hypoxia even in normal room air. To discriminate between the consequences of a local response in photoreceptors and systemic hypoxic effects, we also evaluated the vitreous proteome of wild type mice after exposure to acute hypoxia. 1'043 of the identified proteins were common to all three hypoxia models. 257, 258 and 356 proteins were significantly regulated after systemic hypoxia, in rodΔVhl and in all-coneΔVhl mice, respectively, at least at one of the analyzed time points. Only few of the regulated proteins were shared by the models indicating that the vitreous proteome is differentially affected by systemic hypoxia and the rod or cone-specific hypoxic response. Similarly, the distinct protein compositions in the individual genetic models at early and late time points suggest regulated, cell-specific and time-dependent processes. Among the proteins commonly regulated in the genetic models, guanylate binding protein 2 (GBP2) showed elevated levels in the vitreous that were accompanied by increased mRNA expression in the retina of both rodΔVhl and all-coneΔVhl mice. We hypothesize that some of the differentially regulated proteins at early time points may potentially be used as markers for the detection of a chronic hypoxic response of photoreceptors.


Assuntos
Proteínas do Olho/metabolismo , Hipóxia/metabolismo , Células Fotorreceptoras de Vertebrados/metabolismo , Proteoma/metabolismo , Corpo Vítreo/metabolismo , Animais , Doença Crônica , Modelos Animais de Doenças , Eletrorretinografia , Proteínas do Olho/genética , Proteínas de Ligação ao GTP/genética , Regulação da Expressão Gênica/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Camundongos , Camundongos Endogâmicos C57BL , Proteoma/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Proteína Supressora de Tumor Von Hippel-Lindau/genética
10.
Future Oncol ; 15(20): 2337-2348, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31184937

RESUMO

Von Hippel-Lindau (VHL), a tumor suppressor gene, is frequently inactivated in renal cell carcinoma (RCC). It drives tumorigenesis by activating downstream hypoxia responsive genes and proangiogenic factors like VEGFR, and is responsible for the activity of tyrosine kinase inhibitors in RCC. Resistance to VEGFR therapy eventually occurs, in part due to activation of alternative signaling pathways like AXL and MET. Cabozantinib is a potent inhibitor of VEGF, AXL and MET receptors providing rationale for its use in RCC. Cabozantinib has been approved for use in the first- and second-line setting in patients with advanced RCC. This manuscript reviews the preclinical data, pharmacology, clinical efficacy and safety of the use of cabozantinib in RCC.


Assuntos
Anilidas/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Administração Oral , Anilidas/farmacologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Ensaios Clínicos como Assunto , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Mutação , Estadiamento de Neoplasias , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/metabolismo , Piridinas/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/metabolismo , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Resultado do Tratamento , Proteína Supressora de Tumor Von Hippel-Lindau/genética
11.
Eur J Haematol ; 103(2): 124-130, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31132167

RESUMO

OBJECTIVE: To evaluate the spectrum of genetic defects in Indian patients with unexplained erythrocytosis. METHODS: Fifteen families (18 patients) with unexplained erythrocytosis were enrolled after excluding polycythemia vera and secondary erythrocytosis. Focused Sanger sequencing from genomic DNA was performed for EPOR (exon 8), VHL (exons 2-3), EGLN1 (exons 2-5), EPAS1 (exon 12), and all exons of HBB, HBA1, and HBA2 genes. RESULTS: Eleven of the 18 patients (including two pairs of brothers) had Chuvash polycythemia, that is, homozygosity for VHL:c.598C > T (p.Arg200Trp). Three patients (two of whom were brothers) had HBB mutations associated with increased oxygen-affinity hemoglobin-one had a heterozygous Hb McKees Rocks HBB:c.438T > A (p.Tyr146*), and two brothers showed heterozygous Hb Rainier HBB:c.437A > G (p.Tyr146Cys). No pathogenic variants were found in the remaining four cases. CONCLUSION: A gene-by-gene Sanger sequencing approach could determine a genetic basis for erythrocytosis in 11 of the 15 (73%) Indian families, with homozygous VHL:c.598C > T (p.Arg200Trp) being the commonest pathogenic variant. This first study from the Indian subcontinent provides a rationale for analyzing this variant in patients with suspected congenital erythrocytosis from this region. Rare first occurrences of Hb McKees Rocks and Hb Rainier in Indians are also being reported.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Policitemia/diagnóstico , Policitemia/genética , Adolescente , Adulto , Alelos , Substituição de Aminoácidos , Biomarcadores , Criança , Feminino , Estudos de Associação Genética/métodos , Genótipo , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Mutação , Policitemia/congênito , Policitemia/terapia , Avaliação de Sintomas , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Adulto Jovem
12.
PLoS One ; 14(4): e0215725, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31034483

RESUMO

BACKGROUND: Every year more than 800 patients in Denmark are diagnosed with renal cell carcinoma (RCC) of which 3-5% are expected to be part of a hereditary renal cancer syndrome. We performed genetic screening of causative and putative RCC-genes (VHL, FH, FLCN, MET, SDHB, BAP1, MITF, CDKN2B) in RCC-patients suspected of a genetic predisposition. METHODS: The cohort consisted of forty-eight Danish families or individuals with early onset RCC, a family history of RCC, a family history of RCC and melanoma or both RCC- and melanoma diagnosis in the same individual. DNA was extracted from peripheral blood samples or cancer-free formalin-fixed paraffin-embedded tissue. RESULTS: One start codon variant of unknown clinical significance (VUS) (c.3G>A, p.Met1Ile) and one missense VUS (c.631A>C, p.Met211Leu) was found in VHL in a patient with RCC-onset at twenty-eight years of age but without other manifestations or family history of von Hippel-Lindau (VHL). Furthermore, in three families we found three different variants in BAP1, one of which was a novel non-segregating missense variant (c.1502G>A, p.Ser501Asn) in a family with two brothers affected with RCC. Finally, we found the known E318K-substitution in MITF in a RCC-affected member of a family with multiple melanomas. No variants were detected in CDKN2B. CONCLUSION: Although we did find three VUS's in BAP1 in three families and a pathogenic variant in MITF in one family, pathogenic germline variants in BAP1, MITF or CDKN2B are not frequent causes of hereditary renal cancer in Denmark. It is possible that the high prevalence of risk factors such as male gender, smoking and obesity has influenced the development of cancer in the patients of the current study. Further investigations into putative predisposing genes and risk factors of RCC are necessary to enable better prediction of renal cancer risk or presymptomatic testing of relatives in hereditary renal cancer families.


Assuntos
Neoplasias Renais/genética , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/genética , Estudos de Coortes , Inibidor de Quinase Dependente de Ciclina p15/genética , Dinamarca , Feminino , Predisposição Genética para Doença , Testes Genéticos , Variação Genética , Humanos , Masculino , Melanoma/genética , Fator de Transcrição Associado à Microftalmia/genética , Pessoa de Meia-Idade , Mutação , Síndromes Neoplásicas Hereditárias/genética , Linhagem , Fatores de Risco , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genética
13.
Med Sci Monit ; 25: 2959-2965, 2019 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-31007253

RESUMO

BACKGROUND The aim of this study was to investigate the genomic alterations of renal cell carcinoma (RCC) in Chinese patients and to evaluate the correlations between significantly mutated genes and tumor mutation burden (TMB) levels in RCC. MATERIAL AND METHODS Two batch of specimens were collected from patients with RCC. Cohort 1 enrolled 17 RCC patients. Specimens and clinicopathological data were collected and the duration of disease-free survival were evaluated with a follow-up from 2 weeks to longer than 1 year. Cohort 2 collected 70 clear cell RCC (ccRCC) tissues and blood specimens. Next-generation sequencing were used to detect the genomic variations in those specimens in both cohorts and TMB in cohort 2. Clinicopathological features of the 2 cohorts were collected and the χ² test or Fisher's exact test was used for categorical variables stratified by TMB values. RESULTS Our present study demonstrated that the top 3 most frequent aberrated genes in Chinese ccRCC patients were ABCB1, UGT1A1, and VHL, with percentages of 50.00%, 42.86%, and 34.52% respectively. And only 1 gene, which was ABCB1, showed statistically significant difference (P=0.047) stratified by TMB levels. In addition, 6 oncogenic pathways were involved in ccRCC cases in the 2 cohorts. Only 5 out of the 8 most common altered genes of RCC from COSMIC or TCGA databases were detected in our study. CONCLUSIONS The genomic alterations of Chinese RCC patients were different from that in TCGA and COSMIC. No significant genomic alterations were found correlating to TMB levels in ccRCC. Non-silent mutation of VHL may be a predictor for the outcome of ccRCC treated with axitinib.


Assuntos
Carcinoma de Células Renais/genética , Regulação Neoplásica da Expressão Gênica/genética , Genoma Humano/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático/genética , Carcinoma de Células Renais/patologia , China , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Perfilação da Expressão Gênica/métodos , Genômica/métodos , Glucuronosiltransferase/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genética
14.
PLoS Comput Biol ; 15(4): e1006478, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30943211

RESUMO

Familiar cancers represent a privileged point of view for studying the complex cellular events inducing tumor transformation. Von Hippel-Lindau syndrome, a familiar predisposition to develop cancer is a clear example. Here, we present our efforts to decipher the role of von Hippel-Lindau tumor suppressor protein (pVHL) in cancer insurgence. We collected high quality information about both pVHL mutations and interactors to investigate the association between patient phenotypes, mutated protein surface and impaired interactions. Our data suggest that different phenotypes correlate with localized perturbations of the pVHL structure, with specific cell functions associated to different protein surfaces. We propose five different pVHL interfaces to be selectively involved in modulating proteins regulating gene expression, protein homeostasis as well as to address extracellular matrix (ECM) and ciliogenesis associated functions. These data were used to drive molecular docking of pVHL with its interactors and guide Petri net simulations of the most promising alterations. We predict that disruption of pVHL association with certain interactors can trigger tumor transformation, inducing metabolism imbalance and ECM remodeling. Collectively taken, our findings provide novel insights into VHL-associated tumorigenesis. This highly integrated in silico approach may help elucidate novel treatment paradigms for VHL disease.


Assuntos
Mutação , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Carcinoma de Células Renais/genética , Biologia Computacional , Genes Supressores de Tumor , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Neoplasias Renais/genética , Simulação de Acoplamento Molecular , Policitemia/genética , Domínios e Motivos de Interação entre Proteínas , Mapas de Interação de Proteínas , Processamento de Proteína Pós-Traducional , Proteína Supressora de Tumor Von Hippel-Lindau/química , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo , Doença de von Hippel-Lindau/genética , Doença de von Hippel-Lindau/metabolismo
15.
G3 (Bethesda) ; 9(5): 1729-1737, 2019 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-30898898

RESUMO

Trichloroethylene (TCE) and inorganic arsenic (iAs) are environmental contaminants that can target the kidney. Chronic exposure to TCE is associated with increased incidence of renal cell carcinoma, while co-exposure to TCE and iAs likely occurs in exposed human populations, such as those near Superfund sites. In order to better understand the kidney health consequences of TCE and/or iAs exposure, a genetically heterogeneous mouse population derived from FVB/NJ and CAST/EiJ mouse strains and deficient for multidrug resistance genes (Abcb1atm1Bor , Abcb1btm1Bor ) was chronically exposed for 52-weeks to varying concentrations of TCE and iAs. Although no exposure group resulted in primary renal cell tumors, kidneys from exposed mice did have significant increases in histologic and biochemical evidence of renal tubular disease with each toxicant alone and with combined exposure, with males having significantly higher levels of damage. Although no added increase in tubular disease was observed with combination exposure compared to single toxicants, molecular changes in kidneys from mice that had the combined exposure were similar to those previous observed in an embryonic stem cell assay for the P81S TCE-induced renal cell carcinoma mutation in the Von Hippel-Lindau syndrome (VHL) gene. While this model more accurately reflects human exposure conditions, development of primary renal tumors observed in humans following chronic TCE exposure was not reproduced even after inclusion of genetic heterogeneity and co-carcinogenic iAs.


Assuntos
Arsênico/efeitos adversos , Predisposição Genética para Doença , Neoplasias Renais/etiologia , Neoplasias Renais/patologia , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/patologia , Tricloroetileno/efeitos adversos , Animais , Biomarcadores , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Modelos Animais de Doenças , Sinergismo Farmacológico , Exposição Ambiental/efeitos adversos , Estimativa de Kaplan-Meier , Testes de Função Renal , Neoplasias Renais/metabolismo , Neoplasias Renais/mortalidade , Túbulos Renais/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Mutação , Prognóstico , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo
16.
Nat Commun ; 10(1): 1245, 2019 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-30886153

RESUMO

The genetic landscape of clear cell renal cell carcinoma (ccRCC) had been investigated extensively but its evolution patterns remained unclear. Here we analyze the clonal architectures of 473 patients from three different populations. We find that the mutational signatures vary substantially across different populations and evolution stages. The evolution patterns of ccRCC have great inter-patient heterogeneities, with del(3p) being regarded as the common earliest event followed by three early departure points: VHL and PBRM1 mutations, del(14q) and other somatic copy number alterations (SCNAs) including amp(7), del(1p) and del(6q). We identify three prognostic subtypes of ccRCC with distinct clonal architectures and immune infiltrates: long-lived patients, enriched with VHL but depleted of BAP1 mutations, have high levels of Th17 and CD8+ T cells while short-lived patients with high burden of SCNAs have high levels of Tregs and Th2 cells, highlighting the importance of evaluating evolution patterns in the clinical management of ccRCC.


Assuntos
Carcinoma de Células Renais/genética , Variações do Número de Cópias de DNA/genética , Evolução Molecular , Neoplasias Renais/genética , Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Células Clonais/imunologia , Células Clonais/metabolismo , Estudos de Coortes , Regulação Neoplásica da Expressão Gênica , Heterogeneidade Genética , Humanos , Rim/patologia , Neoplasias Renais/imunologia , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Mutação , Proteínas Nucleares/genética , Prognóstico , Análise de Sobrevida , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Células Th2/imunologia , Fatores de Transcrição/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Sequenciamento Completo do Genoma
17.
Cell Mol Life Sci ; 76(13): 2647-2662, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30903204

RESUMO

Hepatitis B virus (HBV) X protein (HBx) is associated with hepatocarcinogenesis. E2-EPF ubiquitin carrier protein (UCP) catalyzes ubiquitination of itself and von Hippel-Lindau protein (pVHL) for degradation and associates with tumor growth and metastasis. However, it remains unknown whether HBx modulates the enzyme activity of UCP and thereby influences hepatocarcinogenesis. Here, we show that UCP is highly expressed in liver tissues of HBx-transgenic mice, but not non-transgenic mice. UCP was more frequently expressed in HBV-positive liver cancers than in HBV-negative liver cancers. HBx binds to UCP specifically and serotype independently, and forms a ternary complex with UCP and pVHL. HBx inhibits self-ubiquitination of UCP, but enhances UCP-mediated pVHL ubiquitination, resulting in stabilization of hypoxia-inducible factor-1α and -2α. HBx and UCP stabilize each other by mutually inhibiting their ubiquitination. HBx promotes cellular proliferation and metastasis via UCP. Our findings suggest that UCP plays a key role in HBV-related hepatocarcinogenesis.


Assuntos
Carcinoma Hepatocelular/secundário , Hepatite B/complicações , Neoplasias Hepáticas/patologia , Transativadores/metabolismo , Enzimas de Conjugação de Ubiquitina/química , Animais , Apoptose , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/virologia , Proliferação de Células , Progressão da Doença , Feminino , Hepatite B/virologia , Vírus da Hepatite B/isolamento & purificação , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/virologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Camundongos Transgênicos , Estabilidade Proteica , Transdução de Sinais , Transativadores/genética , Células Tumorais Cultivadas , Enzimas de Conjugação de Ubiquitina/genética , Enzimas de Conjugação de Ubiquitina/metabolismo , Ubiquitinação , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
18.
J Cancer Res Ther ; 15(Supplement): S163-S166, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30900640

RESUMO

A 29-year-old hypertensive male with von Hippel-Lindau (VHL) syndrome came to the Endocrinology department for evaluation. Contrast-enhanced computed tomography of the abdomen revealed an adrenal mass, bilateral renal cell carcinoma, and multiple pancreatic cysts. The hormonal investigations for adrenal mass were normal. He underwent left-sided adrenalectomy, and the histopathological report was suggestive of an adrenocortical adenoma. Genetic analysis of VHL gene in this patient revealed a heterogeneous 5' splice site variation of intron 1 of the VHL gene that affects splice site of exon 1 (c. 340 + 1G > A). Adrenocortical adenoma is very rare in VHL syndrome. Only two cases of adrenocortical adenoma in VHL have been reported in the literature, and both were associated with pheochromocytoma. This is probably the first reported case of adrenocortical adenoma in VHL syndrome without accompanying pheochromocytoma.


Assuntos
Neoplasias das Glândulas Suprarrenais/diagnóstico , Adenoma Adrenocortical/diagnóstico , Doença de von Hippel-Lindau/diagnóstico , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/patologia , Neoplasias das Glândulas Suprarrenais/cirurgia , Glândulas Suprarrenais/diagnóstico por imagem , Glândulas Suprarrenais/patologia , Glândulas Suprarrenais/cirurgia , Adrenalectomia , Adenoma Adrenocortical/genética , Adenoma Adrenocortical/patologia , Adenoma Adrenocortical/cirurgia , Adulto , Testes Genéticos , Humanos , Masculino , Tomografia Computadorizada por Raios X , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Doença de von Hippel-Lindau/genética
19.
PLoS One ; 14(1): e0210415, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30682039

RESUMO

BACKGROUND: First-line treatment for metastatic renal cell carcinoma (mRCC) is rapidly changing. It currently includes VEGF targeted therapies (TT), multi-target tyrosine kinase inhibitors (TKIs), mTOR inhibitors, and immunotherapy. To optimize outcomes for individual patients, genomic markers of response to therapy are needed. Here, we aim to identify tumor-based genomic markers of response to VEGF TT to optimize treatment selection. METHODS: From an institutional database, primary tumor tissue was obtained from 79 patients with clear cell mRCC, and targeted sequencing was performed. Clinical outcomes were obtained retrospectively. Progression-free survival (PFS) on first-line VEGF TT was correlated to genomic alterations (GAs) using Kaplan-Meier methodology and Cox proportional hazard models. A composite model of significant GAs predicting PFS in the first-line setting was developed. RESULTS: Absence of VHL mutation was associated with inferior PFS on first-line VEGF TT. A trend for inferior PFS was observed with GAs in TP53 and FLT1 C/C variant. A composite model of these 3 GAs was associated with inferior PFS in a dose-dependent manner. CONCLUSION: In mRCC, a composite model of TP53 mutation, wild type VHL, and FLT1 C/C variant strongly predicted PFS on first-line VEGF TT in a dose-dependent manner. These findings require external validation.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Terapia de Alvo Molecular , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Idoso , Carcinoma de Células Renais/secundário , Feminino , Genes p53 , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Mutação , Prognóstico , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genética
20.
J Clin Endocrinol Metab ; 104(4): 1109-1118, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30698717

RESUMO

CONTEXT: Pheochromocytomas and paragangliomas (PPGLs) are characterized by a strong genetic component, with up to 40% of patients carrying a germline mutation in a PPGL susceptibility gene. International guidelines recommend that genetic screening be proposed to all patients with PPGL. OBJECTIVE: Our objective was to evaluate how a positive genetic test impacts the management and outcome of patients with SDHx or VHL-related PPGL. DESIGN: We performed a multicentric retrospective study involving 221 propositi carrying an SDHB, SDHD, SDHC, or VHL germline mutation. Patients were divided into two groups: genetic patients, who were informed of their genetic status within the year following the first PPGL diagnosis, and historic patients, who only benefited from the genetic test several years after initial PPGL diagnosis. RESULTS: Genetic patients had better follow-up than historic patients, with a greater number of examinations and a reduced number of patients lost to follow-up (9.6% vs 72%, respectively). During follow-up, smaller (18.7 vs 27.6 mm; P = 0.0128) new PPGLs and metastases as well as lower metastatic spread were observed in genetic patients. Of note, these differences were reversed in the historic cohort after genetic testing. Genetic patients who developed metachronous metastases had a better 5-year survival rate than historic patients (P = 0.0127). CONCLUSION: Altogether, our data suggest that early knowledge of genetic status had a positive impact on the management and clinical outcome of patients with a germline SDHx or VHL mutation.


Assuntos
Neoplasias das Glândulas Suprarrenais/diagnóstico , Testes Genéticos , Neoplasias Primárias Múltiplas/diagnóstico , Paraganglioma/diagnóstico , Feocromocitoma/diagnóstico , Adolescente , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/mortalidade , Adulto , Assistência ao Convalescente/métodos , Assistência ao Convalescente/estatística & dados numéricos , Idoso , Criança , Feminino , Seguimentos , Mutação em Linhagem Germinativa , Humanos , Estimativa de Kaplan-Meier , Perda de Seguimento , Masculino , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/genética , Neoplasias Primárias Múltiplas/mortalidade , Paraganglioma/genética , Paraganglioma/mortalidade , Feocromocitoma/genética , Feocromocitoma/mortalidade , Prognóstico , Estudos Retrospectivos , Succinato Desidrogenase/genética , Taxa de Sobrevida , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Adulto Jovem
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