RESUMO
Chromosomal losses resulting in a marked hypodiploidy are a specificity of chromophobe renal cell carcinoma (ChRCC), the third most frequent type of kidney cancer. Its detection is useful in challenging cases. However some ChRCC, especially the eosinophilic variant, do not exhibit hypodiploidy and deserve to be better explored. Using comparative genomic hybridization (array-CGH) we observed chromosomal gains in five cases of nonmetastatic ChRCC. Our objective was to determine whether these apparent chromosomal gains were instead losses within a near-polyploid genome. We performed a retrospective and prospective molecular study of 26 cases of ChRCC retrieved among 643 renal tumors (2012-2019). All tumors were analyzed using array-CGH (Agilent) and array-CGH (Affymetrix) coupled to single nucleotide polymorphism analysis (array-SNP). In silico manual centralization of the fluorescence ratio, fluorescence in situ hybridization (FISH) and next generation sequencing were made in the five cases suspected of polyploidy. Tetraploidization was observed in 19% of our series of ChRCC. None of the methods used individually could identify both chromosomal losses and tetraploidy. Only the combination of manual recentring of array-CGH and FISH provided relevant results. B-allele frequency results indicated that tetraploidization occurred secondarily to chromosomal losses in four cases while it preceded losses in one case. Tetraploidization is a frequent but underestimated phenomenon in ChRCC that may be overlooked using the individual standard genomic methods. Its potential clinical consequences are not identified yet. Whether the mechanisms that induce chromosomal losses in ChRCC are the same that generate tetraploidization is not known.
Assuntos
Cromossomos Humanos Par 11/genética , Melanoma/genética , Neurilemoma/genética , Neoplasias Retroperitoneais/genética , Cromossomos em Anel , Trissomia/genética , Cromossomos Humanos Par 6/genética , Diagnóstico Diferencial , Evolução Fatal , Humanos , Masculino , Melanoma/diagnóstico , Melanoma/secundário , Pessoa de Meia-Idade , Neurilemoma/classificação , Neurilemoma/diagnóstico , Neoplasias Retroperitoneais/classificação , Neoplasias Retroperitoneais/diagnóstico , Falha de TratamentoAssuntos
Transformação Celular Neoplásica/genética , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 7 , Ciclina D1/genética , Neoplasias Femorais/genética , Amplificação de Genes , Tumor de Células Gigantes do Osso/genética , Proteínas Proto-Oncogênicas c-met/genética , Receptores de Fatores de Crescimento/genética , Adulto , Biópsia , Transplante Ósseo , Curetagem , Feminino , Neoplasias Femorais/patologia , Neoplasias Femorais/cirurgia , Tumor de Células Gigantes do Osso/patologia , Tumor de Células Gigantes do Osso/cirurgia , Humanos , Imuno-Histoquímica , Cariotipagem , Invasividade Neoplásica , Resultado do TratamentoRESUMO
Acute myeloid leukemia (AML) cells are characterized by a constitutive and abnormal activation of the nuclear factor-kappaB (NF-kappaB) transcription factor. This study, conducted in vitro on 18 patients, shows that targeting the IKB kinase 2 (IKK2) kinase with the specific pharmacologic inhibitor AS602868 to block NF-kappaB activation led to apoptosis of human primary AML cells. Moreover, AS602868 potentiated the apoptotic response induced by the current chemotherapeutic drugs doxorubicin, cytarabine, or etoposide (VP16). AS602868-induced cell death was associated with rupture of the mitochondrial transmembrane potential and activation of cellular caspases. NF-kappaB inhibition did not affect normal CD34+ hematopoietic precursors, suggesting that it could represent a new adjuvant strategy for AML treatment.