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2.
PLoS One ; 12(7): e0181366, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28704552

RESUMO

Patched homolog 1 gene (PTCH1) expression and the ratio of PTCH1 to Smoothened (SMO) expression have been proposed as prognostic markers of the response of chronic myeloid leukemia (CML) patients to imatinib. We compared these measurements in a realistic cohort of 101 patients with CML in chronic phase (CP) using a simplified qPCR method, and confirmed the prognostic power of each in a competing risk analysis. Gene expression levels were measured in peripheral blood samples at diagnosis. The PTCH1/SMO ratio did not improve PTCH1 prognostic power (area under the receiver operating characteristic curve 0.71 vs. 0.72). In order to reduce the number of genes to be analyzed, PTCH1 was the selected measurement. High and low PTCH1 expression groups had significantly different cumulative incidences of imatinib failure (IF), which was defined as discontinuation of imatinib due to lack of efficacy (5% vs. 25% at 4 years, P = 0.013), probabilities of achieving a major molecular response (81% vs. 53% at first year, P = 0.02), and proportions of early molecular failure (14% vs. 43%, P = 0.015). Every progression to an advanced phase (n = 3) and CML-related death (n = 2) occurred in the low PTCH1 group (P<0.001 for both comparisons). PTCH1 was an independent prognostic factor for the prediction of IF. We also validated previously published thresholds for PTCH1 expression. Therefore, we confirmed that PTCH1 expression can predict the imatinib response in CML patients in CP by applying a more rigorous statistical analysis. Thus, PTCH1 expression is a promising molecular marker for predicting the imatinib response in CML patients in CP.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/fisiologia , Mesilato de Imatinib/uso terapêutico , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Receptor Patched-1/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Farmacológicos , Feminino , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Humanos , Leucemia Mieloide de Fase Crônica/diagnóstico , Leucemia Mieloide de Fase Crônica/genética , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
4.
Nat Genet ; 45(12): 1464-9, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24121791

RESUMO

Urothelial bladder cancer (UBC) is heterogeneous at the clinical, pathological and genetic levels. Tumor invasiveness (T) and grade (G) are the main factors associated with outcome and determine patient management. A discovery exome sequencing screen (n = 17), followed by a prevalence screen (n = 60), identified new genes mutated in this tumor coding for proteins involved in chromatin modification (MLL2, ASXL2 and BPTF), cell division (STAG2, SMC1A and SMC1B) and DNA repair (ATM, ERCC2 and FANCA). STAG2, a subunit of cohesin, was significantly and commonly mutated or lost in UBC, mainly in tumors of low stage or grade, and its loss was associated with improved outcome. Loss of expression was often observed in chromosomally stable tumors, and STAG2 knockdown in bladder cancer cells did not increase aneuploidy. STAG2 reintroduction in non-expressing cells led to reduced colony formation. Our findings indicate that STAG2 is a new UBC tumor suppressor acting through mechanisms that are different from its role in preventing aneuploidy.


Assuntos
Aneuploidia , Antígenos Nucleares/genética , Carcinoma/genética , Inativação Gênica , Neoplasias da Bexiga Urinária/genética , Adulto , Carcinoma/patologia , Proteínas de Ciclo Celular , Divisão Celular/genética , Linhagem Celular Tumoral , Montagem e Desmontagem da Cromatina/genética , Reparo do DNA/genética , Frequência do Gene , Genes Supressores de Tumor , Humanos , Mutação , Neoplasias da Bexiga Urinária/patologia
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