RESUMO
PURPOSE: Bosutinib is approved for adults with chronic myeloid leukemia (CML): 400 mg once daily in newly diagnosed (ND); 500 mg once daily in resistant/intolerant (R/I) patients. Bosutinib has a different tolerability profile than other tyrosine kinase inhibitors (TKIs) and potentially less impact on growth (preclinical data). The primary objective of this first-in-child trial was to determine the recommended phase II dose (RP2D) for pediatric R/I and ND patients. PATIENTS AND METHODS: In the phase I part of this international, open-label trial (ClinicalTrials.gov identifier: NCT04258943), children age 1-18 years with R/I (per European LeukemiaNet 2013) Ph+ CML were enrolled using a 6 + 4 design, testing 300, 350, and 400 mg/m2 once daily with food. The RP2D was the dose resulting in 0/6 or 1/10 dose-limiting toxicities (DLTs) during the first cycle and achieving adult target AUC levels for the respective indication. As ND participants were only enrolled in phase II, the ND RP2D was selected based on data from R/I patients. RESULTS: Thirty patients were enrolled; 27 were evaluable for DLT: six at 300 mg/m2, 11 at 350 mg/m2 (one DLT), and 10 at 400 mg/m2 (one DLT). The mean AUCs at 300 mg/m2, 350 mg/m2, and 400 mg/m2 were 2.20 µg h/mL, 2.52 µg h/mL, and 2.66 µg h/mL, respectively. The most common adverse event was diarrhea (93%; ≥grade 3: 11%). Seven patients stopped because of intolerance and eight because of insufficient response. Complete cytogenetic and major molecular response to bosutinib appeared comparable with other published phase I/II trials with second-generation TKIs in children. CONCLUSION: Bosutinib was safe and effective. The pediatric RP2D was 400 mg/m2 once daily (max 600 mg/d) with food in R/I patients and 300 mg/m2 once daily (max 500 mg/d) with food in ND patients, which achieved targeted exposures as per adult experience.
Assuntos
Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Leucemia Mieloide de Fase Crônica , Quinolinas , Adolescente , Adulto , Criança , Pré-Escolar , Humanos , Lactente , Compostos de Anilina/efeitos adversos , Antineoplásicos/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Nitrilas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Quinolinas/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: Mutation analysis and cytogenetic testing in clear cell renal cell carcinoma (ccRCC) is not yet implemented in a routine diagnostics of ccRCC. MATERIAL AND METHODS: We characterized the chromosomal alterations in 83 ccRCC tumors from Polish patients using whole genome SNP genotyping assay. Moreover, the utility of next generation sequencing of cell free DNA (cfDNA) in patients plasma as a potential tool for non-invasive cytogenetic analysis was tested. Additionally, tumor specific somatic mutations in PBRM1, BAP1 and KDM5C were determined. RESULTS: We confirmed a correlation between deletions at 9p and higher tumor size, and deletion of chromosome 20 and the survival time. In Fuhrman grade 1, only aberrations of 3p and 8p deletion, gain of 5q and 13q and gains of chromosome 7 and 16 were present. The number of aberrations increased with Fuhrman grade, all chromosomes displayed cytogenetic changes in G3 and G4. ccRCC specific chromosome aberrations were observed in cfDNA, although discrepancies were found between cfDNA and tumor samples. In total 12 common and 94 rare variants were detected in PBRM1, BAP1 and KDM5C, with four potentially pathogenic variants. We observed markedly lower mutation load in PBRM1. CONCLUSIONS: Cytogenetic analysis of cfDNA may allow more accurate diagnosis of tumor aberrations and therefore the correlation between the chromosome aberrations in cfDNA and clinical outcome should be studied in larger cohorts. The functional studies on in BAP1, KDM5C, PBRM1 mutations in large, independent sample set would be necessary for the assessment of their prognostic and diagnostic potential.
Assuntos
Carcinoma de Células Renais/epidemiologia , Carcinoma de Células Renais/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Aberrações Cromossômicas , DNA Tumoral Circulante , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Proteínas de Ligação a DNA , Feminino , Histona Desmetilases/genética , Humanos , Biópsia Líquida , Masculino , Mutação , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Proteínas Nucleares/genética , Polônia/epidemiologia , Polimorfismo de Nucleotídeo Único , Prognóstico , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genéticaRESUMO
The functional roles of SNPs within the 8q24 gene desert in the cancer phenotype are not yet well understood. Here, we report that CCAT2, a novel long noncoding RNA transcript (lncRNA) encompassing the rs6983267 SNP, is highly overexpressed in microsatellite-stable colorectal cancer and promotes tumor growth, metastasis, and chromosomal instability. We demonstrate that MYC, miR-17-5p, and miR-20a are up-regulated by CCAT2 through TCF7L2-mediated transcriptional regulation. We further identify the physical interaction between CCAT2 and TCF7L2 resulting in an enhancement of WNT signaling activity. We show that CCAT2 is itself a WNT downstream target, which suggests the existence of a feedback loop. Finally, we demonstrate that the SNP status affects CCAT2 expression and the risk allele G produces more CCAT2 transcript. Our results support a new mechanism of MYC and WNT regulation by the novel lncRNA CCAT2 in colorectal cancer pathogenesis, and provide an alternative explanation of the SNP-conferred cancer risk.
Assuntos
Instabilidade Cromossômica , Cromossomos Humanos Par 8/genética , Neoplasias do Colo/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Estudos de Casos e Controles , Linhagem Celular Tumoral , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Metástase Neoplásica/genética , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteína 1 Semelhante ao Fator 7 de Transcrição/genética , Proteína 1 Semelhante ao Fator 7 de Transcrição/metabolismo , Transcrição Gênica , Via de Sinalização WntAssuntos
Síndrome de Down/complicações , Dosagem de Genes , Leucemia Mieloide/genética , Doença Aguda , Pré-Escolar , Aberrações Cromossômicas , Feminino , Amplificação de Genes , Deleção de Genes , Predisposição Genética para Doença , Humanos , Lactente , Cariotipagem , Leucemia Megacarioblástica Aguda/etiologia , Leucemia Megacarioblástica Aguda/genética , Leucemia Mieloide/etiologia , Masculino , RNA/genética , Telomerase/genética , Telômero/ultraestruturaRESUMO
Nuclear protein in testis midline carcinomas (NMC) are highly aggressive carcinomas typically arising in midline structures in young individuals. These carcinomas are characterized by the presence of a chromosomal rearrangement of nuclear protein in testis the (NUT) gene on chromosome 15 (15q14), resulting from a chromosomal translocation most commonly involving the BRD4 gene on chromosome 19p13. Rarely, in about 1/3 of cases, other translocation partners are involved (termed NUT-variants). Most cases have involved midline structures and with few exceptions were located in the upper aerodigestive tract and the mediastinum. Except for a single case, all reported NMC have been fatal, proving resistant to multimodality treatment. We report an exceptional case of a NMC presenting outside of midline structures in the parotid gland and showing mesenchymal chondroid differentiation in a 15-year-old male. The presence of the t(15;19) chromosomal translocation in the chondroid component was confirmed by fluorescence in situ hybridization analysis and immunohistochemical staining, indicating mesenchymal transdifferentation of the tumor. The findings demonstrate the first case of NMC arising within salivary gland, and the first example of mesenchymal differentiation in this group of tumors.
Assuntos
Carcinoma/genética , Carcinoma/patologia , Proteínas Nucleares/genética , Proteínas de Fusão Oncogênica/genética , Neoplasias Parotídeas/genética , Neoplasias Parotídeas/patologia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma/terapia , Proteínas de Ciclo Celular , Diferenciação Celular , Terapia Combinada , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Masculino , Mesoderma/patologia , Proteínas de Neoplasias , Proteínas Oncogênicas/genética , Procedimentos Cirúrgicos Bucais , Neoplasias Parotídeas/terapia , Radioterapia , Fatores de Transcrição/genética , Translocação GenéticaRESUMO
Cancer of the esophagus is the seventh leading cause of cancer death worldwide. Esophageal carcinoma cell lines are useful models to study the biological and genetic alterations in these tumors. An important prerequisite of cell line research is the authenticity of the used cell lines because the mistaken identity of a cell line may lead to invalid conclusions. Estimates indicate that up to 36% of the cell lines are of a different origin or species than supposed. The TE series, established in late 1970s and early 1980s by Nishihira et al. in Japan, is one of the first esophageal cancer cell line series that was used throughout the world. Fourteen TE cell lines were derived from human esophageal squamous cell carcinomas and one, TE-7, was derived from a primary esophageal adenocarcinoma. In numerous studies, this TE-7 cell line was used as a model for esophageal adenocarcinoma because it is one of the few esophageal adenocarcinoma cell lines existing. We investigated the authenticity of the esophageal adenocarcinoma cell line TE-7 by xenografting, short tandem repeat profiling, mutation analyses, and array-comparative genomic hybridization and showed that cell line TE-7 shared the same genotype as the esophageal squamous cell carcinoma cell lines TE-2, TE-3, TE-12, and TE-13. In addition, for more than a decade, independent TE-7 cultures from Japan, United States, United Kingdom, France, and the Netherlands had the same genotype. Examination of the TE-7 cell line xenograft revealed the histology of a squamous cell carcinoma. We conclude that the TE-7 cell line, used in several laboratories throughout the world, is not an adenocarcinoma, but a squamous cell carcinoma cell line. Furthermore, the cell lines TE-2, TE-3, TE-7, TE-12, and TE-13 should be regarded as one single squamous cell carcinoma cell line.
