RESUMO
Chronic myeloid leukemia (CML) stem cells appear resistant to tyrosine kinase inhibitors (TKIs) in vitro, but their impact and drug sensitivity in vivo has not been systematically assessed. We prospectively analyzed the proportion of Philadelphia chromosome-positive leukemic stem cells (LSCs, Ph+CD34+CD38-) and progenitor cells (LPCs, Ph+CD34+CD38+) from 46 newly diagnosed CML patients both at the diagnosis and during imatinib or dasatinib therapy (ClinicalTrials.gov NCT00852566). At diagnosis, the proportion of LSCs varied markedly (1-100%) between individual patients with a significantly lower median value as compared with LPCs (79% vs 96%, respectively, P=0.0001). The LSC burden correlated with leukocyte count, spleen size, hemoglobin and blast percentage. A low initial LSC percentage was associated with less therapy-related hematological toxicity and superior cytogenetic and molecular responses. After initiation of TKI therapy, the LPCs and LSCs rapidly decreased in both therapy groups, but at 3 months time point the median LPC level was significantly lower in dasatinib group compared with imatinib patients (0.05% vs 0.68%, P=0.032). These data detail for the first time the prognostic significance of the LSC burden at diagnosis and show that in contrast to in vitro data, TKI therapy rapidly eradicates the majority of LSCs in patients.
Assuntos
Benzamidas/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Células-Tronco Neoplásicas/patologia , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Tiazóis/uso terapêutico , Adulto , Idoso , Antineoplásicos/uso terapêutico , Dasatinibe , Feminino , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Valor Preditivo dos Testes , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Resultado do TratamentoAssuntos
ADP-Ribosil Ciclase 1/análise , Antígenos CD34/análise , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Glicoproteínas de Membrana/análise , Células-Tronco Neoplásicas/efeitos dos fármacos , Cromossomo Filadélfia , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Idoso , Benzamidas , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Pessoa de Meia-Idade , Piperazinas/uso terapêutico , Pirimidinas/uso terapêuticoRESUMO
BACKGROUND: BARD1 was originally identified as a BRCA1-interacting protein but has also been described in tumour-suppressive functions independent of BRCA1. Several studies have indicated that the BARD1 gene is a potential target for germline changes predisposing to breast and ovarian cancer. The C-terminal Cys557Ser change has previously been uncovered to associate with an increased risk of breast cancer and was recently shown to result in defective apoptotic activities. AIM AND METHODS: Conformation-sensitive gel electrophoresis, minisequencing, TaqMan assays, denaturing high-performance liquid chromatography analysis and DNA sequencing were used to investigate the prevalence of the Cys557Ser allele in a large Nordic case-control study cohort consisting of 2906 patients with breast or ovarian cancer, 734 with prostate cancer, 188 with colorectal cancer, 128 men with breast cancer, and 3591 controls from Finland, Iceland, Denmark, Sweden and Norway. RESULTS: The frequency of the BARD1 Cys557Ser variant seemed to increase among patients from families with breast or ovarian cancer lacking BRCA1 or BRCA2 mutations: a significant difference was obtained compared with controls (6.8% v 2.7%; p<0.001; odds ratio (OR) 2.6; 95% confidence interval (CI) 1.7 to 4.0) and with patients from BRCA1/BRCA2 mutation-positive families (6.8% v 2.2%; p = 0.01; OR 3.2; 95% CI 1.2 to 8.3). In contrast, no major association with male breast, ovarian, colorectal or prostate cancer was observed. Additionally, a novel BARD1 allele resulting in Ser558Pro was identified in familial breast cancer cases. CONCLUSION: These results provide further evidence that BARD1 Cys557Ser confers a slightly increased risk of breast cancer in women.
Assuntos
Alelos , Neoplasias da Mama/genética , Mutação de Sentido Incorreto , Proteínas Supressoras de Tumor/genética , Ubiquitina-Proteína Ligases/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama Masculina/genética , Estudos de Casos e Controles , Estudos de Coortes , Neoplasias Colorretais/genética , Análise Mutacional de DNA , Feminino , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética , Neoplasias da Próstata/genéticaAssuntos
Alelos , Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Testes Genéticos , Mutação/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina-Proteína Ligases/genética , Sequência de Aminoácidos , Cisteína/genética , Análise Mutacional de DNA , Feminino , Finlândia , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Neoplasias Ovarianas/genética , Linhagem , Serina/genética , Proteínas Supressoras de Tumor/química , Ubiquitina-Proteína Ligases/químicaRESUMO
In the Finnish population, identified mutations in BRCA1 and BRCA2 account for a less than expected proportion of hereditary breast and ovarian cancer. All previous studies performed in our country have concentrated on finding germ-line mutations in the coding and splice-site regions of these two genes. Therefore, we wanted to use a different methodological approach and search for large genomic rearrangements, to exclude the possibility of biased BRCA1 and BRCA2 mutation spectra due to known limitations of the previously used PCR-based detection methods. Our results support earlier notions that other genes than BRCA1 and BRCA2 will explain a majority of the still unexplained cases of hereditary susceptibility to breast and ovarian cancer.
Assuntos
Proteína BRCA1/genética , Neoplasias da Mama/genética , Testes Genéticos , Proteínas de Neoplasias/genética , Neoplasias Ovarianas/genética , Deleção de Sequência , Fatores de Transcrição/genética , Proteína BRCA2 , Southern Blotting , Neoplasias da Mama/epidemiologia , Família , Feminino , Finlândia/epidemiologia , Predisposição Genética para Doença , Humanos , Neoplasias Ovarianas/epidemiologiaRESUMO
We have screened for germline TP53 mutations in Finnish BRCA1 and BRCA2 mutation-negative families. This study represents the largest survey of the entire protein-encoding portion of TP53, and indicates that mutations are only found at conserved domains in breast cancer families also meeting the criteria for Li-Fraumeni/Li-Fraumeni-like syndrome, explaining only a very small additional fraction of the hereditary breast cancer cases.
Assuntos
Neoplasias da Mama/genética , Sequência Conservada/genética , Genes p53/genética , Mutação em Linhagem Germinativa/genética , Síndromes Neoplásicas Hereditárias/genética , Proteína Supressora de Tumor p53/genética , Estudos de Coortes , Feminino , Finlândia/etnologia , Humanos , LinhagemRESUMO
In the Finnish breast and ovarian cancer families six BRCA1 and five BRCA2 mutations have been found recurrently. Some of these recurrent mutations have also been seen elsewhere in the world, while others are exclusively of Finnish origin. A haplotype analysis of 26 Finnish families carrying a BRCA1 mutation and 20 families with a BRCA2 mutation indicated that the carriers of each recurrent mutation have common ancestors. The common ancestors were estimated to trace back to 7-36 generations (150-800 years). The time estimates and the geographical clustering of these founder mutations in Finland are in concordance with the population history of this country. Analysis of the cancer phenotypes showed differential ovarian cancer expression in families carrying mutations in the 5' and 3' ends of the BRCA1 gene, and earlier age of ovarian cancer onset in families with BRCA1 mutations compared with families with BRCA2 mutations. The identification of prominent and regional BRCA1 and BRCA2 founder mutations in Finland will have significant impact on diagnostics in Finnish breast and ovarian cancer families. An isolated population with known history and multiple local founder effects in multigenic disease may offer distinct advantages also for mapping novel predisposing genes.
