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1.
Leukemia ; 20(11): 2034-40, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17024118

RESUMO

A specific role for increased level of expression of CKS1B, as a consequence of chromosome 1q21 copy number gain, has been postulated as both pathogenic, as well as a powerful clinical prognostic factor in multiple myeloma (MM). The purpose of this study is to determine the clinical associations and prognostic impact of copy number gain at chromosome 1q21 (with a bacteria artificial chromosome clone containing CKS1B) and CKS1B gene level of expression in MM. We studied the chromosome region 1q21 for copy number change in a cohort of myeloma patients treated by high-dose therapy with stem-cell rescue (HDT) (n = 159). A separate cohort of patients, treated by HDT was studied for CKS1B messenger RNA expression by gene expression profiling (n = 67). 1q21 gain was then correlated with clinical parameters and survival. Gain of 1q21 copy number was detected in about a third of MM and was associated with more proliferative disease and poor-risk cytogenetic categories such as t(4;14), and chromosome 13 deletion. Both 1q21 gain and increase gene expression level were significantly associated with reduced survival. However, neither is an independent prognostic marker in MM on multivariate Cox proportional hazard analysis.


Assuntos
Proteínas de Transporte/genética , Cromossomos Humanos Par 1 , Quinases Ciclina-Dependentes/genética , Hibridização in Situ Fluorescente , Mieloma Múltiplo/genética , Mieloma Múltiplo/mortalidade , Biomarcadores Tumorais/genética , Quinases relacionadas a CDC2 e CDC28 , Divisão Celular/genética , Dosagem de Genes , Regulação Neoplásica da Expressão Gênica , Transplante de Células-Tronco Hematopoéticas , Humanos , Mieloma Múltiplo/terapia , Prevalência , Prognóstico , Modelos de Riscos Proporcionais , RNA Mensageiro/genética , Fatores de Risco , Taxa de Sobrevida
2.
Cancer Res ; 60(8): 2225-31, 2000 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-10786688

RESUMO

Two microsatellite instability (MSI) phenotypes have been described in colorectal cancer (CRC): MSI-H (instability at >30% of the loci examined) and MSI-L (MSI at 1-30% of the loci examined). The MSI-H phenotype, observed in both hereditary nonpolyposis colon cancer-associated CRC and approximately 15% of sporadic CRC, generally results from mutational or epigenetic inactivation of the DNA mismatch repair (MMR) genes hMSH2 or hMLH1. The genetic basis for the MSI-L phenotype, however, is unknown. Several other proteins, including hMSH3 and hMSH6, also participate in DNA MMR. Inactivating mutations of MSH6 in yeast and human tumor cell lines are associated with an impaired ability to repair single-base mispairs and small insertion-deletion loops but not large insertion-deletion loops. This suggests that hMSH6 mutations are more likely to be associated with a MSI-L phenotype than a MSI-H phenotype in CRC. To explore this possibility, we screened tumors from 41 patients with MSI-L CRC for hMSH6 mutations with conformation-sensitive gel electrophoresis (CSGE) and for hMSH6 protein expression by immunohistochemistry. Alterations found with CSGE were confirmed by DNA sequencing of normal and tumor tissue. One somatic (Asp389Asn) and 15 germ-line changes were found. Of the 15 germ-line changes, 9 were found in an intron (none involving splice junctions), and 6 were found in an exon (Gly39Glu, Leu395Val, and 4 silent alterations). Immunohistochemical staining for hMSH6 performed on 34 of the 41 tumors revealed strong nuclear hMSH6 expression in all of the cases. Overall, our results suggest that hMSH6 mutations do not play a major role in the development of sporadic CRC with a MSI-L phenotype.


Assuntos
Neoplasias Colorretais/genética , Proteínas de Ligação a DNA/genética , Mutação/genética , Expansão das Repetições de Trinucleotídeos/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Núcleo Celular/metabolismo , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Análise Mutacional de DNA , Proteínas de Ligação a DNA/metabolismo , Éxons/genética , Saúde da Família , Feminino , Testes Genéticos , Mutação em Linhagem Germinativa/genética , Humanos , Imuno-Histoquímica , Íntrons/genética , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo Genético/genética
3.
Blood Cancer J ; 5: e346, 2015 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-26314988

RESUMO

Lack of remission or early relapse remains a major clinical issue in diffuse large B-cell lymphoma (DLBCL), with 30% of patients failing standard of care. Although clinical factors and molecular signatures can partially predict DLBCL outcome, additional information is needed to identify high-risk patients, particularly biologic factors that might ultimately be amenable to intervention. Using whole-exome sequencing data from 51 newly diagnosed and immunochemotherapy-treated DLBCL patients, we evaluated the association of somatic genomic alterations with patient outcome, defined as failure to achieve event-free survival at 24 months after diagnosis (EFS24). We identified 16 genes with mutations, 374 with copy number gains and 151 with copy number losses that were associated with failure to achieve EFS24 (P<0.05). Except for FOXO1 and CIITA, known driver mutations did not correlate with EFS24. Gene losses were localized to 6q21-6q24.2, and gains to 3q13.12-3q29, 11q23.1-11q23.3 and 19q13.12-19q13.43. Globally, the number of gains was highly associated with poor outcome (P=7.4 × 10(-12)) and when combined with FOXO1 mutations identified 77% of cases that failed to achieve EFS24. One gene (SLC22A16) at 6q21, a doxorubicin transporter, was lost in 54% of EFS24 failures and our findings suggest it functions as a doxorubicin transporter in DLBCL cells.


Assuntos
Exoma/genética , Linfoma Difuso de Grandes Células B/genética , Proteínas de Transporte de Cátions Orgânicos/genética , Idoso , Idoso de 80 Anos ou mais , Transporte Biológico , Terapia Combinada , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Doxorrubicina/metabolismo , Feminino , Estudos de Associação Genética , Genoma Humano , Humanos , Estimativa de Kaplan-Meier , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/terapia , Masculino , Pessoa de Meia-Idade , Deleção de Sequência , Resultado do Tratamento
4.
Leukemia ; 28(9): 1872-84, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24569779

RESUMO

Transforming growth factor beta (TGF-ß) has an important role in mediating T-cell suppression in B-cell non-Hodgkin lymphoma (NHL). However, the underlying mechanism responsible for TGF-ß-mediated inhibition of effector memory T (Tm) cells is largely unknown. As reported here, we show that exhaustion is a major mechanism by which TGF-ß inhibits Tm cells, and TGF-ß mediated exhaustion is associated with upregulation of CD70. We found that TGF-ß upregulates CD70 expression on effector Tm cells while it preferentially induces Foxp3 expression in naive T cells. CD70 induction by TGF-ß is Smad3-dependent and involves IL-2/Stat5 signaling. CD70+ T cells account for TGF-ß-induced exhaustion of effector Tm cells. Both TGF-ß-induced and preexisting intratumoral CD70+ effector Tm cells from B-cell NHL have an exhausted phenotype and express higher levels of PD-1 and TIM-3 compared with CD70- T cells. Signaling transduction, proliferation and cytokine production are profoundly decreased in these cells, and they are highly susceptible to apoptosis. Clinically, intratumoral CD70-expressing T cells are prevalent in follicular B-cell lymphoma (FL) biopsy specimens, and increased numbers of intratumoral CD70+ T cells correlate with an inferior patient outcome. These findings confirm TGF-ß-mediated effector Tm cell exhaustion as an important mechanism of immune suppression in B-cell NHL.


Assuntos
Ligante CD27/fisiologia , Memória Imunológica , Linfoma de Células B/imunologia , Linfócitos T/imunologia , Fator de Crescimento Transformador beta/farmacologia , Apoptose , Ligante CD27/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Receptor Celular 2 do Vírus da Hepatite A , Humanos , Interleucina-2/fisiologia , Proteínas de Membrana/análise , Receptor de Morte Celular Programada 1/análise , Fator de Transcrição STAT5/fisiologia , Transdução de Sinais , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/fisiologia
5.
Blood Cancer J ; 4: e183, 2014 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-24531446

RESUMO

Massively parallel sequencing analyses have revealed a common mutation within the MYD88 gene (MYD88L265P) occurring at high frequencies in many non-Hodgkin lymphomas (NHLs) including the rare lymphoplasmacytic lymphoma, Waldenström's macroglobulinemia (WM). Using whole-exome sequencing, Sanger sequencing and allele-specific PCR, we validate the initial studies and detect the MYD88L265P mutation in the tumor genome of 97% of WM patients analyzed (n=39). Due to the high frequency of MYD88 mutation in WM and other NHL, and its known effects on malignant B-cell survival, therapeutic targeting of MYD88 signaling pathways may be clinically useful. However, we are lacking a thorough characterization of the role of intermediary signaling proteins on the biology of MYD88L265P-expressing B cells. We report here that MYD88L265P signaling is constitutively active in both WM and diffuse large B-cell lymphoma cells leading to heightened MYD88L265P, IRAK and TRAF6 oligomerization and NF-κB activation. Furthermore, we have identified the signaling protein, TAK1, to be an essential mediator of MYD88L265P-driven signaling, cellular proliferation and cytokine secretion in malignant B cells. Our studies highlight the biological significance of MYD88L265P in NHL and reveal TAK1 inhibition to be a potential therapeutic strategy for the treatment of WM and other diseases characterized by MYD88L265P.

8.
Blood Cancer J ; 1(6): e24, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22829168

RESUMO

MicroRNAs (miRNAs) are involved in the regulation of many cellular processes including hematopoiesis, with the aberrant expression of differentiation-stage specific miRNA associated with lymphomagenesis. miRNA profiling has been essential for understanding the underlying biology of many hematological malignancies; however the miRNA signature of the diverse tumor clone associated with Waldenstrom's macroglobulinemia (WM), consisting of B lymphocytes, plasmacytes and lymphoplasmacytic cells, has not been characterized. We have investigated the expression of over 13 000 known and candidate miRNAs in both CD19(+) and CD138(+) WM tumor cells, as well as in their malignant and non-malignant counterparts. Although neither CD19(+) nor CD138(+) WM cells were defined by a distinct miRNA profile, the combination of all WM cells revealed a unique miRNA transcriptome characterized by the dysregulation of many miRNAs previously identified as crucial for normal B-cell lineage differentiation. Specifically, miRNA-9(*)/152/182 were underexpressed in WM, whereas the expression of miRNA-21/125b/181a/193b/223/363 were notably increased (analysis of variance; P<0.0001). Future studies focusing on the effects of these dysregulated miRNAs will provide further insight into the mechanisms responsible for the pathogenesis of WM.

11.
Leukemia ; 22(5): 1044-52, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18216867

RESUMO

Plasma cell leukemia (PCL) is an aggressive and rare hematological malignancy that originates either as primary disease (pPCL) or as a secondary leukemic transformation (sPCL) of multiple myeloma (MM). We report here the genetic aberrations and survival of 80 patients with pPCL or sPCL and make comparisons with 439 cases of MM. pPCL presents a decade earlier than sPCL (54.7 vs 65.3 years) and is associated with longer median overall survival (11.1 vs 1.3 months; P<0.001). 14q32 (IgH) translocations are highly prevalent in both sPCL and pPCL (82-87%); in pPCL IgH translocations almost exclusively involve 11q13 (CCND1), supporting a central etiological role, while in sPCL multiple partner oncogenes are involved, including 11q13, 4p16 (FGFR3/MMSET) and 16q23 (MAF), recapitulating MM. Both show ubiquitous inactivation of TP53 (pPCL 56%; sPCL 83%) by coding mutation or 17p13 deletion; complemented by p14ARF epigenetic silencing in sPCL (29%). Both show frequent N-RAS or K-RAS mutation. Poor survival in pPCL was predicted by MYC translocation (P=0.006). Survival in sPCL was consistently short. Overall pPCL and sPCL are different disorders with distinct natural histories, genetics and survival.


Assuntos
Leucemia Plasmocitária/genética , Mutação , Segunda Neoplasia Primária/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Epigênese Genética , Feminino , Humanos , Leucemia Plasmocitária/diagnóstico , Leucemia Plasmocitária/mortalidade , Masculino , Pessoa de Meia-Idade , Epidemiologia Molecular , Segunda Neoplasia Primária/diagnóstico , Segunda Neoplasia Primária/mortalidade , Taxa de Sobrevida , Translocação Genética
12.
Genes Chromosomes Cancer ; 30(2): 181-6, 2001 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11135435

RESUMO

Twenty percent of colorectal cancers (CRCs) arise in people who have a family history of CRC in at least one other relative. Although a fraction of these CRCs are explained by two well-described autosomal dominant syndromes-5% by hereditary nonpolyposis colorectal cancer (HNPCC) and 1% by familial adenomatous polyposis (FAP)-the cause of the remaining 14% of familial aggregates of CRC is unknown. Many cases of HNPCC are due to germline mutations in DNA mismatch repair genes, leading to the tumor phenotype of microsatellite instability (MSI), and most cases of FAP are caused by germline APC mutations. To date, non-FAP familial CRC aggregates have not been evaluated for germline APC mutations. In this study, we examined the involvement of germline APC mutations in 79 individuals with CRC who had early-age onset of their cancer (age < 50 years) and/or a family history of CRC. Cases with FAP or HNPCC due to defective mismatch repair were excluded from the study. Using conformation-sensitive gel electrophoresis and the protein truncation test as the screening methods, no functionally significant germline mutations were detected for any of the cases. An apparently silent polymorphism resulting in a 1-bp alteration of A --> G (proline --> proline) in exon 4 was observed. Additionally, four intervening sequence (IVS) alterations were detected: IVS2-53t-->c in 3 cases; IVS4-17ins T in 3 cases; IVS5+32t-->c in 16 cases; and IVS5+33g-->a in 1 case. All appeared to be polymorphisms present in similar proportions in an average-risk population. We conclude that germline APC mutations do not account for familial MSS (stable microsatellite) CRC associated with few synchronous polyps.


Assuntos
Pareamento Incorreto de Bases/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais/genética , Reparo do DNA/genética , Genes APC/genética , Mutação em Linhagem Germinativa/genética , Adulto , Idade de Início , Idoso , Eletroforese em Gel de Poliacrilamida , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Conformação de Ácido Nucleico , Deleção de Sequência/genética
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