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1.
Oncol Lett ; 17(6): 5705-5710, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31186796

RESUMO

BCR/ABL1 gene fusion is the hallmark of chronic myeloid leukemia (CML), and is generated in 5-10% of patients by a variant translocation involving 9q34, 22q11.2 and one or more additional genomic regions. The objective of the present study was to characterize, by conventional and molecular cytogenetics, 32 complex variant Philadelphia (Ph) translocations present at diagnosis in patients with CML. The chromosomes most frequently involved were 1 and 5, and the breakpoint most frequently involved was 12p13. The q-chromosome arm was more frequently involved (60%) than the p-arm. The breakpoints were located in the G-light bands in the majority of cases (85%). Additional chromosomal abnormalities were observed in 6 out of 32 (19%) patients. In conclusion, the combination of conventional and molecular cytogenetics studies has allowed us to: i) Detect and quantify the BCR/ABL1 fusion gene; ii) characterize the complex variant translocations and detect cryptic translocations; iii) confirm that the breakpoints are commonly localized in the G-light bands; (iv) confirm that the genesis of variant translocations could be via either the one-step or two-step mechanisms; and v) to report new cases of complex variant translocations.

2.
Histopathology ; 75(6): 799-812, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30861172

RESUMO

AIMS: The clinical implications of the programmed cell death 1 (PD1)/programmed cell death-ligand 1 (PD-L1) axis in patients with post-transplant lymphoproliferative disorders are largely unknown, and its association with Epstein-Barr virus (EBV) status and PD-L1 copy number alterations (CNAs) has not been thoroughly studied. METHODS AND RESULTS: PD1/PD-L1 expression was studied in 50 adult post-transplant lymphoproliferative disorders, and the correlations with PD-L1 CNAs, EBV, clinicopathological features and outcome were evaluated. Thirty-seven (74%) cases were classified as diffuse large B-cell lymphoma (DLBCL), nine (18%) cases were classified as polymorphic, and four (8%) cases were classified as classic Hodgkin lymphoma. Thirty-four cases were EBV-positive, with 29 of 34 (85%) having latency II or III, and 15 of 34 (44%) having viral replication. PD-L1 expression in tumour cells and tumour-associated macrophages was observed in 30 (60%) and 37 (74%) cases, respectively. PD1 positivity was seen in 16 (32%) cases. PD-L1 expression was associated with EBV with latency II or III (P = 0.001) and organ rejection (P = 0.04), and, in DLBCL, with non-germinal centre type DLBCL (P < 0.001). Cases with PD-L1-positive tumour cells showed a higher number of PD-L1 CNAs than PD-L1-negative cases (P = 0.001). Patients with EBV/latency III/replication and simultaneous PD-L1 expression showed the worst overall survival (P < 0.001). CONCLUSIONS: The PD1/PD-L1 axis is deregulated in post-transplant lymphoproliferative disorders, with frequent PD-L1 expression and PD1 negativity. PD-L1 expression is associated with EBV latency II or III and PD-L1 CNAs, and probably reflects a proinflammatory tumour microenvironment. The combined analysis of EBV status and PD-L1 expression may help to identify deeply immunosuppressed patients who can benefit from immune reconstitution approaches.

3.
Leuk Res ; 63: 85-89, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29121539

RESUMO

Isolate loss of chromosome Y (-Y) in myelodysplastic syndromes (MDS) is associated to a better outcome but it is also well described as an age-related phenomenon. In this study we aimed to analyze the prognostic impact of -Y in the context of the IPSS-R cytogenetic classification, evaluate the clinical significance of the percentage of metaphases with isolated -Y, and test whether finding -Y may predispose to over-diagnose MDS in patients with borderline morphological features. We evaluated 3581 male patients from the Spanish MDS Registry with a diagnosis of MDS or chronic myelomonocytic leukemia (CMML). -Y was identified in 177 patients (4.9%). Compared with the 2246 male patients with normal karyotype, -Y group showed a reduced risk of leukemic transformation that did not translate into a survival advantage. The overall survival and the risk of leukemic transformation were not influenced by the percentage of metaphases with -Y. The -Y group was not enriched in patients with minor morphologic traits of dysplasia, suggesting that the better outcome in the -Y group cannot be explained by enrichment in cases misdiagnosed as MDS. In conclusion, our results support the current recommendation of classifying patients with -Y within the very good risk category of the IPSS-R for MDS and rule out a selection bias as a possible explanation of this better outcome. An analysis of the molecular basis of MDS with isolated -Y would be of interest as it may provide a biological basis of protection against progression to acute leukemia.


Assuntos
Biomarcadores Tumorais/genética , Aberrações Cromossômicas , Cromossomos Humanos Y , Leucemia Mielomonocítica Crônica/genética , Síndromes Mielodisplásicas/genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Cariotipagem , Leucemia Mielomonocítica Crônica/patologia , Masculino , Síndromes Mielodisplásicas/patologia , Prognóstico , Taxa de Sobrevida
4.
Genes Chromosomes Cancer ; 55(4): 322-7, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26690722

RESUMO

Chromosomal translocations are rare in the myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). With the exception of t(3q), translocations are not explicitly considered in the cytogenetic classification of the IPSS-R and their impact on disease progression and patient survival is unknown. The present study was aimed at determining the prognostic impact of translocations in the context of the cytogenetic classification of the IPSS-R. We evaluated 1,653 patients from the Spanish Registry of MDS diagnosed with MDS or CMML and an abnormal karyotype by conventional cytogenetic analysis. Translocations were identified in 168 patients (T group). Compared with the 1,485 patients with abnormal karyotype without translocations (non-T group), the T group had a larger proportion of patients with refractory anemia with excess of blasts and higher scores in both the cytogenetic and global IPSS-R. Translocations were associated with a significantly shorter survival and higher incidence of transformation into AML at univariate analysis but both features disappeared after multivariate adjustment for the IPSS-R cytogenetic category. Patients with single or double translocations other than t(3q) had an outcome similar to those in the non-T group in the intermediate cytogenetic risk category of the IPSS-R. In conclusion, the presence of translocations identifies a subgroup of MDS/CMML patients with a more aggressive clinical presentation that can be explained by a higher incidence of complex karyotypes. Single or double translocations other than t(3q) should be explicitly considered into the intermediate risk category of cytogenetic IPSS-R classification.


Assuntos
Leucemia Mielomonocítica Crônica/genética , Síndromes Mielodisplásicas/genética , Translocação Genética , Idoso , Feminino , Humanos , Cariotipagem , Masculino , Pessoa de Meia-Idade , Prognóstico , Espanha , Taxa de Sobrevida
5.
Acta Haematol ; 135(2): 94-100, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26509426

RESUMO

Recurrent translocations are uncommon in myelodysplastic syndromes (MDS). Three new recurrent translocations, namely der(12)t(3;12)(q13;p13), t(11;13;22)(q13;q14;q12) and der(17)t(13;17)(q21;p13), identified by conventional cytogenetics (CC) in 4 MDS patients, were further characterized using a panel of commercial and homemade fluorescence in situ hybridization (FISH) probes. The goal of this study was to determine the precise breakpoints and to identify genes that could be related with the neoplastic process. Half of the breakpoints (4/8) were precisely identified and in the remaining half they were narrowed to a region ranging from 14 to 926 kb. All the studied breakpoints had interstitial or terminal deletions ranging from 536 kb to 89 Mb, and only those 7 Mb were detected by CC. The genes located in or around the breakpoints described in our study have not been previously related to MDS. The deleted regions include the ETV6 and RB1 genes, among others, and exclude the TP53 gene. FISH studies were useful to refine the breakpoints of the translocations, but further studies are needed to determine the role of the involved genes in the neoplastic process.


Assuntos
Síndromes Mielodisplásicas/genética , Translocação Genética , Idoso , Idoso de 80 Anos ou mais , Mapeamento Cromossômico , Feminino , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/patologia , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Repressoras/genética , Proteína do Retinoblastoma/genética , Proteína Supressora de Tumor p53/genética
6.
Genes Chromosomes Cancer ; 52(10): 920-7, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23893575

RESUMO

Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder characterized with highly variable clinical course. The most common chromosomal abnormalities in CLL, using conventional and molecular cytogenetics, are trisomy 12, del(13)(q14), del(11)(q22-23), del(17)(p13), and del(6)(q21). Whereas the prognostic marker such as IGHV mutational status remains stable during course of the diseases, chromosomal aberrations may be acquired over time. The aim of this study was to determine the incidence, and biological significance of clonal evolution (CE) using conventional and molecular cytogenetics and its relationship with prognostic markers such as CD38, ZAP70, and the mutational status of IGHV and NOTCH1. One hundred and forty-three untreated CLL patients were included in the study. The median time interval between analyses was 32 months (range 6-156 months). Forty-seven patients (33%) had CE as evidenced by detection of new cytogenetic abnormalities during follow-up. CE was not correlated with high expression of ZAP70, unmutated IGHV genes or NOTCH1 mutations. Multivariate analysis revealed that CE and IGHV mutation status had a significant impact on TFS. The combination of conventional and molecular cytogenetics increased the detection of CE, this phenomenon probably being a reflection of genomic instability and conferring a more aggressive clinical course.


Assuntos
Evolução Clonal , Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina , Leucemia Linfocítica Crônica de Células B/genética , Mutação , Receptor Notch1/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Aberrações Cromossômicas , Análise Mutacional de DNA , Feminino , Humanos , Hibridização in Situ Fluorescente , Incidência , Masculino , Pessoa de Meia-Idade , Análise Multivariada
7.
Genes Chromosomes Cancer ; 52(8): 753-63, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23686965

RESUMO

The infrequency of translocations in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemias (CMML) makes their identification and reporting interesting for the recognition of the recurrent ones and the genes involved in these neoplasias. The aims of this study were to identify new translocations associated with MDS and CMML and to establish their frequency in a cohort of 8,016 patients from the Spanish Group of MDS database. The karyotype was evaluable in 5,654 (70%) patients. Among those, 2,014 (36%) had chromosomal abnormalities, including 213 (10%) translocations identified in 195 patients. The translocations were balanced in 183 (86%) cases and unbalanced in 30 (14%) cases. All chromosomes were found to be involved in translocations, with the single exception of the Y chromosome. The chromosomes most frequently involved were in decreasing frequency: 3, 1, 7, 2, 11, 5, 12, 6, and 17. Translocations were found in karyotypes as the unique chromosomal abnormality (33%), associated with another chromosomal abnormality (11%), as a part of a complex karyotype (17%), and as a part of a monosomal karyotype (38%). There were 155 translocations not previously described in MDS or CMML and nine of them appeared to be recurrent.


Assuntos
Cromossomos Humanos/genética , Leucemia Mielomonocítica Crônica/genética , Síndromes Mielodisplásicas/genética , Translocação Genética/genética , Cromossomos Humanos/classificação , Humanos , Cariótipo , Leucemia Mielomonocítica Crônica/patologia , Síndromes Mielodisplásicas/patologia
8.
Acta Haematol ; 129(2): 65-71, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23154527

RESUMO

Significant progress in the understanding of the genetic basis of acute myeloid leukemia (AML) has been made during the last 30 years. The aim of the present study was to assess whether the detection of recurrent gene rearrangements by fluorescent in situ hybridization (FISH) studies and NPM1 and FLT3 gene mutations by molecular studies added clinically relevant information to the karyotype in 113 AML patients. Thus, FISH and molecular studies were found to add new information in 22 and 55% of the patients, respectively, particularly in cases with normal karyotype (NK) or when a cytogenetic analysis failed. Patients with NK changed their genetic risk group to favorable in 27 and 29% of cases using FISH and molecular biology studies, respectively. Our results demonstrate that molecular biology and FISH studies provide relevant information in AML and should be routinely performed.


Assuntos
Leucemia Mieloide Aguda/genética , Proteínas Nucleares/genética , Tirosina Quinase 3 Semelhante a fms/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Citogenética , Feminino , Rearranjo Gênico , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico
9.
Genes Chromosomes Cancer ; 51(9): 881-9, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22619094

RESUMO

Chronic lymphocytic leukemia (CLL) is the most common leukemia among adults in Western countries. Chromosomal abnormalities commonly found using conventional cytogenetics and FISH are del(11)(q22-23), trisomy 12, del(13)(q14), and del(17)(p13). Trisomy 12 is the most frequent numerical abnormality in CLL. It can appear isolated or associated with other chromosomal aberrations, including t(14;18)(q32;q21) and trisomy 18. The aim of this study was to determine whether CLL patients with isolated trisomy 12 or associated with other chromosomal alterations have different clinico-pathological features, including a different distribution NOTCH1 mutation. Patients were classified into four groups: Group 1, isolated trisomy 12 (n=14); Group 2, trisomy 12 plus trisomy 18 (n=4); Group 3, trisomy 12 plus t(14;18) (n=8); and Group 4: patients with trisomy 12 plus other abnormalities not involving BCL2 (n=28). The Binet stage and expression of ZAP70 were significantly different among cytogenetic groups. NOTCH1 mutations were detected in 6/12 (50%) patients from Group 1, 4/25 (16%) patients from Group 4, and in no patient from groups 2 and 3 (P=0.020). Patients in Group 2 had a more rapid disease progression (median Treatment-free Survival 2 months) as against patients from Groups 1 (50 months), 3 (69 months), or 4 (68 months; P=0.001). These findings indicate that the distribution of NOTCH1 mutations in CLL with trisomy 12 is heterogeneous and that the presence of additional chromosomal abnormalities such as trisomy 18 could change the prognosis of these patients.


Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 12/genética , Leucemia Linfocítica Crônica de Células B/genética , Mutação/genética , Receptor Notch1/genética , Trissomia/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , DNA de Neoplasias/genética , Progressão da Doença , Feminino , Humanos , Hibridização in Situ Fluorescente , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , Reação em Cadeia da Polimerase , Prognóstico , Taxa de Sobrevida
10.
Br J Haematol ; 156(5): 612-8, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22150335

RESUMO

The analysis of chromosomal abnormalities provides significant prognostic information in patients with chronic lymphocytic leukaemia (CLL), a disease with a highly heterogeneous clinical course. Chromosomal abnormalities commonly found are trisomy 12, del(13)(q14), del(11)(q22-23), del(17)(p13) and del(6)(q21). Translocations are present in some patients and affect regions recurrently involved in CLL. This report describes the clinical and pathological characteristics of four CLL patients showing a new recurrent chromosomal abnormality dic(8;17)(p11;p11), that implied loss of the TP53 gene in all cases. In addition, TP53 gene was mutated in three out of four patients. Mechanically, Low Copy Repeats (LCR) in 17p12 and 8p11 may explain the origin of the translocation by non-allelic homologous recombination (NAHR). Isolated dic(8;17)(p11;p11) in patients with mutated IGHV genes status may not have the same prognostic impact as other mutations or deletions affecting the TP53 gene. Larger series are needed to better evaluate the clinical impact of this chromosomal aberration during the course of the disease.


Assuntos
Deleção de Genes , Genes p53/genética , Leucemia Linfocítica Crônica de Células B/genética , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 8/genética , Análise Mutacional de DNA/métodos , Feminino , Genes de Cadeia Pesada de Imunoglobulina/genética , Humanos , Hibridização in Situ Fluorescente , Cariótipo , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Translocação Genética
11.
Cancer Genet Cytogenet ; 170(2): 115-20, 2006 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-17011981

RESUMO

Chromosomal rearrangements involving 3q26 are a recurrent aberration in malignant myeloid disorders. Several of these rearrangements involve the EVI1 oncogene or its surrounding sequences and are associated with a poor prognosis. Fluorescence in situ hybridization (FISH) studies using bacterial artificial chromosome (BAC) clones were conducted to determine whether the EVI1 locus was rearranged in nine patients with hematological malignancies carrying 3q abnormalities. A dual-color probe was constructed with nine BACs; centromeric clones covering 1 Mb and including the EVI1 gene were labeled with a red fluorescent dye and telomeric clones covering 1 Mb were labeled with a green fluorescent dye. Two patients showed normal copies of the EVI1 locus, four patients showed one EVI1 locus rearranged (in all of them the breakpoint on 3q26 was telomeric to EVI1), one patient showed one copy of the EVI1 locus translocated to another chromosome, one patient showed one copy of the EVI1 locus rearranged and the other copy translocated, and one patient showed one extra copy of the EVI1 locus. In four cases, FISH studies using the EVI1 clones detected different 3q abnormalities not previously found by conventional cytogenetics. FISH analysis with BAC clones was a useful tool for identifying the chromosome breakpoints affecting the EVI1 locus in patients with 3q26 rearrangements.


Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 3 , Proteínas de Ligação a DNA/genética , Neoplasias Hematológicas/genética , Hibridização in Situ Fluorescente , Proto-Oncogenes/genética , Fatores de Transcrição/genética , Cromossomos Artificiais Bacterianos , Duplicação Gênica , Humanos , Proteína do Locus do Complexo MDS1 e EVI1 , Translocação Genética
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