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1.
Artigo em Inglês | MEDLINE | ID: mdl-31512579

RESUMO

We report here a case of primitive plasma cell leukemia with immunoglobulin (Ig) E. IgE myeloma is an exceptional variant of multiple myeloma, with a very poor prognosis. Its biological diagnosis requires specific analyzes in order to detect IgE gammopathy. Plasma cell leukemia (PCL) is also a very rare and very severe form of multiple myeloma. There are two variants: primitive PCL (pPCL) occurring de novo and secondary PCL (sPCL), evolution of a preexisting myeloma. Its diagnosis is essentially biological since it is defined by a blood plasmocytosis greater than 2 G/L or 20% of the leucocytes.

3.
Blood ; 133(11): 1205-1216, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30602617

RESUMO

Recent evidence suggests that complex karyotype (CK) defined by the presence of ≥3 chromosomal aberrations (structural and/or numerical) identified by using chromosome-banding analysis (CBA) may be relevant for treatment decision-making in chronic lymphocytic leukemia (CLL). However, many challenges toward the routine clinical application of CBA remain. In a retrospective study of 5290 patients with available CBA data, we explored both clinicobiological associations and the clinical impact of CK in CLL. We found that patients with ≥5 abnormalities, defined as high-CK, exhibit uniformly dismal clinical outcomes, independently of clinical stage, TP53 aberrations (deletion of chromosome 17p and/or TP53 mutations [TP53abs]), and the expression of somatically hypermutated (M-CLL) or unmutated immunoglobulin heavy variable genes. Thus, they contrasted with CK cases with 3 or 4 aberrations (low-CK and intermediate-CK, respectively) who followed aggressive disease courses only in the presence of TP53abs. At the other end of the spectrum, patients with CK and +12,+19 displayed an exceptionally indolent profile. Building upon CK, TP53abs, and immunoglobulin heavy variable gene somatic hypermutation status, we propose a novel hierarchical model in which patients with high-CK exhibit the worst prognosis, whereas those with mutated CLL lacking CK or TP53abs, as well as CK with +12,+19, show the longest overall survival. Thus, CK should not be axiomatically considered unfavorable in CLL, representing a heterogeneous group with variable clinical behavior. High-CK with ≥5 chromosomal aberrations emerges as prognostically adverse, independent of other biomarkers. Prospective clinical validation is warranted before ultimately incorporating high-CK in risk stratification of CLL.

4.
Genes Chromosomes Cancer ; 57(11): 533-540, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30203893

RESUMO

Trisomy 12 (tri12) is the second most frequent chromosomal aberration (15%-20%) in chronic lymphocytic leukemia (CLL). Tri12 confers an intermediate prognosis but is a heterogeneous entity. We examined whether additional mutational or chromosomal alterations might impact tri12 patient outcomes. This retrospective study, carried out by the French Innovative Leukemia Organization, included 188 tri12 patients with comprehensive information on immunoglobulin heavy chain (IGHV) gene status, karyotypic/FISH abnormalities, and NOTCH1, TP53, SF3B1, and MYD88 mutations. The main cytogenetic abnormalities associated with tri12 were del(13q) (25%), additional trisomies (14%) (including tri19 (10%) and tri18 (4%)), 14q32 translocations (10%), del(17p) (6.5%), del(14q) (4%), and del(11q) (4%). Unmutated (UM) IGHV, NOTCH1, and TP53, mutations were identified in respectively 66%, 25%, and 8.5% of cases. Multivariate analyses showed that additional trisomies (HR = 0.43, 95% CI = 0.23-0.78, P = .01) were associated with a significantly longer time to first treatment in Binet stage A patients and with a lower risk of relapse (HR = 0.37, 95% CI = 0.15-0.9, P = .03) in the overall tri12 population. Binet stage B/C, TP53 disruption, and UM IGHV status were associated with a shorter time to next treatment, while Binet stage B/C (HR = 4, 95% CI = 1.6-4.9, P = .002) and TP53 disruption (HR = 5, 95% CI = 1.94-12.66, P = .001) conferred shorter overall survival in multivariate comparisons. These data indicate that additional cytogenetic and mutational abnormalities, and particularly additional trisomies, IGHV status, and TP53 disruption, influence tri12 patient outcomes and could improve risk stratification in this population.

5.
Br J Haematol ; 182(6): 843-850, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30004110

RESUMO

Isolated trisomy 8 (+8) is a frequent cytogenetic abnormality in the myelodysplastic syndromes (MDS), but its characteristics are poorly reported. We performed a retrospective study of 138 MDS patients with isolated +8, classified or reclassified as MDS (excluding MDS/myeloproliferative neoplasm). Myeloproliferative (MP) features were defined by the repeated presence of one of the following: white blood cell count >10 × 109 /l, myelemia (presence of circulating immature granulocytes with a predominance of more mature forms) >2%, palpable splenomegaly. Fifty-four patients (39·1%) had MP features: 28 at diagnosis, 26 were acquired during evolution. MP forms had more EZH2 (33·3% vs. 12·0% in non-MP, P = 0·047), ASXL1 (66·7% vs. 42·3%, P = 0·048) and STAG2 mutations (77·8% vs. 21·7%, P = 0·006). Median event-free survival (EFS) and overall survival (OS) were 25 and 27 months for patients with MP features at diagnosis, versus 28 (P = 0·15) and 39 months (P = 0·085) for those without MP features, respectively. Among the 57 patients who received hypomethylating agent (HMA), OS was lower in MP cases (13 months vs. 23 months in non-MP cases, P = 0.02). In conclusion, MP features are frequent in MDS with isolated +8. MP forms had more EZH2, ASXL1 and STAG2 mutations, responded poorly to HMA, and tended to have poorer survival than non-MP forms.

7.
Am J Hematol ; 93(3): 375-382, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29194741

RESUMO

Chronic lymphocytic leukemia (CLL) with 17p deletion (17p-) is associated with a lack of response to standard treatment and thus the worst possible clinical outcome. Various chromosomal abnormalities (including unbalanced translocations, deletions, ring chromosomes and isochromosomes) result in the loss of 17p and one copy of the TP53 gene. The objective of the present study was to determine whether the type of chromosomal abnormality leading to 17p- and the additional aberrations influenced the prognosis in a series of 195 patients with 17p-CLL. Loss of 17p resulted primarily from an unbalanced translocation (70%) with several chromosome partners (the most frequent being chromosome 18q), followed by deletion 17p (23%), monosomy 17 (8%), isochromosome 17q [i(17q)] (5%) and a ring chromosome 17 (2%). In a univariate analysis, monosomy 17, a highly complex karyotype (≥5 abnormalities), and 8q24 gain were associated with poor treatment-free survival, and i(17q) (P = .04), unbalanced translocations (P = .03) and 8q24 gain (P = .001) were significantly associated with poor overall survival. In a multivariate analysis, 8q24 gain remained a significant predictor of poor overall survival. We conclude that 17p deletion and 8q24 gain have a synergistic impact on outcome, and so patients with this "double-hit" CLL have a particularly poor prognosis. Systematic, targeting screening for 8q24 gain should therefore be considered in cases of 17p- CLL.

9.
Leuk Res ; 63: 72-77, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29112938

RESUMO

Karyotype according to the revised IPSS is a strong independent prognostic factor for overall survival (OS) in myelodysplastic syndromes (MDS), however established in untreated patients. The prognostic impact of cytogenetics and cytogenetic response (CyR) in MDS patients receiving azacitidine (AZA) remains uncertain. We examined the prognostic value of baseline cytogenetics and CyR for overall response rate (ORR) and OS in 702 AZA-treated higher risk MDS and low blast count acute myeloid leukemia (AML), including 493 (70%) with abnormal karyotype. None of the cytogenetic abnormalities had significant impact on ORR (43.9%) or complete response (15.35%), except 3q abnormalities and complex karyotypes, which were associated with a lower ORR. OS differed significantly across all R-IPSS cytogenetic subgroups (p<10-4) but patients with non complex del(7q) had similar survival as patients with normal cytogenetics. CyR was achieved in 32% of the 281 evaluable patients with abnormal cytogenetics, was complete (CCyR) in 71 (25.3%) patients. We found no correlation between hematological response and cytogenetic response and 21% of the patients with CCyR did not achieve morphological response. In the 281 patients, we found no impact of CyR on survival, but when restricting to MDS (ie: <20% marrow blasts) achievement of CCyR was associated with better OS.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/uso terapêutico , Aberrações Cromossômicas , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Cariotipagem , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/patologia , Prognóstico , Indução de Remissão , Fatores de Risco , Taxa de Sobrevida
10.
Blood ; 130(16): 1832-1844, 2017 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-28790105

RESUMO

Multiple cytogenetic subgroups have been described in adult Philadelphia chromosome (Ph)-negative B-cell precursor (BCP) acute lymphoblastic leukemia (ALL), often comprising small numbers of patients. In this study, we aimed to reassess the prognostic value of cytogenetic abnormalities in a large series of 617 adult patients with Ph-negative BCP-ALL (median age, 38 years), treated in the intensified Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-2003/2005 trials. Combined data from karyotype, DNA index, fluorescence in situ hybridization, and polymerase chain reaction screening for relevant abnormalities were centrally reviewed and were informative in 542 cases (88%), allowing classification in 10 exclusive primary cytogenetic subgroups and in secondary subgroups, including complex and monosomal karyotypes. Prognostic analyses focused on cumulative incidence of failure (including primary refractoriness and relapse), event-free survival, and overall survival. Only 2 subgroups, namely t(4;11)/KMT2A-AFF1 and 14q32/IGH translocations, displayed a significantly worse outcome in this context, still observed after adjustment for age and after censoring patients who received allogeneic stem cell transplantation (SCT) in first remission at SCT time. A worse outcome was also observed in patients with low hypodiploidy/near triploidy, but this was likely related to their higher age and worse tolerance to therapy. The other cytogenetic abnormalities, including complex and monosomal karyotypes, had no prognostic value in these intensive protocols designed for adult patients up to the age of 60 years.


Assuntos
Aberrações Cromossômicas , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Adolescente , Adulto , Aberrações Cromossômicas/estatística & dados numéricos , Ensaios Clínicos como Assunto/estatística & dados numéricos , Análise Citogenética , Feminino , Humanos , Cariotipagem , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto/estatística & dados numéricos , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Adulto Jovem
11.
Ann Biol Clin (Paris) ; 74(5): 561-567, 2016 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-27628190

RESUMO

Acquired recurrent cytogenetic abnormalities are frequent in chronic lymphocytic leukaemia (CLL). They can be associated with good or poor prognostic factors, and also with gene mutations. Chromosomal abnormalities could be clonal or sub-clonal. Assessing the TP53 status (deletion/mutation) is currently mandatory before treating patients. The search for 11q deletion (ATM gene) is also recommended. Finally, the prognostic value of other chromosomal abnormalities including complex karyotype is still debated.


Assuntos
Análise Citogenética/normas , Leucemia Linfocítica Crônica de Células B/terapia , Aberrações Cromossômicas , Análise Citogenética/métodos , Análise Citogenética/tendências , França , Hematologia/organização & administração , Hematologia/normas , Hematologia/tendências , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/genética , Prognóstico , Sociedades Médicas/organização & administração , Sociedades Médicas/normas
12.
Ann Biol Clin (Paris) ; 74(5): 517-523, 2016 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-27477946

RESUMO

The recent years have witnessed tremendous progress in the molecular characterization of Philadelphia-negative myeloproliferative neoplasms (MPN). Beside a better understanding of pathophysiology, these abnormalities often constitute very useful diagnostic markers in diseases where exclusion of reactive states used to be the strongest argument. However, conventional and molecular cytogenetics keep a major interest in MPN, either as a second line exploration, in cases where no molecular marker is available, for differential diagnosis or as a proof of clonality or in first line for cases with hyperleukocytosis, for differential diagnosis (CML), to evidence druggable targets (ABL1, RET, PDGFR…) or as a prognosis marker. In this article, we will review the interest of cytogenetic techniques in myeloproliferative neoplasms.


Assuntos
Análise Citogenética/normas , Hematologia/normas , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/diagnóstico , Transtornos Mieloproliferativos/diagnóstico , Análise Citogenética/métodos , Análise Citogenética/tendências , Hematologia/organização & administração , Humanos , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/genética , Transtornos Mieloproliferativos/genética , Cromossomo Filadélfia , Sociedades Médicas/normas
13.
Ann Biol Clin (Paris) ; 74(5): 525-534, 2016 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-27546835

RESUMO

The myelodysplastic syndromes (MDS) are preleukemic diseases of elderly patients characterized by defective maturation of clonal hematopoietic progenitor cells resulting in peripheral blood cytopenias. Clonal chromosomal abnormalities are heterogeneous and can be detected in less than 50% of patients with de novo MDS and more frequently in secondary MDS (up to 80%). The karyotype plays an important role in the pathogenesis, diagnosis, and prognosis to evaluate the risk of leukemic transformation and, more recently, in treatment allocation. The gold standard for cytogenetic diagnosis in MDS is conventional chromosome banding analyses of bone marrow metaphases. The most frequent abnormalities are deletions and losses of chromosomes 5 (-5/5q-) and 7 (-7/7q-) and various isolated or combined abnormalities. Fluorescent in situ hybridization and array comparative genomic hybridization can reveal cryptic genetic abnormalities but are not recommended in routine diagnosis. New techniques including next generation sequencing revealed somatic driver mutations especially those affecting genes involved in RNA splicing or those harboring important prognostic value (TP53, ASXL1…) with potential applications in clinical practice in the future.


Assuntos
Análise Citogenética/estatística & dados numéricos , Hematologia/normas , Síndromes Mielodisplásicas/terapia , Hibridização Genômica Comparativa , Análise Citogenética/métodos , Análise Citogenética/normas , França , Hematologia/organização & administração , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hibridização in Situ Fluorescente , Síndromes Mielodisplásicas/diagnóstico , Sociedades Médicas/normas
14.
Ann Biol Clin (Paris) ; 74(5): 509-510, 2016 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-27465598

RESUMO

Cytogenetic analysis is still important in the management of many hematological malignancies, despite the new techniques available such as the high-throughput sequencing analysis, and the discovery of many acquired gene mutations in these diseases. The Groupe francophone de cytogénétique hématologique (GFCH) published in 2004 the recommendations for the cytogenetic management of hematological malignancies. It reports here the update of these recommendations, with a review of the literature for each disease.


Assuntos
Análise Citogenética , Neoplasias Hematológicas/diagnóstico , Hematologia/normas , Análise Citogenética/métodos , Análise Citogenética/normas , Análise Citogenética/tendências , França , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/terapia , Hematologia/organização & administração , Humanos , Sociedades Médicas/normas
15.
Int J Cancer ; 139(8): 1759-63, 2016 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-27270786

RESUMO

TP53 abnormalities lead to resistance to purine analogues and are found in over 40% of patients with refractory chronic lymphocytic leukemia (CLL). At diagnosis, no more than 5% of patients carry the 17p deletion, most cases harbour mutations within the other TP53 allele. The incidence of a TP53 mutation as the only alteration is approximately 5%, but this depends on the sensitivity of the technique. Recently, having a complex karyotype has been considered a strong adverse prognostic factor. However, there are no longitudinal studies simultaneously examining the presence of the 17p deletion, TP53 mutations and karyotype abnormalities. We conducted a retrospective longitudinal study of 31 relapsed/refractory CLL patients. Two to six blood samples per patient were analyzed, with a median follow-up of 8 years. In this report, we assessed the sequence of events of TP53 clonal evolution and correlated the presence of TP53 abnormalities to genetic instability during progression and treatment. Next-generation sequencing allowed the early detection of TP53 mutated clones and was able to be performed on a routine basis, demonstrating an excellent correlation between the Illumina and Ion Torrent technologies. We concluded that TP53 mutations are early events and precede clonal evolution to complex karyotypes. We strongly recommend the early and iterated detection of TP53 mutations in progressive cases.


Assuntos
Genes p53 , Leucemia Linfocítica Crônica de Células B/genética , Mutação , Proteína Supressora de Tumor p53/genética , Progressão da Doença , Humanos , Hibridização in Situ Fluorescente , Cariótipo , Leucemia Linfocítica Crônica de Células B/sangue , Leucemia Linfocítica Crônica de Células B/patologia , Estudos Longitudinais , Estudos Retrospectivos
16.
Am J Hematol ; 90(8): 737-8, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26017030

RESUMO

Acquired α-thalassemia myelodysplastic syndrome (MDS) (ATMDS) is an acquired syndrome characterized by a somatic point mutation or splicing defect in the ATRX gene in patients with myeloid disorders, primarily MDS. In a large MDS patient series, the incidence of ATMDS was below 0.5%. But no large series has yet assessed the incidence of ATMDS in microcytic MDS. In this study, we focused on patients with MDS and unexplained microcytosis, which was defined as absence of iron deficiency, inflammatory disease, or history of inherited hemoglobinopathy. Our data confirm the low frequency of ATRX mutations in MDS: 0% in an unselected clinical trial cohort of 80 low risk MDS, 0.2-0.8% in a multicenter registry of 2,980 MDS and 43% of MDS with unexplained microcytosis in this same registry. In addition, we reported four novel mutations of the ATRX gene in ATMDS. This study further determines the frequency of ATRX mutations and highlights the importance of microcytosis to detect ATRX mutations within MDS patients.


Assuntos
DNA Helicases/genética , Células-Tronco Hematopoéticas/patologia , Taxa de Mutação , Síndromes Mielodisplásicas/genética , Proteínas Nucleares/genética , Talassemia alfa/genética , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Expressão Gênica , Células-Tronco Hematopoéticas/metabolismo , Humanos , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/patologia , Análise de Sobrevida , Proteína Nuclear Ligada ao X , Talassemia alfa/metabolismo , Talassemia alfa/mortalidade , Talassemia alfa/patologia
17.
Am J Hematol ; 90(1): E5-8, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25263543

RESUMO

Only a minority of chronic lymphocytic leukemia (CLL) patients harboring a positive direct antiglobulin test (DAT) will develop autoimmune hemolytic anemia (AIHA). In a single institution cohort of 378 CLL patients, 56 patients (14.8%) had at least one positive DAT during the course of the disease, either at diagnosis or later. We found no relationship between the time of the first positive DAT and overall survival (OS). However, patients with a positive DAT who did not develop AIHA had the same adverse outcome as patients who developed AIHA. Of the patients who were in Binet stage A at diagnosis, those with a positive DAT had a significantly shorter OS, regardless of their IGHV mutational status, however, there was a strong association with VH1-69. By multivariate analysis, a positive DAT was found to be an independent adverse prognostic factor for OS. Thus, DAT represents a strong adverse prognostic factor and its determination should be repeated during follow-up.


Assuntos
Anemia Hemolítica Autoimune/diagnóstico , Teste de Coombs , Leucemia Linfocítica Crônica de Células B/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia Hemolítica Autoimune/etiologia , Anemia Hemolítica Autoimune/imunologia , Anemia Hemolítica Autoimune/mortalidade , Estudos de Coortes , Complemento C3d/análise , Interpretação Estatística de Dados , Progressão da Doença , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Imunoglobulina G/sangue , Estimativa de Kaplan-Meier , Leucemia Linfocítica Crônica de Células B/complicações , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico
18.
Leuk Res ; 38(7): 751-5, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24836762

RESUMO

TP53 mutations are found in 5-10% of MDS and AML, where they are generally associated with complex karyotype and an overall poor prognosis. However, the impact of TP53 mutations in MDS treated with azacitidine (AZA) remains unclear. We analyzed TP53 mutations in 62 patients with high risk MDS or AML treated with AZA. A TP53 mutation was found in 23 patients (37.1%), associated with complex karyotype in 18 (78.3%) of them. TP53 mutations had no significant impact on response or complete response to AZA (p=0.60 and p=0.26, respectively). By univariate analysis, OS was negatively influenced by the presence of TP53 mutation (median OS 12.4 months versus 23.7 months, p<10(-4)), abnormal cytogenetics (median OS 14.4 months vs 33 months, p=0.02) complex cytogenetics (median OS 12.7 months versus 23.7 months, p=0.0005), and a diagnosis of AML (median 14.5 months vs 21.2 months for MDS or CMML, p=0.02). By multivariate analysis, only TP53 mutational status (HR 2.89 (95% confidence interval 1.38-6.04; p=0.005) retained statistical significance for OS. Results were similar when the analysis was restricted to MDS and CMML patients, excluding AML (HR=2.46 (95% confidence interval: 1.1-6.4); p=0.04)). Thus, TP53 mutations strongly correlated with poorer survival in higher risk MDS and AML treated with AZA.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/uso terapêutico , Genes p53 , Leucemia Mieloide Aguda/genética , Mutação , Síndromes Mielodisplásicas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/mortalidade , Prognóstico
19.
Genes Chromosomes Cancer ; 53(8): 657-66, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24729385

RESUMO

Deletions of the long arm of chromosome 14 [del(14q)] are rare but recurrently observed in mature B-cell neoplasms, particularly in chronic lymphocytic leukemia (CLL). To further characterize this aberration, we studied 81 cases with del(14q): 54 of CLL and 27 of small lymphocytic lymphoma (SLL), the largest reported series to date. Using karyotype and fluorescence in situ hybridization (FISH), the most frequent additional abnormality was trisomy 12 (tri12), observed in 28/79 (35%) cases, followed by del13q14 (12/79, 15%), delTP53 (11/80, 14%) delATM (5/79, 6%), and del6q21 (3/76, 4%). IGHV genes were unmutated in 41/53 (77%) patients, with a high frequency of IGHV1-69 (21/52, 40%). NOTCH1 gene was mutated in 14/45 (31%) patients. There was no significant difference in cytogenetic and molecular abnormalities between CLL and SLL. Investigations using FISH and SNP-array demonstrated the heterogeneous size of the 14q deletions. However, a group with the same del(14)(q24.1q32.33) was identified in 48% of cases. In this group, tri12 (P = 0.004) and NOTCH1 mutations (P = 0.02) were significantly more frequent than in the other patients. In CLL patients with del(14q), median treatment-free survival (TFS) was 27 months. In conclusion, del(14q) is associated with tri12 and with pejorative prognostic factors: unmutated IGHV genes (with over-representation of the IGHV1-69 repertoire), NOTCH1 mutations, and a short TFS.


Assuntos
Cromossomos Humanos Par 14/genética , Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Leucemia Linfocítica Crônica de Células B/genética , Receptor Notch1/genética , Trissomia/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 12/genética , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Mutação
20.
Am J Hematol ; 88(4): 306-11, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23460398

RESUMO

Germline heterozygous alterations of the tumor-suppressor gene neurofibromatosis-1 (NF1) lead to neurofibromatosis type 1, a genetic disorder characterized by a higher risk to develop juvenile myelomonocytic leukemia and/or acute myeloid leukemia (AML). More recently, somatic 17q11 deletions encompassing NF1 have been described in many adult myeloid malignancies. In this context, we aimed to define NF1 involvement in AML. We screened a total of 488 previously untreated de novo AML patients for the NF1 deletion using either array comparative genomic hybridization (aCGH) or real-time quantitative PCR/fluorescence in situ hybridization approaches. We also applied massively parallel sequencing for in depth mutation analysis of NF1 in 20 patients including five NF1-deleted patients. We defined a small ∼0.3 Mb minimal deleted region involving NF1 by aCGH and an overall frequency of NF1 deletion of 3.5% (17/485). NF1 deletion is significantly associated with unfavorable cytogenetics and with monosomal karyotype notably. We discovered six NF1 variants of unknown significance in 7/20 patients of which only one out of four disappeared in corresponding complete remission sample. In addition, only one out of five NF1-deleted patients has an acquired coding mutation in the remaining allele. In conclusion, direct NF1 inactivation is infrequent in de novo AML and may be a secondary event probably involved in leukemic progression.


Assuntos
Deleção de Genes , Leucemia Mieloide Aguda/genética , Neurofibromatose 1/genética , Neurofibromina 1/genética , Adolescente , Adulto , Idoso , Alelos , Hibridização Genômica Comparativa , Feminino , Frequência do Gene , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , Neurofibromina 1/deficiência , Reação em Cadeia da Polimerase em Tempo Real
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