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1.
Artigo em Inglês | MEDLINE | ID: mdl-31677197

RESUMO

T-cell prolymphocytic leukemia (T-PLL) is an aggressive tumor with leukemic presentation of mature T-lymphocytes. Here, we aimed at characterizing the initial events in the molecular pathogenesis of T-PLL and particularly, at determining the point in T-cell differentiation when the hallmark oncogenic events, that is, inv(14)(q11q32)/t(14;14)(q11;q32) and t(X;14)(q28;q11) occur. To this end, we mined whole genome and transcriptome sequencing data of 17 and 11 T-PLL cases, respectively. Mapping of the 14q32.1 locus breakpoints identified only TCL1A, which was moreover significantly overexpressed in T-PLL as compared to benign CD4+ and CD8+ T-cells, as the only common oncogenic target of aberrations. In cases with t(14;14), the breakpoints mapped telomeric and in cases with inv(14) centromeric or in the 3'-untranslated region of TCL1A. Regarding the T-cell receptor alpha (TRA) locus-TCL1A breakpoint junctions, all 17 breakpoints involved recombination signal sequences and 15 junctions contained nontemplated (N-) nucleotides. All T-PLL cases studied carried in-frame TRA rearrangements on the intact allele, which skewed significantly toward usage of distal/central TRAV/TRAJ gene segments as compared to the illegitimate TRA rearrangements. Our findings suggest that the oncogenic TRA-TCL1A/MTCP1 rearrangements in T-PLL occur during opening of the TRA locus, that is, during the progression from CD4+ immature single positive to early double positive thymocyte stage, just before physiologic TCL1A expression is silenced. The cell carrying such an oncogenic event continues maturation and rearranges the second TRA allele to achieve a functional T-cell receptor. Thereafter, it switches off RAG and DNTT expression in line with the mature T-cell phenotype at presentation of T-PLL.

3.
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.

4.
Blood ; 133(9): 940-951, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30538135

RESUMO

Mantle cell lymphoma (MCL) is characterized by the t(11;14)(q13;q32) translocation resulting in overexpression of cyclin D1. However, a small subset of cyclin D1- MCL has been recognized, and approximately one-half of them harbor CCND2 translocations while the primary event in cyclin D1-/D2- MCL remains elusive. To identify other potential mechanisms driving MCL pathogenesis, we investigated 56 cyclin D1-/SOX11+ MCL by fluorescence in situ hybridization (FISH), whole-genome/exome sequencing, and gene-expression and copy-number arrays. FISH with break-apart probes identified CCND2 rearrangements in 39 cases (70%) but not CCND3 rearrangements. We analyzed 3 of these negative cases by whole-genome/exome sequencing and identified IGK (n = 2) and IGL (n = 1) enhancer hijackings near CCND3 that were associated with cyclin D3 overexpression. By specific FISH probes, including the IGK enhancer region, we detected 10 additional cryptic IGK juxtapositions to CCND3 (6 cases) and CCND2 (4 cases) in MCL that overexpressed, respectively, these cyclins. A minor subset of 4 cyclin D1- MCL cases lacked cyclin D rearrangements and showed upregulation of CCNE1 and CCNE2. These cases had blastoid morphology, high genomic complexity, and CDKN2A and RB1 deletions. Both genomic and gene-expression profiles of cyclin D1- MCL cases were indistinguishable from cyclin D1+ MCL. In conclusion, virtually all cyclin D1- MCLs carry CCND2/CCND3 rearrangements with immunoglobulin genes, including a novel IGK/L enhancer hijacking mechanism. A subset of cyclin D1-/D2-/D3- MCL with aggressive features has cyclin E dysregulation. Specific FISH probes may allow the molecular identification and diagnosis of cyclin D1- MCL.


Assuntos
Ciclina D2/genética , Ciclina D3/genética , Elementos Facilitadores Genéticos , Rearranjo Gênico , Cadeias Leves de Imunoglobulina/genética , Linfoma de Célula do Manto/genética , Idoso , Ciclina D1/genética , Ciclina D1/metabolismo , Feminino , Humanos , Linfoma de Célula do Manto/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Transcrição SOXC/genética , Translocação Genética
6.
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
7.
Oncotarget ; 8(33): 54297-54303, 2017 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-28903342

RESUMO

Genomic complexity identified by chromosome banding analysis (CBA) predicts a worse clinical outcome in CLL patients treated either with standard or new treatments. Herein, we analyzed the clinical impact of complex karyotypes (CK) with or without high-risk FISH deletions (ATM and/or TP53, HR-FISH) in a cohort of 1045 untreated MBL/CLL patients. In all, 99/1045 (9.5%) patients displayed a CK. Despite ATM and TP53 deletions were more common in CK (25% vs 7%; P < 0.001; 40% vs 5%; P < 0.001, respectively), only 44% (40/90) patients with TP53 deletions showed a CK. CK group showed a significant higher two-year cumulative incidence of treatment (48% vs 20%; P < 0.001), as well as a shorter overall survival (OS) (79 mo vs not reached; P < 0.001). When patients were categorized regarding CK and HR-FISH, those with both characteristics showed the worst median OS (52 mo) being clearly distinct from those non-CK and non-HR-FISH (median not reached), but no significant differences were detected between cases with only CK or HR-FISH. Both CK and TP53 deletion remained statistically significant in the multivariate analysis for OS. In conclusion, CK group is globally associated with advanced disease and poor prognostic markers. Further investigation in larger cohorts with CK lacking HR-FISH is needed to elucidate which mechanisms underlie the poor outcome of this subgroup.

9.
Am J Surg Pathol ; 41(7): 877-886, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28288039

RESUMO

MYC translocation is a defining feature of Burkitt lymphoma (BL), and the new category of high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 translocations, and occurs in 6% to 15% of diffuse large B-cell lymphomas (DLBCLs). The low incidence of MYC translocations in DLBCL makes the genetic study of all these lymphomas cumbersome. Strategies based on an initial immunophenotypic screening to select cases with a high probability of carrying the translocation may be useful. LMO2 is a germinal center marker expressed in most lymphomas originated in these cells. Mining gene expression profiling studies, we observed LMO2 downregulation in BL and large B-cell lymphoma (LBCL) with MYC translocations, and postulated that LMO2 protein expression could assist to identify such cases. We analyzed LMO2 protein expression in 46 BLs and 284 LBCL. LMO2 was expressed in 1/46 (2%) BL cases, 146/268 (54.5%) DLBCL cases, and 2/16 (12.5%) high-grade B-cell lymphoma cases with MYC and BCL2 and/or BCL6 translocations. All BLs carried MYC translocation (P<0.001), whereas LMO2 was only positive in 6/42 (14%) LBCL with MYC translocation (P<0.001). The relationship between LMO2 negativity and MYC translocation was further analyzed in different subsets of tumors according to CD10 expression and cell of origin. Lack of LMO2 expression was associated with the detection of MYC translocations with high sensitivity (87%), specificity (87%), positive predictive value and negative predictive value (74% and 94%, respectively), and accuracy (87%) in CD10 LBCL. Comparing LMO2 and MYC protein expression, all statistic measures of performance of LMO2 surpassed MYC in CD10 LBCL. These findings suggest that LMO2 loss may be a good predictor for the presence of MYC translocation in CD10 LBCL.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Biomarcadores Tumorais/metabolismo , Linfoma de Burkitt/metabolismo , Genes myc , Proteínas com Domínio LIM/metabolismo , Linfoma Difuso de Grandes Células B/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Translocação Genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfoma de Burkitt/genética , Linfoma de Burkitt/patologia , Criança , Pré-Escolar , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
10.
Am J Hematol ; 92(2): 149-154, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27859564

RESUMO

Myelodysplastic syndromes (MDS) are the commonest hematologic malignancies in the elderly. Since many patients with MDS actually die from age-related ailments, the very disease burden of MDS remains largely unknown. This registry-based study was aimed at investigating the excess mortality attributable to MDS. We analyzed 7,408 adult patients diagnosed with primary MDS from 1980 to 2014. Excess mortality was estimated by comparing the patients' survival with that expected in the matched general population. Median age of patients was 74 years, 58% were males, and 65% belonged to the lower risk categories of the Revised International Prognostic Scoring System (IPSS-R). Excess mortality accounted for three-fourths of the all-cause mortality and was mainly driven by factors unrelated to leukemic transformation. Excess mortality increased with the IPSS-R risk category [Incidence rate ratio (IRR): 2.1, 95% CI: 1.9-2.3; P < .001]. Older age and male sex retained an independent association with higher excess mortality after discounting demographic effects. Excess mortality increased in the most recent periods just in the higher risk IPSS-R categories (IRR: 1.2; 95% CI: 1.1-1.3 when comparing periods 2007-14, 2000-06, and 1980-99). In conclusion, MDS carry a significant excess mortality, even in the lower risk categories, that is mainly driven by factors unrelated to leukemic transformation, and increases with older age, male sex, and poorer risk categories. Excess mortality has increased in recent years in the higher risk patients, which might be ascribed to a parallel increase in age-related comorbidities. Our results claim for more comprehensive treatment strategies for patients with MDS. Am. J. Hematol. 92:149-154, 2017. © 2016 Wiley Periodicals, Inc.


Assuntos
Síndromes Mielodisplásicas/mortalidade , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Bases de Dados Factuais , Feminino , Humanos , Incidência , Masculino , Mortalidade/tendências , Prognóstico , Fatores Sexuais , Espanha , Análise de Sobrevida
11.
Am J Surg Pathol ; 40(2): 192-201, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26426381

RESUMO

Splenic diffuse red pulp small B-cell lymphoma (SDRPL) is considered an indolent neoplasm and its pathogenesis is not well known. We investigated the molecular characteristics of 19 SDRPL patients, 5 of them with progressive disease. IGHV genes were mutated in 9/13 (69%). Cytogenetic and molecular studies identified complex karyotypes in 2 cases, and IGH rearrangements in 3, with PAX5 and potentially TCL1 as partners in each one of them. Copy number arrays showed aberrations in 69% of the tumors, including recurrent losses of 10q23, 14q31-q32, and 17p13 in 3, and 9p21 in 2 cases. Deletion of 7q31.3-q32.3 was present in only 1 case and no trisomies 3 or 18 were detected. NOTCH1 and MAP2K1 were mutated in 2 cases each, whereas BRAF, TP53, and SF3B1 were mutated each in single cases. No mutations were found in NOTCH2 or MYD88. Four of the 5 patients with aggressive disease had mutations in NOTCH1 (2 cases), TP53 (1 case), and MAP2K1 (1 case). The progression-free survival of patients with mutated genes was significantly shorter than in the unmutated (P=0.011). These findings show that SDRPL share some mutated genes but not chromosomal alterations, with other splenic lymphomas, that may confer a more aggressive behavior.


Assuntos
Biomarcadores Tumorais/genética , Linfoma de Células B/genética , MAP Quinase Quinase 1/genética , Mutação , Receptor Notch1/genética , Neoplasias Esplênicas/genética , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Biomarcadores Tumorais/análise , Biópsia , Chile , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Progressão da Doença , Intervalo Livre de Doença , Europa (Continente) , Feminino , Deleção de Genes , Dosagem de Genes , Rearranjo Gênico , Genes de Cadeia Pesada de Imunoglobulina , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Linfoma de Células B/química , Linfoma de Células B/patologia , Linfoma de Células B/terapia , Masculino , Pessoa de Meia-Idade , Técnicas de Diagnóstico Molecular , Fenótipo , Valor Preditivo dos Testes , Fatores de Risco , Neoplasias Esplênicas/química , Neoplasias Esplênicas/patologia , Neoplasias Esplênicas/terapia , Fatores de Tempo
12.
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
13.
Br J Haematol ; 172(1): 48-55, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26559905

RESUMO

We investigated CD49d (also termed ITGA4) expression and its biological and clinical correlations in 415 patients with chronic lymphocytic leukaemia. CD49d expression was stable over the course of the disease. A high expression of CD49d (>30%) was found in 142/415 (34%) patients and was associated with progressive disease (advanced clinical stage, high serum lactate dehydrogenase or ß2 -microglobulin levels; all p < 0·05) and aggressive disease biology (increased ZAP70 or CD38, unmutated IGHV, trisomy 12, mutations of NOTCH1 and SF3B1; all P < 0·05). A higher CD49d expression was also associated with a lower blood lymphocyte count and a higher number of lymphoid areas involved by the disease. Patients with high CD49d expression were treated more frequently (55% vs. 27%; P < 0·001) and earlier (median time to treatment [TTT] 65·4 months vs. not reached; P < 0·001) than those with low CD49d expression. However, no significant differences in response rates were observed. In the subgroup of patients with mutated IGHV, high CD49d expression was predictive of a shorter TTT while other markers, such as ZAP70 and CD38, were not. In conclusion, in this study CD49d expression correlated with high-risk CLL biomarkers and proved to be useful for separating patients with mutated IGHV into two different prognostic groups.


Assuntos
Biomarcadores Tumorais/sangue , Cadeias Pesadas de Imunoglobulinas/genética , Integrina alfa4/sangue , Leucemia Linfocítica Crônica de Células B/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/terapia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Fatores de Tempo
14.
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
15.
Cancer Cell Int ; 15: 122, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26696777

RESUMO

BACKGROUND: The resulting clinical impact of the combined use of G-CSF with chemotherapy as a chemosensitizing strategy for treatment of acute myeloid leukemia (AML) patients is still controversial. In this study, the effect of ex vivo treatment with G-CSF on AML primary blasts was studied. METHODS: Peripheral blood mononuclear cells from AML patients were treated with G-CSF at increasing doses, alone or in co-culture with HS-5 stromal cells. Cell viability and surface phenotype was determined by flow cytometry 72 h after treatment. For clonogenicity assays, AML primary samples were treated for 18 h with G-CSF at increasing concentrations and cultured in methyl-cellulose for 14 days. Colonies were counted based on cellularity and morphology criteria. RESULTS: The presence of G-CSF reduced the overall viability of AML cells co-cultured with bone marrow stroma; whereas, in absence of stroma, a negligible effect was observed. Moreover, clonogenic capacity of AML cells was significantly reduced upon treatment with G-CSF. Interestingly, reduction in the AML clonogenic capacity correlated with the sensitivity to chemotherapy observed in vivo. CONCLUSIONS: These ex vivo results would provide a biological basis to data available from studies showing a clinical benefit with the use of G-CSF as a priming agent in patients with a chemosensitive AML and would support implementation of further studies exploring new strategies of chemotherapy priming in AML.

16.
Leuk Res ; 2015 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-26354683

RESUMO

Although specific prognostic models for chronic myelomonocytic leukemia (CMML) exist, few are based on large series of patients. MD Anderson prognostic score (MDAPS) has been the most useful for CMML risk assessment. Due to recent emergence of CMML-specific prognostic scoring system (CPSS) and Mayo prognostic model, we compared the three scores. One hundred forty-six CMML patients diagnosed between 1998 and 2014 were retrospectively analyzed. Univariate analysis was performed to assess prognostic impact on overall survival (OS) and leukemia-free survival (LFS) of the variables composing the scores and all items showed prognostic value on OS with the exception of the presence of circulating immature myeloid cells. Regarding LFS, only CPSS variables, bone marrow blast ≥10% and an absolute monocyte count >10×109/L had an impact. When the scores were applied, all showed an impact on OS and retained their significance in multivariate analysis. By using ROC curves and C-index, CPSS showed a slightly better predictive value for mortality and leukemia transformation. Variables composing the three indexes were compared in multivariate analysis and only CPSS parameters and platelets<100×109/L retained their significance. Based on these findings, by adding platelet count to CPSS, a new score was implemented (CPSS-P) showing the best risk prediction capability in our series. This study reinforces the validity of the tested scores.

17.
Genes Chromosomes Cancer ; 54(11): 668-80, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26305789

RESUMO

Chronic lymphocytic leukemia (CLL) is a common disease with highly variable clinical course. Several recurrent chromosomal alterations are associated with prognosis and may guide risk-adapted therapy. We have developed a targeted genome-wide array to provide a robust tool for ascertaining abnormalities in CLL and to overcome limitations of the 4-marker fluorescence in situ hybridization (FISH). DNA from 180 CLL patients were hybridized to the qChip®Hemo array with a high density of probes covering commonly altered loci in CLL (11q22-q23, 13q14, and 17p13), nine focal regions (2p15-p16.1, 2p24.3, 2q13, 2q36.3-q37.1, 3p21.31, 8q24.21, 9p21.3, 10q24.32, and 18q21.32-q21.33) and two larger regions (6q14.1-q22.31 and 7q31.33-q33). Overall, 86% of the cases presented copy number alterations (CNA) by array. There was a high concordance of array findings with FISH (84% sensitivity, 100% specificity); all discrepancies corresponded to subclonal alterations detected only by FISH. A chromothripsis-like pattern was detected in eight cases. Three showed concomitant shattered 5p with gain of TERT along with isochromosome 17q. Presence of 11q loss was associated with shorter time to first treatment (P = 0.003), whereas 17p loss, increased genomic complexity, and chromothripsis were associated with shorter overall survival (P < 0.001, P = 0.001, and P = 0.02, respectively). In conclusion, we have validated a targeted array for the diagnosis of CLL that accurately detects, in a single experiment, all relevant CNAs, genomic complexity, chromothripsis, copy number neutral loss of heterozygosity, and CNAs not covered by the FISH panel. This test may be used as a practical tool to stratify CLL patients for routine diagnostics or clinical trials.


Assuntos
Aberrações Cromossômicas , Leucemia Linfocítica Crônica de Células B/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Dosagem de Genes , Genoma Humano , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Masculino , Pessoa de Meia-Idade , Mutação , Análise de Sequência com Séries de Oligonucleotídeos/métodos
18.
Nature ; 526(7574): 519-24, 2015 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-26200345

RESUMO

Chronic lymphocytic leukaemia (CLL) is a frequent disease in which the genetic alterations determining the clinicobiological behaviour are not fully understood. Here we describe a comprehensive evaluation of the genomic landscape of 452 CLL cases and 54 patients with monoclonal B-lymphocytosis, a precursor disorder. We extend the number of CLL driver alterations, including changes in ZNF292, ZMYM3, ARID1A and PTPN11. We also identify novel recurrent mutations in non-coding regions, including the 3' region of NOTCH1, which cause aberrant splicing events, increase NOTCH1 activity and result in a more aggressive disease. In addition, mutations in an enhancer located on chromosome 9p13 result in reduced expression of the B-cell-specific transcription factor PAX5. The accumulative number of driver alterations (0 to ≥4) discriminated between patients with differences in clinical behaviour. This study provides an integrated portrait of the CLL genomic landscape, identifies new recurrent driver mutations of the disease, and suggests clinical interventions that may improve the management of this neoplasia.


Assuntos
Leucemia Linfocítica Crônica de Células B/genética , Mutação/genética , Regiões 3' não Traduzidas/genética , Processamento Alternativo/genética , Linfócitos B/metabolismo , Proteínas de Transporte/genética , Cromossomos Humanos Par 9/genética , Análise Mutacional de DNA , DNA de Neoplasias/genética , Elementos Facilitadores Genéticos/genética , Genômica , Humanos , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Fator de Transcrição PAX5/biossíntese , Fator de Transcrição PAX5/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Receptor Notch1/genética , Receptor Notch1/metabolismo , Fatores de Transcrição/genética
19.
Prog. obstet. ginecol. (Ed. impr.) ; 58(5): 209-220, jun. 2015. ilus, tab, graf
Artigo em Espanhol | IBECS | ID: ibc-135518

RESUMO

La evaluación del cribado de cáncer de cuello uterino en el sistema público de salud de Cataluña ha identificado, en mujeres de 25-65 años, una cobertura citológica a 3 años del 40,8%; un intervalo entre citologías de 2,4 años y una pérdida de seguimiento del 50% a 3 años. La introducción de la prueba de detección del virus del papiloma humano en el seguimiento de mujeres con resultados citológicos de atipias intraepiteliales de significado indeterminado y como adyuvante a la citología en mujeres con una historia de cribado inadecuada facilita el manejo y detección de las mujeres en riesgo de desarrollar una neoplasia intraepitelial cervical de grado 2 o peor (CIN2 + ). La prueba de detección del virus del papiloma humano ha demostrado tener una buena sensibilidad y especificidad a tres años para la detección de CIN2+ resultando ser sensiblemente superior a la citología. Por otro lado, ha demostrado tener unos niveles de reproducibilidad altos entre laboratorios y un fácil manejo en situaciones de rutina. El uso de protocolos homogéneos y la existencia de herramientas informáticas de amplio uso han permitido una evaluación equitativa y fiable entre centros. El protocolo ha sido complementado con actividades de formación a profesionales y una monitorización periódica de todas las actividades. En conclusión, la implantación de un programa de cribado poblacional y la introducción de la prueba de detección del virus del papiloma humano en mujeres mayores de 30 años puede mejorar considerablemente los esfuerzos para la prevención secundaria del cáncer de cuello uterino en Cataluña (AU)


Analysis of the cervical cancer screening activity in the National Health System of Catalonia has identified a cytological coverage at 3 years of 40.8%, an interval of 2.4 years between Pap smears and a loss to follow-up of 50% at 3 years in women aged 25-65 years old. The introduction of human papillomavirus testing in the management of women with cytological results of atypical squamous cell of undetermined significance and as an adjunct to cytology in women with a history of inadequate screening has facilitated the management and detection of women at risk of developing cervical intraepithelial neoplasia grade 2 or worse (CIN2 + ). Human papillomavirus testing has demonstrated high sensitivity and specificity at 3 years in the detection of CIN2 + and was substantially superior to cytology. Furthermore, it had good inter-laboratory reproducibility and was easy to perform in routine situations. The use of uniform protocols and the extensive availability of software tools have allowed comprehensive and reliable assessment across Catalonia. The protocol has been complemented with educational interventions for healthcare professionals and regular monitoring of all activities. We conclude that the introduction of organized screening programs and human papillomavirus testing among women older than 30 years can greatly enhance efforts for the secondary prevention of CC in Catalonia (AU)


Assuntos
Humanos , Feminino , Programas de Rastreamento/métodos , Neoplasias do Colo do Útero/epidemiologia , Papillomaviridae/patogenicidade , Papiloma/epidemiologia , Detecção Precoce de Câncer/métodos , Saúde Pública/estatística & dados numéricos , Políticas Públicas de Saúde , Prevenção Secundária/organização & administração , Teste de Papanicolaou
20.
Ecancermedicalscience ; 9: 532, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25987901

RESUMO

The early detection of intraepithelial lesions of the cervix, through the periodic examination of cervical cells, has been fundamental for the prevention of invasive cervical cancer and its related mortality. In this report, we summarise the cervical cancer screening activities carried out in Catalonia, Spain, within the National Health System during 2008-2011. The study population covers over two million women resident in the area. The evaluation includes 758,690 cervical cytologies performed on a total of 595,868 women. The three-year coverage of cervical cytology among women aged between 25 and 65 years was 40.8%. About 50% of first screened women with negative results had not returned to the second screening round. The introduction of high-risk human papillomavirus DNA (HPV) detection, as a primary screening cotest with cytology among women over age 40 with a poor screening history, significantly improved the detection of cervical intraepithelial neoplasia grade 2 or worse (CIN2+), being far superior to cytology alone. Cotesting did not improve the detection of CIN2+. The use of the HPV test for the triage of atypical squamous cell undetermined significance (ASC-US) improved the selection of women at high risk of CIN2+. Sampling (both cytology and HPV test) was largely performed by midwives (66.7%), followed by obstetricians (23.8%) and nurses (7%). Over half of the centres (54.8%) had full use of online medical records. During the study period, educational activities for professionals and for women were carried out periodically. The organisation of screening as a population activity in which women are actively called to the screening visit and the introduction of HPV testing as a primary screening tool are strongly recommended to ensure the maximum population impact in the reduction of the cervical cancer burden.

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