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1.
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.

2.
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
3.
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
4.
Diagn Pathol ; 10: 158, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26369323

RESUMO

We report an unusual case of a 70-year-old male with history of hereditary spherocytosis (HS) and secondary paraspinal extramedullary hematopoiesis with a concurrent follicular lymphoma. The lesion presented as a thoracic paraspinal mass of 9 cm, extending longitudinally between T6 and T9 vertebral bodies. Incisional biopsy revealed that this mass included mature hematopoietic tissue compatible with extramedullary hematopoiesis (EMH). The tissue also presented an extensive and diffuse infiltration by an atypical lymphoid population composed predominantly by small cells. The immunohistochemical study revealed that the atypical lymphoid population had a germinal center phenotype, consistent with the diffuse variant of follicular lymphoma (FL). The simultaneous presence of both EMH and FL in the same lesion made the interpretation and the final diagnosis of this case difficult. The presence of EMH in this clinical context may eclipse the diagnosis of the underlying lymphoproliferative neoplasm. The close association between the tumor cells and extramedullary hematopoietic tissue in the absence of lymphadenopathies or other tissue involvement suggests a relationship of this tumor with the recently described primary FL of the bone marrow.


Assuntos
Hematopoese Extramedular , Linfoma Folicular/complicações , Linfoma Folicular/patologia , Esferocitose Hereditária/complicações , Idoso , Biomarcadores Tumorais/análise , Humanos , Imuno-Histoquímica , Masculino
5.
Rev. esp. patol ; 48(3): 170-175, jul.-sept. 2015. tab, ilus
Artigo em Inglês | IBECS | ID: ibc-139262

RESUMO

We report a unusual case of a 45-year-old woman with a massive metaplastic carcinoma of the breast with a complex admixture of components including giant pleomorphic cells, sarcomatoid areas, cysts with undifferentiated stratified epithelium, squamous carcinoma foci, high grade comedo-type ductal carcinoma in situ, high grade invasive carcinoma not otherwise specified (NOS) and foci with osseous differentiation. An extensive immunohistochemical panel showed expression of both epithelial and mesenchymal markers. The self-renewal marker SOX2 was expressed in different cell types, which was interpreted as a sign of the pluripotency what can in turn explain the diversity of histologic lineages present in this tumour (AU)


Presentamos el caso de una mujer de 45 años con un carcinoma metaplásico de presentación clínica exuberante, que mostraba una combinación compleja de diversos componentes, incluyendo células gigantes pleomórficas, áreas sarcomatoides, quistes con epitelio escamoso indiferenciado, focos de carcinoma escamoso, carcinoma ductal in situ de tipo comedo, carcinoma infiltrante de tipo usual y focos de diferenciación ósea. El amplio panel inmunohistoquímico mostraba expresión de marcadores tanto epiteliales como mesenquimales. El marcador de autorenovación SOX2 se expresaba en diferentes tipos celulares, lo cual fue interpretado como un signo de pluripotencialidad y podría explicar la diversidad de tipos histológicos presentes en este tumour (AU)


Assuntos
Feminino , Humanos , Neoplasias da Mama/patologia , Metaplasia/complicações , Metaplasia/patologia , Carcinoma Ductal de Mama/patologia , Imuno-Histoquímica/métodos , Imuno-Histoquímica
6.
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
8.
Genes Chromosomes Cancer ; 53(9): 788-97, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24915757

RESUMO

Deletion of 13q14 as the sole abnormality is a good prognostic marker in chronic lymphocytic leukemia (CLL). Nonetheless, the prognostic value of reciprocal 13q14 translocations [t(13q)] with related 13q losses has not been fully elucidated. We described clinical and biological characteristics of 25 CLL patients with t(13q), and compared with 62 patients carrying interstitial del(13q) by conventional G-banding cytogenetics (CGC) [i-del(13q)] and 295 patients with del(13q) only detected by fluorescence in situ hybridization (FISH) [F-del(13q)]. Besides from the CLL FISH panel (D13S319, CEP12, ATM, TP53), we studied RB1 deletions in all t(13q) cases and a representative group of i-del(13q) and F-del(13q). We analyzed NOTCH1, SF3B1, and MYD88 mutations in t(13q) cases by Sanger sequencing. In all, 25 distinct t(13q) were described. All these cases showed D13S319 deletion while 32% also lost RB1. The median percentage of 13q-deleted nuclei did not differ from i-del(13q) patients (73% vs. 64%), but both were significantly higher than F-del(13q) (52%, P < 0.001). Moreover, t(13q) patients showed an increased incidence of biallelic del(13q) (52% vs. 11.3% and 14.9%, P < 0.001) and higher rates of concomitant 17p deletion (37.5% vs. 8.6% and 7.2%, P < 0.001). RB1 involvement was significantly higher in the i-del(13q) group (79%, P < 0.001). Two t(13q) patients (11.8%) carried NOTCH1 mutations. Time to first treatment in t(13q) and i-del(13q) was shorter than F-del(13q) (67, 44, and 137 months, P = 0.029), and preserved significance in the multivariate analysis. In conclusion, t(13q) and del(13q) patients detected by CGC constitute a subgroup within the 13q-deleted CLL patients associated with a worse clinical outcome.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 13/genética , Leucemia Linfocítica Crônica de Células B/diagnóstico , Translocação Genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Aberrações Cromossômicas , Estudos de Coortes , Feminino , Humanos , Cariótipo , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Fator 88 de Diferenciação Mieloide/genética , Fosfoproteínas/genética , Prognóstico , Fatores de Processamento de RNA , Receptor Notch1/genética , Proteína do Retinoblastoma/genética , Ribonucleoproteína Nuclear Pequena U2/genética
9.
Br J Haematol ; 163(1): 47-54, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23869550

RESUMO

Losses in 13q as a sole abnormality confer a good prognosis in chronic lymphocytic leukaemia (CLL). Nevertheless, its heterogeneity has been demonstrated and the clinical significance of biallelic 13q deletions remains controversial. We compared the clinico-biological characteristics of a series of 627 patients harbouring isolated 13q deletions by fluorescence in situ hybridization (FISH), either monoallelic (13q × 1), biallelic (13q × 2), or the coexistence of both clones (13qM). The most frequent 13q deletion was 13q × 1 (82·1%), while 13q × 2 and 13qM represented 8·6% and 9·3% of patients respectively. The median percentage of altered nuclei significantly differed across groups: 55%, 72·5% and 80% in 13q × 1, 13q × 2 and 13qM (P < 0·001). However, no significant differences in the clinical outcome among 13q groups were found. From 84 patients with sequential FISH studies, eight patients lost the remaining allele of 13q whereas none of them changed from 13q × 2 to the 13q × 1 group. The percentage of abnormal cells detected by FISH had a significant impact on the five-year cumulative incidence of treatment and the overall survival, 90% being the highest predictive power cut-off. In conclusion, loss of the remaining 13q allele is not enough to entail a worse prognosis in CLL. The presence of isolated 13q deletion can be risk-stratified according to the percentage of altered cells.


Assuntos
Alelos , Deleção Cromossômica , Cromossomos Humanos Par 13 , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Bandeamento Cromossômico , Feminino , Humanos , Hibridização in Situ Fluorescente , Leucemia Linfocítica Crônica de Células B/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento
10.
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
11.
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
12.
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
13.
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
14.
Am J Med Genet A ; 158A(5): 1071-6, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22488686

RESUMO

Congenital balanced reciprocal translocations are one of the most frequent structural chromosomal aberrations in the population. We report a familial translocation t(12;22)(p13.3;pter) responsible for intellectual disabilities and congenital anomalies characterized by FISH and array CGH. Two patients carried a der(12)t(12;22)(p13.3;pter), resulting in a 6 Mb 12pter deletion. Patients presented with intellectual disabilities, pre- and post-natal growth retardation, ponderal development delay, global hypotonia, feeding problems and dysmorphic features. Two relatives presented with the reciprocal 12pter duplication, which had no clinical manifestations associated. For this translocation, we propose a mechanism based on a non-allelic recombination model, in which recombination of direct oriented segmental duplications between non-homologous chromatids leads to the reciprocal translocation. The characterization of this translocation has been critical for the family. Translocation carriers have a risk of 40% of having offspring carrying unbalanced products. 12p13.3 deletion carriers present with a recognizable syndrome and on the contrary, 12p13.3 duplication carriers present without clinical manifestations. Other published cases of 12p13.3 duplication show that this syndrome has a variable phenotype. It is advisable to delineate the duplication size and to discard other genetic aberrations, in order to give an accurate genetic counseling in patients carrying 12pter duplications.


Assuntos
Cromossomos Humanos Par 12/genética , Rearranjo Gênico , Deficiência Intelectual/genética , Deleção de Sequência , Família , Humanos , Duplicações Segmentares Genômicas , Translocação Genética
15.
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
16.
Leuk Res ; 34(11): 1437-41, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20226525

RESUMO

Although conventional cytogenetics is considered the gold standard to detect chromosomal abnormalities in myelodysplastic syndromes (MDS), fluorescence in situ hybridization (FISH) is being increasingly used additionally. However, the real contribution of FISH analysis in the cytogenetic diagnosis of MDS has not been well defined. The aim of this study was to evaluate whether FISH studies are able to reveal chromosomal abnormalities in MDS patients undetected by conventional cytogenetics. One hundred seventy-four FISH studies were performed on bone marrow samples of 60 patients with MDS. The number of FISH studies in each patient was variable (1-5). FISH studies confirmed the G-banding cytogenetic findings in 99.4% (153/154) of samples and detected cytogenetic abnormalities in 25% (5/20) of cases in which the conventional cytognetic study failed. These results indicate that FISH studies provide relevant information in MSD in which the conventional cytogenetic analysis was unsuccessful but add little value to a normal katyotype in conventional cytogenetic analysis.


Assuntos
Hibridização in Situ Fluorescente/normas , Síndromes Mielodisplásicas/genética , Exame de Medula Óssea , Aberrações Cromossômicas , Bandeamento Cromossômico , Análise Citogenética/métodos , Análise Citogenética/normas , Humanos , Hibridização in Situ Fluorescente/estatística & dados numéricos , Síndromes Mielodisplásicas/diagnóstico
18.
Genes Chromosomes Cancer ; 49(5): 439-51, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20143418

RESUMO

Mantle cell lymphoma (MCL) is a mature B-cell neoplasm with an aggressive behavior, characterized by the t(11;14)(q13;q32). Several secondary genetic abnormalities with a potential role in the oncogenic process have been described. Studies of large MCL series using conventional cytogenetics, and correlating with proliferation and survival, are scarce. We selected 145 MCL cases at diagnosis, displaying an aberrant karyotype, from centers belonging to the Spanish Cooperative Group for Hematological Cytogenetics. Histological subtype, proliferative index and survival data were ascertained. Combined cytogenetic and molecular analyses detected CCND1 translocations in all cases, mostly t(11;14)(q13;q32). Secondary aberrations were present in 58% of patients, the most frequent being deletions of 1p, 13q and 17p, 10p alterations and 3q gains. The most recurrent breakpoints were identified at 1p31-32, 1p21-22, 17p13, and 1p36. Aggressive blastoid/pleomorphic variants displayed a higher karyotypic complexity, a higher frequency of 1p and 17p deletions and 10p alterations, a higher proliferation index and poor survival. Gains of 3q and 13q and 17p13 losses were associated with reduced survival times. Interestingly, gains of 3q and 17p losses added prognostic significance to the morphology in a multivariate analysis. Our findings confirm previous observations indicating that proliferation index, morphology and several secondary genetic alterations (3q gains and 13q and 17p losses) have prognostic value in patients with MCL. Additionally, we observed that 3q gains and 17p losses detected by conventional cytogenetics are proliferation-independent prognostic markers indicating poor outcome.


Assuntos
Aberrações Cromossômicas , Linfoma de Célula do Manto/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Processos de Crescimento Celular/genética , Distribuição de Qui-Quadrado , Estudos de Coortes , Ciclina D1/genética , Análise Citogenética , Feminino , Rearranjo Gênico , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Linfoma de Célula do Manto/diagnóstico , Linfoma de Célula do Manto/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais
19.
Genes Chromosomes Cancer ; 47(12): 1086-97, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18709664

RESUMO

Mantle cell lymphoma (MCL) is genetically characterized by 11q13 translocations leading to the overexpression of CCND1, and additional secondary genomic alterations that may be important in the progression of this disease. We have analyzed 22 MCL cases and 10 MCL cell lines using multicolor fluorescence in situ hybridization (M-FISH), FISH, and comparative genomic hybridization (CGH). The 19 cases with abnormal karyotype showed the t(11;14)(q13;q32) translocation and, additionally, 89% of cases showed both numerical (n = 58) and structural (n = 77) aberrations. All but one MCL cell line showed t(11;14) and structural and numerical alterations in highly complex karyotypes. Besides 11 and 14, the most commonly rearranged chromosomes were 1, 8, and 10 in the tumors and 1, 8, and 9 in the cell lines. No recurrent translocations other than the t(11;14) were identified. However, we identified 17 recurrent breakpoints, the most frequent being 1p22 and 8p11, each observed in four cases and two cell lines. Interestingly, five tumors and four cell lines displayed a complex t(11;14), cryptic in one case and two cell lines, preferentially involving chromosome 8. In typical MCL, ATM gene deletions were significantly associated with a high number of structural and numerical alterations. In conclusion, MCL does not have recurrent translocations other than t(11;14), but shows recurrent chromosomal breakpoints. Furthermore, most MCL harbor complex karyotypes with a high number of both structural and numerical alterations affecting several common breakpoints, leading to various balanced and unbalanced translocations.


Assuntos
Quebra Cromossômica , Linfoma de Célula do Manto/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Deleção Cromossômica , Mapeamento Cromossômico , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 14/genética , Análise Citogenética , Feminino , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Masculino , Pessoa de Meia-Idade , Translocação Genética
20.
Fetal Diagn Ther ; 23(2): 126-31, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18046070

RESUMO

OBJECTIVES: To report our experience over the past 10 years of chorionic villi sampling (CVS) prenatal diagnosis in a high-risk population for chromosomal anomalies, and to analyze, according to the results, the advantages and disadvantages of using quantitative fluorescence polymerase chain reaction (QF-PCR) in amniotic fluid with respect to a conventional semi-direct cytogenetic CVS method in a retrospective theoretical review. METHODS: We performed 3,868 cytogenetic analyses from CVS using a semi-direct culture method in a selected high-risk population for chromosomal abnormalities and we compare our findings with the theoretical results obtained using QF-PCR on amniotic fluid. RESULTS: The rate of chromosomal anomalies detected with the semi-direct CVS cytogenetic study, excluding confined placental mosaicism (CPM), was 6.8%. 26.3% of all them would be missed by using QF-PCR only and among them, 21.4% of cases would represent a severe adverse obstetric outcome. CONCLUSIONS: We think that semi-direct CVS cytogenetic analysis in comparison with QF-PCR in amniotic fluid is similarly rapid, performed earlier and more complete, allowing the chromosomal diagnosis in the first trimester of gestation. We propose the use of QF-PCR as an additional method to semi-direct CVS analysis in order to avoid false-negative results, as a rapid alternative to long-term culture.


Assuntos
Amostra da Vilosidade Coriônica/métodos , Aberrações Cromossômicas , Aconselhamento Genético/métodos , Diagnóstico Pré-Natal/métodos , Adulto , Amostra da Vilosidade Coriônica/normas , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Feminino , Aconselhamento Genético/normas , Humanos , Gravidez , Diagnóstico Pré-Natal/normas , Estudos Retrospectivos
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