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1.
Genes Chromosomes Cancer ; 59(1): 6-12, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31112346

RESUMO

The cytogenetic alterations in renal oncocytoma (RO) are poorly understood. We analyzed 130 consecutive RO for karyotypic alterations. Clonal chromosome abnormalities were identified in 63 (49%) cases, which could be categorized into three classes of mutually exclusive cytogenetic categories. Class 1 (N = 20) RO had diploid karyotypes with characteristic 11q13 rearrangement in balanced translocations with 10 or more different chromosome partners in all cases. We identified recurrent translocation partners at 5q35, 6p21, 9p24, 11p13-14, and 11q23, and confirmed that CCND1 gene rearrangement at 11q13 utilizing fluorescence in situ hybridization (FISH). Class 2 RO (N = 25) exhibited hypodiploid karyotypes with loss of chromosome 1 and/or losses of Y in males and X in females in all cases. The class 3 tumors comprising of 18 cases showed diverse types of abnormalities with the involvement of two or more chromosomes exclusive of abnormalities seen in classes 1 and 2 tumors. Furthermore, karyotypically uninformative cases were subjected to FISH analysis to identify classes 1 and 2 abnormalities. In this group, we found similar frequencies of CCND1 rearrangement, loss of chromosome 1 or Y as with karyotypically abnormal cases. We validated our results against 91 tumors from the Mitelman database. Correlation of clinical data with all the three classes of ROs showed no clear evidence of overall patient survival. Our findings support the hypothesis that RO exhibit three principal cytogenetic categories, which may have different roles in initiation and/or progression. These cytogenetic markers provide a key tool in the diagnostic evaluation of RO.

2.
J Urol ; 193(5): 1479-85, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25498568

RESUMO

PURPOSE: Accurate discrimination of benign oncocytoma and malignant renal cell carcinoma is useful for planning appropriate treatment strategies for patients with renal masses. Classification of renal neoplasms solely based on histopathology can be challenging, especially the distinction between chromophobe renal cell carcinoma and oncocytoma. In this study we develop and validate an algorithm based on genomic alterations for the classification of common renal neoplasms. MATERIALS AND METHODS: Using TCGA renal cell carcinoma copy number profiles and the published literature, a classification algorithm was developed and scoring criteria were established for the presence of each genomic marker. As validation, 191 surgically resected formalin fixed paraffin embedded renal neoplasms were blindly submitted to targeted array comparative genomic hybridization and classified according to the algorithm. CCND1 rearrangement was assessed by fluorescence in situ hybridization. RESULTS: The optimal classification algorithm comprised 15 genomic markers, and involved loss of VHL, 3p21 and 8p, and chromosomes 1, 2, 6, 10 and 17, and gain of 5qter, 16p, 17q and 20q, and chromosomes 3, 7 and 12. On histological rereview (leading to the exclusion of 3 specimens) and using histology as the gold standard, 58 of 62 (93%) clear cell, 51 of 56 (91%) papillary and 33 of 34 (97%) chromophobe renal cell carcinomas were classified correctly. Of the 36 oncocytoma specimens 33 were classified as oncocytoma (17 by array comparative genomic hybridization and 10 by array comparative genomic hybridization plus fluorescence in situ hybridization) or benign (6). Overall 93% diagnostic sensitivity and 97% specificity were achieved. CONCLUSIONS: In a clinical diagnostic setting the implementation of genome based molecular classification could serve as an ancillary assay to assist in the histological classification of common renal neoplasms.


Assuntos
Adenoma Oxífilo/classificação , Adenoma Oxífilo/genética , Algoritmos , Carcinoma de Células Renais/classificação , Carcinoma de Células Renais/genética , Genômica , Córtex Renal , Neoplasias Renais/classificação , Neoplasias Renais/genética , Hibridização Genômica Comparativa , Humanos , Hibridização in Situ Fluorescente
3.
Genes Chromosomes Cancer ; 52(11): 1030-41, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23929756

RESUMO

PCDH10 is epigenetically inactivated in multiple tumor types; however, studies in mature lymphoid malignancies are limited. Here, we have investigated the presence of promoter hypermethylation of the PCDH10 gene in a large cohort of well-characterized subsets of lymphomas. PCDH10 promoter hypermethylation was identified by methylation-specific PCR in 57 to 100% of both primary B- and T-cell lymphoma specimens and cell lines. These findings were further validated by Sequenom Mass-array analysis. Promoter hypermethylation was also identified in 28.6% cases of reactive follicular hyperplasia, more commonly occurring in states of immune deregulation and associated with rare presence of clonal karyotypic aberrations, suggesting that PCDH10 methylation occurs early in lymphomagenesis. PCDH10 expression was down regulated via promoter hypermethylation in T- and B-cell lymphoma cell lines. The transcriptional down-regulation resulting from PCDH10 methylation could be restored by pharmacologic inhibition of DNA methyltransferases in cell lines. Both T- and B-cell lymphoma cell lines harboring methylation-mediated inactivation of PCDH10 were resistant to doxorubicin treatment, suggesting that hypermethylation of this gene might contribute to chemotherapy response.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Caderinas/genética , Metilação de DNA , Doxorrubicina/farmacologia , Linfoma não Hodgkin/genética , Mieloma Múltiplo/genética , Regiões Promotoras Genéticas , Apoptose/efeitos dos fármacos , Carcinogênese/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Metilases de Modificação do DNA/antagonistas & inibidores , Regulação para Baixo/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Cariótipo , Linfoma não Hodgkin/patologia , Mieloma Múltiplo/patologia , Protocaderinas , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
4.
Gastrointest Endosc ; 75(1): 74-9, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22100297

RESUMO

BACKGROUND: The diagnosis of indeterminate biliary strictures is limited because of the low sensitivity of cytology. However, an accurate diagnosis of malignancy is critical in the management of patients with suspected biliary malignancy. Testing for chromosomal aneuploidy by fluorescence in situ hybridization (FISH) may increase the yield. OBJECTIVE: To evaluate the diagnostic accuracy of FISH in indeterminate biliary strictures and the additional value of including deletion of 9p21 (p16) in the diagnostic criteria of malignant biliary strictures. DESIGN: Retrospective review. SETTING: Academic medical center. PATIENTS: This study involved 76 consecutive patients who were seen for the evaluation of indeterminate strictures at our institution. These patients were screened, and 50 patients with either a final pathologic diagnosis or ≥ 12 months' conclusive follow-up were included in the analysis. MAIN OUTCOME MEASUREMENTS: Sensitivity, specificity, and area under the curve (AUC) analysis of cytology alone compared with the presence of FISH polysomy versus FISH polysomy and 9p21 deletion. RESULTS: The presence of increased copy numbers (polysomy) of chromosome 3, 7, or 17 by FISH increased the sensitivity of brush cytology from 21% to 58%, and when the presence of 9p21 deletion was included, the sensitivity increased to 89%. The specificity of FISH was 97% (vs 100% for cytology). The accuracy of cytology combined with FISH polysomy (AUC = 0.93) or p16 deletion was significantly greater than the accuracy of cytology alone (AUC 0.6; P < .001) or even cytology combined with FISH polysomy (AUC = 0.77; P ≤ .05). LIMITATIONS: Sample size. There is a relatively high incidence of malignant biliary strictures in the entire cohort but low incidence among primary sclerosing cholangitis patients, and the majority of cancers are cholangiocarcinomas (as opposed to pancreatic). CONCLUSION: FISH significantly improves the diagnostic accuracy of brush cytology in indeterminate biliary strictures. In our series, the addition of 9p21 deletion to FISH polysomy and cytology further improved sensitivity. This suggests that 9p21 deletion may be added to the diagnostic criteria in indeterminate strictures.


Assuntos
Neoplasias dos Ductos Biliares/genética , Ductos Biliares Intra-Hepáticos/patologia , Colangiocarcinoma/genética , Deleção Cromossômica , DNA de Neoplasias/genética , Genes p16 , Hibridização in Situ Fluorescente , Aneuploidia , Área Sob a Curva , Neoplasias dos Ductos Biliares/complicações , Neoplasias dos Ductos Biliares/diagnóstico , Colangiocarcinoma/complicações , Colangiocarcinoma/diagnóstico , Colangite Esclerosante/complicações , Colangite Esclerosante/diagnóstico , Cromossomos Humanos Par 17 , Cromossomos Humanos Par 3 , Cromossomos Humanos Par 7 , Cromossomos Humanos Par 9 , Constrição Patológica/etiologia , Constrição Patológica/patologia , Citodiagnóstico , Feminino , Humanos , Masculino , Curva ROC , Estudos Retrospectivos
5.
Genes Chromosomes Cancer ; 50(12): 1043-53, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21960365

RESUMO

PCDH10 has been implicated as a tumor suppressor, since epigenetic alterations of this gene have been noted in multiple tumor types. However, to date, studies regarding its role in acute and chronic leukemias are lacking. Here, we have investigated the presence of promoter hypermethylation of two CpG islands of the PCDH10 gene by methylation-specific PCR in 215 cases of various subsets of myeloid- and lymphoid-lineage leukemias. We found that PCDH10 promoter hypermethylation was frequent in both B-cell (81.9%) and T-cell (80%) acute lymphoblastic leukemia (ALL), while it was present in low frequency in most subtypes of myeloid leukemias (25.9%) and rare in chronic myeloid leukemia (2.2%). PCDH10 expression was downregulated via promoter hypermethylation in primary ALL samples (N = 4) and leukemia cell lines (N = 11). The transcriptional repression caused by PCDH10 methylation could be restored by pharmacologic inhibition of DNA methyltransferases. ALL cell lines harboring methylation-mediated inactivation of PCDH10 were less sensitive to commonly used leukemia-specific drugs suggesting that PCDH10 methylation might serve as a biomarker of chemotherapy response. Our results demonstrate that PCDH10 is a target of epigenetic silencing in ALL, a phenomenon that may impact lymphoid-lineage leukemogenesis, serve as an indicator of drug resistance and may also have potential implications for targeted epigenetic therapy.


Assuntos
Caderinas/genética , Metilação de DNA , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Linfócitos B/metabolismo , Medula Óssea/metabolismo , Caderinas/metabolismo , Linhagem Celular Tumoral , Ilhas de CpG , Regulação para Baixo/genética , Resistencia a Medicamentos Antineoplásicos/genética , Epigênese Genética/genética , Genes Supressores de Tumor , Humanos , Reação em Cadeia da Polimerase/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Regiões Promotoras Genéticas , Protocaderinas , Linfócitos T/metabolismo , Proteínas Supressoras de Tumor/genética
6.
Hematol Oncol ; 29(2): 81-90, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20687199

RESUMO

Non-random karyotypic abnormalities associated with non-Hodgkin lymphomas (NHLs) have been described in cases of reactive lymphoid hyperplasia (RLH). However, the frequency and types of cytogenetic aberrations detected and their clinical relevance are unknown. To address these questions, we undertook a retrospective analysis of a large series of RLH diagnosed at our institute over 8 years. Cytogenetic abnormalities were identified in 20 of 116 (17%) cases with informative karyotypes, comprising 14 (70%) structural and 11 (55%) numerical changes. Clonal (n = 14, 70%) and non-clonal (n = 6, 30%) abnormalities were observed. Aberrations of chromosome 14 were the most frequent (n = 8, 42%, 7 represented IgH translocations), followed by chromosome 3 (n = 4, 3 represented BCL6 translocations), and chromosome 12 (n = 4). Abnormal karyotypes were most often associated with florid follicular hyperplasia. Isolated lymphoid organ (lymph node, tonsil or spleen) enlargement (12/20, 60%) was more common, no specific etiology was identified in 10/20 (50%) cases and only 1 of 18 patients with clinical follow-up (range 2-107 months, median 60 months) developed lymphoma. In our experience, cytogenetic abnormalities involving loci associated with B-cell NHL are not infrequently detected in RLH. Their occurrence portends low risk for lymphomagenesis, however longer follow-up is prudent to further evaluate the natural history of such cases.


Assuntos
Aberrações Cromossômicas , Centro Germinativo/metabolismo , Linfoma/genética , Pseudolinfoma/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Rearranjo Gênico , Centro Germinativo/patologia , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Hibridização In Situ , Hibridização in Situ Fluorescente , Lactente , Cariotipagem , Linfoma/patologia , Masculino , Pessoa de Meia-Idade , Pseudolinfoma/patologia , Receptores de Antígenos de Linfócitos T gama-delta/genética , Estudos Retrospectivos , Adulto Jovem
7.
Nature ; 459(7247): 717-21, 2009 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-19412164

RESUMO

Diffuse large B-cell lymphoma (DLBCL), the most common form of lymphoma in adulthood, comprises multiple biologically and clinically distinct subtypes including germinal centre B-cell-like (GCB) and activated B-cell-like (ABC) DLBCL. Gene expression profile studies have shown that its most aggressive subtype, ABC-DLBCL, is associated with constitutive activation of the NF-kappaB transcription complex. However, except for a small fraction of cases, it remains unclear whether NF-kappaB activation in these tumours represents an intrinsic program of the tumour cell of origin or a pathogenetic event. Here we show that >50% of ABC-DLBCL and a smaller fraction of GCB-DLBCL carry somatic mutations in multiple genes, including negative (TNFAIP3, also called A20) and positive (CARD11, TRAF2, TRAF5, MAP3K7 (TAK1) and TNFRSF11A (RANK)) regulators of NF-kappaB. Of these, the A20 gene, which encodes a ubiquitin-modifying enzyme involved in termination of NF-kappaB responses, is most commonly affected, with approximately 30% of patients displaying biallelic inactivation by mutations and/or deletions. When reintroduced in cell lines carrying biallelic inactivation of the gene, A20 induced apoptosis and cell growth arrest, indicating a tumour suppressor role. Less frequently, missense mutations of TRAF2 and CARD11 produce molecules with significantly enhanced ability to activate NF-kappaB. Thus, our results demonstrate that NF-kappaB activation in DLBCL is caused by genetic lesions affecting multiple genes, the loss or activation of which may promote lymphomagenesis by leading to abnormally prolonged NF-kappaB responses.


Assuntos
Regulação Neoplásica da Expressão Gênica , Genes/genética , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/fisiopatologia , Mutação/genética , NF-kappa B/metabolismo , Apoptose , Linhagem Celular Tumoral , Proteínas de Ligação a DNA , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , Proteínas Nucleares/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfa
8.
Hematol Oncol ; 27(4): 203-10, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19337983

RESUMO

Primary effusion lymphoma (PEL) is a rare type of B-cell non-Hodgkin lymphoma (NHL), which predominantly occurs in HIV-infected individuals, and is pathogenetically linked with Kaposi sarcoma (KS)-associated herpes virus/human herpes virus-8 (KSHV/HHV-8) infection with or without evidence of Epstein-Barr virus (EBV) co-infection. Although uncommon, PELs have been reported in immunocompetent patients and recipients of solid organ allografts. Rare cases of KSHV(-) EBV(+) post-transplant effusion lymphomas resembling PEL have also been described, as have KSHV(-) EBV(-) effusion lymphomas, the latter including those arising in individuals with chronic liver disease. We report a unique KSHV(-) EBV(-) post-transplant effusion lymphoma associated with serum paraproteins, occurring in an HIV(-) individual, which had cytologic features and phenotype similar to PEL, and displayed a complex karyotype including isochromosome 12p and translocation t(8;22), resulting in rearrangement of c-MYC.


Assuntos
Linfoma de Efusão Primária/patologia , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/patologia , Herpesvirus Humano 4/isolamento & purificação , Herpesvirus Humano 8/isolamento & purificação , Humanos , Imunofenotipagem , Transplante de Fígado , Linfoma de Efusão Primária/genética , Linfoma de Efusão Primária/virologia , Masculino , Pessoa de Meia-Idade , Plasmócitos/patologia , Sarcoma de Kaposi/genética , Sarcoma de Kaposi/patologia , Sarcoma de Kaposi/virologia
9.
Blood ; 113(20): 4918-21, 2009 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-19258598

RESUMO

Unique and shared cytogenetic abnormalities have been documented for marginal zone lymphomas (MZLs) arising at different sites. Recently, homozygous deletions of the chromosomal band 6q23, involving the tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20) gene, a negative regulator of NF-kappaB, were described in ocular adnexal MZL, suggesting a role for A20 as a tumor suppressor in this disease. Here, we investigated inactivation of A20 by DNA mutations or deletions in a panel of extranodal MZL (EMZL), nodal MZL (NMZL), and splenic MZL (SMZL). Inactivating mutations encoding truncated A20 proteins were identified in 6 (19%) of 32 MZLs, including 2 (18%) of 11 EMZLs, 3 (33%) of 9 NMZLs, and 1 (8%) of 12 SMZLs. Two additional unmutated nonsplenic MZLs also showed monoallelic or biallelic A20 deletions by fluorescent in situ hybridization (FISH) and/or SNP-arrays. Thus, A20 inactivation by either somatic mutation and/or deletion represents a common genetic aberration across all MZL subtypes, which may contribute to lymphomagenesis by inducing constitutive NF-kappaB activation.


Assuntos
Deleção de Genes , Peptídeos e Proteínas de Sinalização Intracelular/genética , Linfoma de Zona Marginal Tipo Células B/genética , Mutação de Sentido Incorreto , Proteínas Nucleares/genética , Estudos de Casos e Controles , Transformação Celular Neoplásica/genética , Análise Mutacional de DNA , Proteínas de Ligação a DNA , Perfilação da Expressão Gênica , Humanos , Mutação de Sentido Incorreto/fisiologia , NF-kappa B/antagonistas & inibidores , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Proteína 3 Induzida por Fator de Necrose Tumoral alfa
10.
Hum Pathol ; 40(4): 588-93, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18992913

RESUMO

Cytogenetic abnormalities of chromosome 12p involving the TEL/ETV6 gene are observed in a variety of hematopoietic neoplasms including acute leukemias, myelodysplastic syndromes, and myeloproliferative disorders. Karyotypic aberrations, including rearrangements, deletions, and amplifications of chromosome 12p, have been documented in B-cell non-Hodgkin lymphoma; however, rearrangements targeting TEL have rarely been reported. Here we describe a diffuse large B-cell lymphoma that had a complex karyotype including t(9;12)(q22;p13), which was confirmed by fluorescence in situ hybridization to represent rearrangement of TEL. Additional cytogenetic abnormalities included t(3;14)(q27;q32) involving the variant, alternative breakpoint region of the BCL6 gene and del(6)(q13q23), resulting in the loss of 1 allele of BLIMP1. This case reiterates the importance of correlating morphologic and phenotypic findings with the results of cytogenetic analysis to avoid errors in diagnosing hematologic neoplasms and highlights the rare association of B-cell non-Hodgkin lymphoma with aberrations of TEL.


Assuntos
Linfoma Difuso de Grandes Células B/genética , Segunda Neoplasia Primária/genética , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Repressoras/genética , Adulto , Aberrações Cromossômicas , Feminino , Citometria de Fluxo , Rearranjo Gênico do Linfócito B , Doença de Hodgkin/complicações , Doença de Hodgkin/terapia , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Linfoma Difuso de Grandes Células B/complicações , Linfoma Difuso de Grandes Células B/patologia , Segunda Neoplasia Primária/patologia , Segunda Neoplasia Primária/terapia , Translocação Genética , Variante 6 da Proteína do Fator de Translocação ETS
11.
Mol Cancer ; 7: 58, 2008 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-18559093

RESUMO

BACKGROUND: Copy number gains and amplifications are characteristic feature of cervical cancer (CC) genomes for which the underlying mechanisms are unclear. These changes may possess oncogenic properties by deregulating tumor-related genes. Gain of short arm of chromosome 5 (5p) is the most frequent karyotypic change in CC. METHODS: To examine the role of 5p gain, we performed a combination of single nucleotide polymorphism (SNP) array, fluorescence in situ hybridization (FISH), and gene expression analyses on invasive cancer and in various stages of CC progression. RESULTS: The SNP and FISH analyses revealed copy number increase (CNI) of 5p in 63% of invasive CC, which arises at later stages of precancerous lesions in CC development. We integrated chromosome 5 genomic copy number and gene expression data to identify key target over expressed genes as a consequence of 5p gain. One of the candidates identified was Drosha (RNASEN), a gene that is required in the first step of microRNA (miRNA) processing in the nucleus. Other 5p genes identified as targets of CNI play a role in DNA repair and cell cycle regulation (BASP1, TARS, PAIP1, BRD9, RAD1, SKP2, and POLS), signal transduction (OSMR), and mitochondrial oxidative phosphorylation (NNT, SDHA, and NDUFS6), suggesting that disruption of pathways involving these genes may contribute to CC progression. CONCLUSION: Taken together, we demonstrate the power of integrating genomics data with expression data in deciphering tumor-related targets of CNI. Identification of 5p gene targets in CC denotes an important step towards biomarker development and forms a framework for testing as molecular therapeutic targets.


Assuntos
Cromossomos Humanos Par 5 , Amplificação de Genes , Regulação Neoplásica da Expressão Gênica , Genômica , Lesões Pré-Cancerosas/genética , Ribonuclease III/genética , Displasia do Colo do Útero/genética , Neoplasias do Colo do Útero/genética , Linhagem Celular Tumoral , Colômbia , Progressão da Doença , Feminino , Alemanha , Humanos , Hibridização in Situ Fluorescente , Invasividade Neoplásica , New York , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Lesões Pré-Cancerosas/patologia , Reprodutibilidade dos Testes , Transcrição Gênica , Neoplasias do Colo do Útero/patologia , Displasia do Colo do Útero/patologia
12.
Genes Chromosomes Cancer ; 47(9): 755-65, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18506748

RESUMO

Recurrent karyotypic abnormalities are a characteristic feature of cervical cancer (CC) cells, which may result in deregulated expression of important genes that contribute to tumor initiation and progression. To examine the role of gain of the long arm of chromosome 20 (20q), one of the common chromosomal gains in CC, we evaluated CC at various stages of progression using single nucleotide polymorphism (SNP) array, gene expression profiling, and fluorescence in situ hybridization (FISH) analyses. This analysis revealed copy number increase (CNI) of 20q in >50% of invasive CC and identified two focal amplicons at 20q11.2 and 20q13.13 in a subset of tumors. We further demonstrate that the acquisition of 20q gain occurs at an early stage in CC development and the high-grade squamous intraepithelial lesions (HSIL) that exhibit 20q CNI are associated (P = 0.05) with persistence or progression to invasive cancer. We identified a total of 26 overexpressed genes as consequence of 20q gain (N = 14), as targets of amplicon 1 (N = 9; two genes also commonly expressed with 20q gain) and amplicon 2 (N = 6; one gene also commonly expressed with 20q gain). These include a number of functionally important genes in cell cycle regulation (E2F1, TPX2, KIF3B, PIGT, and B4GALT5), nuclear function (CSEL1), viral replication (PSMA7 and LAMA5), methylation and chromatin remodeling (ASXL1, AHCY, and C20orf20), and transcription regulation (TCEA2). Our findings implicate a role for these genes in CC tumorigenesis, represent an important step toward the development of clinically significant biomarkers, and form a framework for testing as molecular therapeutic targets.


Assuntos
Cromossomos Humanos Par 20 , Amplificação de Genes , Dosagem de Genes , Neoplasias do Colo do Útero/genética , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Genoma , Genômica , Humanos , Hibridização in Situ Fluorescente , Polimorfismo de Nucleotídeo Único , Neoplasias do Colo do Útero/patologia
13.
J Biol Chem ; 282(47): 34325-33, 2007 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-17848578

RESUMO

The BRCA1 tumor suppressor exists as a heterodimeric complex with BARD1, and this complex is thought to mediate many of the functions ascribed to BRCA1, including its role in tumor suppression. The two proteins share a common structural organization that features an N-terminal RING domain and two C-terminal BRCT motifs, whereas BARD1 alone also contains three tandem ankyrin repeats. In normal cells, the BRCA1/BARD1 heterodimer is believed to enhance chromosome stability by promoting homology-directed repair (HDR) of double strand DNA breaks. Here we have investigated the structural requirements for BARD1 in this process by complementation of Bard1-null mouse mammary carcinoma cells. Our results demonstrate that the ankyrin and BRCT motifs of BARD1 are each essential for both chromosome stability and HDR. Tandem BRCT motifs, including those found at the C terminus of BARD1, are known to form a phosphoprotein recognition module. Nonetheless, the HDR function of BARD1 was not perturbed by synthetic mutations predicted to ablate the phospho-recognition activity of its BRCT sequences, suggesting that some functions of the BRCT domains are not dependent on their ability to bind phosphorylated ligands. Also, cancer-associated missense mutations in the BRCT domains of BARD1 (e.g. C557S, Q564H, V695L, and S761N) have been observed in patients with breast, ovarian, and endometrial tumors. However, none of these was found to affect the HDR activity of BARD1, suggesting that any increased cancer risk conferred by these mutations is not because of defects in this repair mechanism.


Assuntos
Proteína BRCA1/metabolismo , Instabilidade Cromossômica , Quebras de DNA de Cadeia Dupla , Neoplasias Mamárias Animais/metabolismo , Complexos Multiproteicos/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Substituição de Aminoácidos , Animais , Anquirinas/genética , Proteína BRCA1/genética , Linhagem Celular Tumoral , Instabilidade Cromossômica/genética , Reparo do DNA/genética , Feminino , Teste de Complementação Genética , Humanos , Masculino , Neoplasias Mamárias Animais/genética , Camundongos , Complexos Multiproteicos/genética , Mutação de Sentido Incorreto , Domínios RING Finger/genética , Fatores de Risco , Relação Estrutura-Atividade , Proteínas Supressoras de Tumor/genética , Ubiquitina-Proteína Ligases/genética
14.
Genes Chromosomes Cancer ; 46(4): 373-84, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17243165

RESUMO

Cervical cancer (CC) cells exhibit complex karyotypic alterations, which is consistent with deregulation of numerous critical genes in its formation and progression. To characterize this karyotypic complexity at the molecular level, we used cDNA array comparative genomic hybridization (aCGH) to analyze 29 CC cases and identified a number of over represented and deleted genes. The aCGH analysis revealed at least 17 recurrent amplicons and six common regions of deletions. These regions contain several known tumor-associated genes, such as those involved in transcription, apoptosis, cytoskeletal remodeling, ion-transport, drug metabolism, and immune response. Using the fluorescence in situ hybridization (FISH) approach we demonstrated the presence of high-level amplifications at the 8q24.3, 11q22.2, and 20q13 regions in CC cell lines. To identify amplification-associated genes that correspond to focal amplicons, we examined one or more genes in each of the 17 amplicons by Affymetrix U133A expression arrays and semiquantitative reverse-transcription PCR (RT-PCR) in 31 CC tumors. This analysis exhibited frequent and robust upregulated expression in CC relative to normal cervix for genes EPHB2 (1p36), CDCA8 (1p34.3), AIM2 (1q22-23), RFC4, MUC4, and HRASLS (3q27-29), SKP2 (5p12-13), CENTD3 (5q31.3), PTK2, RECQL4 (8q24), MMP1 and MMP13 (11q22.2), AKT1 (14q32.3), ABCC3 (17q21-22), SMARCA4 (19p13.3) LIG1 (19q13.3), UBE2C (20q13.1), SMC1L1 (Xp11), KIF4A (Xq12), TMSNB (Xq22), and CSAG2 (Xq28). Thus, the gene dosage and expression profiles generated here have enabled the identification of focal amplicons characteristic for the CC genome and facilitated the validation of relevant genes in these amplicons. These data, thus, form an important step toward the identification of biologically relevant genes in CC pathogenesis. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.


Assuntos
Amplificação de Genes , Dosagem de Genes , Expressão Gênica , Análise de Sequência com Séries de Oligonucleotídeos , Neoplasias do Colo do Útero/genética , Linhagem Celular Tumoral , Feminino , Humanos
15.
Hum Pathol ; 38(2): 315-25, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17134734

RESUMO

Cytogenetic abnormalities in B-cell posttransplant lymphoproliferative disorders (PTLD) have not been well characterized. We thus performed cytogenetic analysis of 28 cases of B-cell PTLD, 1 infectious mononucleosis (IM)-like lesion, 9 polymorphic PTLD, 17 monomorphic PTLD, and 1 classical Hodgkin lymphoma (HL), and correlated the karyotypic findings with the phenotype, Epstein-Barr virus infection status, and clinical outcome. Karyotypes of 19 cases of posttransplant florid follicular hyperplasia (FFH) were also analyzed. Informative karyotypes were obtained in 20 (71.4%) of 28 PTLDs and 18 (94.7%) of 19 FFHs. Clonal karyotypic abnormalities were detected in 13 (65%) of 20 PTLDs, including 9 (75%) of 12 monomorphic PTLDs, 2 (33.3%) of 6 polymorphic PTLDs, 1 IM-like lesion, and 1 HL, and 2 (11.1%) of 18 FFHs. Recurrent chromosome breaks at 1q11-21 (n = 6, including 1 FFH), 14q32 (n = 3, including 1 FFH), 16p13 (n = 3), 11q23-24 (n = 2), and 8q24 (c-MYC) (n = 2); gains of chromosome 7 (n = 4), X (n = 3), 2 (n = 3), 12 (n = 2); and loss of chromosome 22 (n = 2, including 1 IM-like lesion) were identified. The presence of cytogenetic abnormalities did not correlate with PTLD phenotype, Epstein-Barr virus infection, or clinical outcome. We describe novel karyotypic aberrations in PTLD and report clonal cytogenetic abnormalities in posttransplant FFH and an IM-like lesion for the first time. Our findings provide validation of the current World Health Organization classification of PTLD and also suggest incorporation of FFH as the earliest recognizable precursor of PTLD.


Assuntos
Linfócitos B/patologia , Linfonodos/patologia , Transtornos Linfoproliferativos/etiologia , Adolescente , Adulto , Linfócitos B/metabolismo , Criança , Pré-Escolar , Aberrações Cromossômicas , Bandeamento Cromossômico , Células Clonais/metabolismo , Células Clonais/patologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/virologia , Feminino , Genótipo , Humanos , Hiperplasia , Hibridização in Situ Fluorescente , Cariotipagem , Transplante de Fígado/efeitos adversos , Linfonodos/metabolismo , Transtornos Linfoproliferativos/classificação , Transtornos Linfoproliferativos/genética , Masculino , Pessoa de Meia-Idade , Transplante de Órgãos/efeitos adversos , Fenótipo , Organização Mundial da Saúde
16.
Methods Mol Biol ; 383: 165-85, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-18217685

RESUMO

Cancer cells exhibit nonrandom and complex chromosome abnormalities. The role of genomic changes in cancer is well established. However, the identification of complex and cryptic chromosomal changes is beyond the resolution of conventional banding methods. The fluorescence microscopy afforded by imaging technologies, developed recently, facilitates a precise identification of these chromosome alterations in cancer. The three most commonly utilized molecular cytogenetics methods comparative genomic hybridization, spectral karyotype, and fluorescence in situ hybridization, that have already become benchmark tools in cancer cytogenetics, are described in this chapter. Comparative genomic hybridization is a powerful tool for screening copy-number changes in tumor genomes without the need for preparation of metaphases from tumor cells. Multicolor spectral karyotype permits visualization of all chromosomes in one experiment permitting identification of precise chromosomal changes on metaphases derived from tumor cells. The uses of fluorescence in situ hybridization are diverse, including mapping of alteration in single copy genes, chromosomal regions, or entire chromosomes. The opportunities to detect genetic alterations in cancer cells continue to evolve with the use of these methodologies both in diagnosis and research.


Assuntos
Aberrações Cromossômicas , Análise Citogenética/métodos , Neoplasias/genética , Humanos , Hibridização in Situ Fluorescente , Hibridização de Ácido Nucleico , Cariotipagem Espectral
17.
J Exp Med ; 203(2): 311-7, 2006 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-16492805

RESUMO

PR domain containing 1 with zinc finger domain (PRDM1)/B lymphocyte-induced maturation protein 1 (BLIMP1) is a transcriptional repressor expressed in a subset of germinal center (GC) B cells and in all plasma cells, and required for terminal B cell differentiation. The BLIMP1 locus lies on chromosome 6q21-q22.1, a region frequently deleted in B cell lymphomas, suggesting that it may harbor a tumor suppressor gene. We report here that the BLIMP1 gene is inactivated by structural alterations in 24% (8 out of 34) activated B cell-like diffuse large cell lymphoma (ABC-DLBCL), but not in GC B cell-like (n = 0/37) or unclassified (n = 0/21) DLBCL. BLIMP1 alterations included gene truncations, nonsense mutations, frameshift deletions, and splice site mutations that generate aberrant transcripts encoding truncated BLIMP1 proteins. In all cases studied, both BLIMP1 alleles were inactivated by deletions or mutations. Furthermore, most non-GC type DLBCL cases (n = 20/26, 77%) lack BLIMP1 protein expression, despite the presence of BLIMP1 mRNA. These results indicate that a sizable fraction of ABC-DLBCL carry an inactive BLIMP1 gene, and suggest that the same gene is inactivated by epigenetic mechanisms in an additional large number of cases. These findings point to a role for BLIMP1 as a tumor suppressor gene, whose inactivation may contribute to lymphomagenesis by blocking post-GC differentiation of B cells toward plasma cells.


Assuntos
Inativação Gênica , Linfoma de Células B/genética , Linfoma Difuso de Grandes Células B/genética , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/genética , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/genética , Linfócitos B/patologia , Diferenciação Celular/genética , Linhagem Celular Tumoral , Códon sem Sentido , Mutação da Fase de Leitura , Genes Supressores de Tumor , Humanos , Linfoma de Células B/classificação , Linfoma de Células B/metabolismo , Linfoma Difuso de Grandes Células B/classificação , Linfoma Difuso de Grandes Células B/metabolismo , Plasmócitos/patologia , Fator 1 de Ligação ao Domínio I Regulador Positivo , Sítios de Splice de RNA/genética , Proteínas Repressoras/biossíntese , Fatores de Transcrição/biossíntese
18.
Leuk Lymphoma ; 46(8): 1223-7, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16085566

RESUMO

Congenital acute leukemia is a rare form of childhood leukemia, in which lineage conversion at relapse is very rarely reported. Here we describe a case of congenital B-cell acute lymphoblastic leukemia (B-ALL) with t(4;11) and t(1;6) translocations, which at relapse underwent a switch to monocytic lineage with persistence of the original cytogenetic translocations and clonal rearrangement of the JH gene. Similar to the other described cases of congenital acute leukemia with lineage conversion, our case had a MLL gene rearrangement and followed an aggressive clinical course.


Assuntos
Linfoma de Burkitt/genética , Leucemia Mieloide Aguda/genética , Proteína de Leucina Linfoide-Mieloide/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocação Genética , Linfoma de Burkitt/congênito , Linfoma de Burkitt/diagnóstico , Linhagem da Célula , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 4/genética , Cromossomos Humanos Par 6/genética , Análise Citogenética , Progressão da Doença , Evolução Fatal , Feminino , Histona-Lisina N-Metiltransferase , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Cadeias J de Imunoglobulina/genética , Imunofenotipagem , Recém-Nascido , Leucemia Mieloide Aguda/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/congênito , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Prognóstico , Recidiva
19.
Cancer Cell ; 7(5): 445-55, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15894265

RESUMO

Diffuse large B cell lymphomas (DLBCL) derive from germinal center (GC) B cells and display chromosomal alterations deregulating the expression of BCL6, a transcriptional repressor required for GC formation. To investigate the role of BCL6 in DLBCL pathogenesis, we have engineered mice that express BCL6 constitutively in B cells by mimicking a chromosomal translocation found in human DLBCL. These mice display increased GC formation and perturbed post-GC differentiation characterized by a decreased number of post-isotype switch plasma cells. Subsequently, these mice develop a lymphoproliferative syndrome that culminates with the development of lymphomas displaying features typical of human DLBCL. These results define the oncogenic role of BCL6 in the pathogenesis of DLBCL and provide a faithful mouse model of this common disease.


Assuntos
Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Expressão Gênica/genética , Linfoma de Células B/patologia , Linfoma Difuso de Grandes Células B/patologia , Animais , Diferenciação Celular/genética , Aberrações Cromossômicas , Proteínas de Ligação a DNA/metabolismo , Genes de Imunoglobulinas/genética , Centro Germinativo/química , Centro Germinativo/metabolismo , Centro Germinativo/patologia , Hemaglutininas/genética , Humanos , Linfoma de Células B/genética , Linfoma Difuso de Grandes Células B/genética , Linfoma não Hodgkin/genética , Linfoma não Hodgkin/patologia , Transtornos Linfoproliferativos/genética , Transtornos Linfoproliferativos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Knockout , Camundongos Transgênicos , Plasmócitos/química , Plasmócitos/metabolismo , Plasmócitos/patologia , Regiões Promotoras Genéticas/genética , Proteínas Proto-Oncogênicas c-bcl-6 , Baço/química , Baço/metabolismo , Baço/patologia , Esplenomegalia/patologia , Análise de Sobrevida , Fatores de Tempo
20.
Genes Chromosomes Cancer ; 42(4): 372-83, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15645498

RESUMO

Loss of chromosome arm 18q is a common event in human pancreatic, colon, and breast cancers and is often interpreted as representing loss of one or more tumor-suppressor genes. In this article, we describe two novel biallelic deletions at chromosome band 18q21.1 in a recently characterized human breast cancer cell line, HCC-1428. One lesion deletes a fragment of approximately 300 kb between SMAD4 and DCC that encodes no known genes. The second lesion is an in-frame SMAD4 deletion (amino acids 49-51) that affects the level of SMAD4 protein but not the SMAD4 message. This change accelerates 26S proteasome-mediated degradation of both endogenous and exogenous mutant SMAD4. Examination of normal DNA from the same patient demonstrated that both lesions are somatic and associated with loss of both normal alleles. These data support the concept that two independent tumor-suppressor loci exist at chromosome segment 18q21.1, one at SMAD4 and the other potentially at an enhancer of DCC or an unrelated novel gene.


Assuntos
Alelos , Neoplasias da Mama/genética , Proteínas de Ligação a DNA/genética , Transativadores/genética , Animais , Células COS , Linhagem Celular Tumoral , Deleção Cromossômica , Coloração Cromossômica , Cromossomos Artificiais Bacterianos , Cromossomos Humanos Par 18 , Humanos , Immunoblotting , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Proteína Smad4
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