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1.
Genes Chromosomes Cancer ; 49(1): 1-8, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19787783

RESUMO

Recently, amplification of PPFIA1, encoding a member of the liprin family located about 600 kb telomeric to CCND1 on chromosome band 11q13, was described in squamous cell carcinoma of head and neck. Because 11q13 amplification is frequent in breast cancer, and PPFIA1 has been suggested to contribute to mammary gland development, we hypothesized that PPFIA1 might also be involved in the 11q13 amplicon in breast cancer and contribute to breast cancer development. A tissue microarray containing more than 2000 human breast cancers was analyzed for gene copy numbers of PPFIA1 and CCND1 by means of fluorescence in situ hybridization. PPFIA1 amplification was found in 248/1583 (15.4%) of breast cancers. Coamplification with CCND1 was found in all (248/248, 100%) PPFIA1-amplified cancers. CCND1 amplification without PPFIA1 coamplification was found in additional 117 (4.7%) tumors. Amplification of both PPFIA1 and CCND1 were significantly associated with high-grade phenotype (P = 0.0002) but were unrelated to tumor stage (P = 0.7066) or nodal stage (P = 0.5807). No difference in patient prognosis was found between 248 CCND1/PPFIA1 coamplified tumors and 117 tumors with CCND1 amplification alone (P = 0.6419). These data show that PPFIA1 amplification occurs frequently in breast cancer. The higher incidence of CCND1 amplification when compared with PPFIA1, the lack of prognostic relevance of coamplifications, and the fact that PPFIA1 amplification was found exclusively in CCND1-amplified cancers suggest that PPFIA1 gene copy number changes represent concurrent events of CCND1 amplification rather than specific biological incidents.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasias da Mama/genética , Ciclina D1/genética , Amplificação de Genes , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Cromossomos Humanos Par 11 , Feminino , Dosagem de Genes , Humanos , Incidência , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Análise Serial de Tecidos
2.
Histopathology ; 57(3): 418-26, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20840671

RESUMO

AIMS: The epidermal growth factor receptor (EGFR) is a tyrosine kinase (TK) involved in the tumour progression of many cancer types and may serve as an important therapeutic target (erlotinib, cetuximab). Heterogeneity of EGFR amplification and expression could represent a major drawback for anti-EGFR therapy. The aim of this study was performed to determine the potential impact of tumour heterogeneity on anti-EGFR therapy in Barrett's adenocarcinoma (BAC). METHODS AND RESULTS: Tissue microarray (TMA) sections of 112 BAC and 45 lymph node metastases were analysed for EGFR amplification and expression using fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). A subset of 20 samples was also sequenced for EGFR exons 18-21 and Kirsten rat sarcoma viral oncogene homologue (KRAS) exons 2-3 mutations. EGFR amplification was seen in seven (6.25%) of 112 interpretable BAC and typically high-level with more than 10-20 EGFR copies per tumour cell (EGFR/centromere 7 ratio >3). EGFR amplification was associated with high pT, pN and poor prognosis (P = 0.0004). Identical EGFR amplification status was found in 29 primary tumours and 29 matched lymph node metastases. Moreover, FISH analysis of three to 16 large sections from all amplified BAC and corresponding lymph node metastases did not reveal any heterogeneity of EGFR amplification. No EGFR mutation but one KRAS mutation was found. CONCLUSION: The high level and homogeneity of EGFR amplification in primary tumours and metastases suggests the potential therapeutic utility of anti-EGFR drugs in BAC.


Assuntos
Adenocarcinoma/patologia , Esôfago de Barrett/patologia , Receptores ErbB/genética , Neoplasias Esofágicas/patologia , Amplificação de Genes , Adulto , Idoso , Idoso de 80 Anos ou mais , Esôfago de Barrett/metabolismo , Receptores ErbB/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico
3.
Methods Mol Biol ; 1381: 53-65, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26667454

RESUMO

Modern next-generation sequencing and microarray technologies allow for the simultaneous analysis of all human genes on the DNA, RNA, miRNA, and methylation RNA level. Studies using such techniques have lead to the identification of hundreds of genes with a potential role in cancer or other diseases. The validation of all of these candidate genes requires in situ analysis of high numbers of clinical tissues samples. The tissue microarray technology greatly facilitates such analysis. In this method minute tissue samples (typically 0.6 mm in diameter) from up to 1000 different tissues can be analyzed on one microscope glass slide. All in situ methods suitable for histological studies can be applied to TMAs without major changes of protocols, including immunohistochemistry, fluorescence in situ hybridization, or RNA in situ hybridization. Because all tissues are analyzed simultaneously with the same batch of reagents, TMA studies provide an unprecedented degree of standardization, speed, and cost efficiency.


Assuntos
Análise Serial de Tecidos/métodos , Sequenciamento de Nucleotídeos em Larga Escala/economia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Ensaios de Triagem em Larga Escala/economia , Ensaios de Triagem em Larga Escala/métodos , Humanos , Imuno-Histoquímica/economia , Imuno-Histoquímica/métodos , Hibridização in Situ Fluorescente/economia , Hibridização in Situ Fluorescente/métodos , Análise Serial de Tecidos/economia
4.
Anticancer Res ; 33(11): 4975-82, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24222138

RESUMO

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) is an important prognostic factor in several types of solid tumours. Although HER2 seems not to influence survival in esophageal carcinomas, an impact of the HER2 status of disseminated tumour cells (DTCs) on survival has been shown. The aim of our study was to investigate the significance of the HER2 status in primary esophageal carcinomas and matched lymph node metastases. MATERIALS AND METHODS: The HER2 status of primary tumours and matched lymph node metastases were analysed for 158 patients with esophageal carcinoma using immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH). RESULTS: The study specimen included 90 adenocarcinomas (AC) and 68 squamous cell carcinomas (SCC). HER2 amplification was found in 12% and overexpression in 8.9% of all primary tumours. HER2 amplification was identical in the primary tumour and lymph node metastases in all AC and in 75% of SCC. Discordant-positive HER2 lymph node status and negative primary tumour status was found in 4.4% of AC and 1.5% of SCC in FISH analyses. No significant associations were found between HER2 amplification/overexpression and overall survival. CONCLUSION: HER2 gene status remains highly conserved in metastatic esophageal carcinoma. Discrepancies occur rarely between primary tumour and lymph node metastases and might be due to heterogeneity of the HER2 status of the primary tumour. This could be the reason for heterogeneity of DTCs and may result in metastasis of only a subset of tumour cells.


Assuntos
Adenocarcinoma/mortalidade , Biomarcadores Tumorais/análise , Carcinoma de Células Escamosas/mortalidade , Neoplasias Esofágicas/mortalidade , Receptor ErbB-2/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/secundário , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Feminino , Seguimentos , Amplificação de Genes , Humanos , Técnicas Imunoenzimáticas , Hibridização in Situ Fluorescente , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Receptor ErbB-2/genética , Taxa de Sobrevida , Análise Serial de Tecidos
5.
Methods Mol Biol ; 576: 49-60, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-19882257

RESUMO

Modern array technologies allow for the simultaneous screening of virtually all human genes on the DNA and RNA level. Studies using such techniques have lead to the identification of hundreds of genes with a potential role in cancer or other diseases. The validation of all of these candidate genes requires in situ analysis of high numbers of clinical tissues samples. The tissue microarray (TMA) technology greatly facilitates such analysis. In this method, minute tissue samples (0.6 mm in diameter) from up to 1,000 different tissues can be analyzed on one microscope glass slide. All in situ methods suitable for histological studies can be applied to TMAs without major changes of protocols, including immunohistochemistry, fluorescence in situ hybridization, or RNA in situ hybridization. Because all tissues are analyzed simultaneously with the same batch of reagents, TMA studies provide an unprecedented degree of standardization, speed, and cost efficiency.


Assuntos
Imuno-Histoquímica/métodos , Hibridização in Situ Fluorescente/métodos , Análise em Microsséries/métodos , Neoplasias/metabolismo , Biópsia , Humanos , Hibridização In Situ/métodos , Biologia Molecular/métodos , Técnicas de Diagnóstico Molecular , Técnicas de Sonda Molecular , Neoplasias/patologia
6.
Mol Cancer Ther ; 9(7): 2037-45, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20606043

RESUMO

This study aimed to determine the targeted efficacy of trastuzumab (Herceptin) on human epidermal growth factor receptor 2 (HER-2)-overexpressing metastatic esophageal cancer in an orthotopic mouse model. HER-2 overexpression and amplification of human esophageal primary and metastatic tumors were shown with HER-2-fluorescence in situ hybridization analysis and HER-2 immunostaining. Following orthotopic implantation with the HER-2-overexpressing OE19 human esophageal cancer cell line, mice were treated with trastuzumab. Sequential magnetic resonance imaging was used to monitor primary tumor and metastasis during treatment. After six weeks, a significant inhibition of primary tumor development was imaged in trastuzumab-treated animals in comparison with the control group. Trastuzumab treatment also led to a reduction of lymphatic metastasis. Thus, HER-2 targeted therapy with trastuzumab resulted in a significant primary tumor growth reduction as well as a decrease of lymph node metastases in the orthotopic model of metastatic esophageal carcinoma. The results of the present study suggest the clinical use of trastuzumab for HER-2-overexpressing esophageal cancer, which is a significant fraction of the patient population. Treatment of this highly treatment-resistant disease with trastuzumab in the adjuvant setting to prevent lymph node metastasis after primary tumor resection is suggested by the data in this report.


Assuntos
Anticorpos Monoclonais/farmacologia , Neoplasias Esofágicas/tratamento farmacológico , Receptor ErbB-2/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Anticorpos Monoclonais Humanizados , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática/prevenção & controle , Imageamento por Ressonância Magnética , Camundongos , Camundongos Endogâmicos , Camundongos Nus , Metástase Neoplásica , Receptor ErbB-2/genética , Receptor ErbB-2/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Trastuzumab , Carga Tumoral/efeitos dos fármacos
7.
Hum Pathol ; 40(6): 769-77, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19269014

RESUMO

Her-2 is the molecular target for antibody-based treatment of breast cancer (trastuzumab). The potential benefit of anti-Her-2 therapy is currently investigated in several other HER-2-amplified cancers including gastric cancer. Although HER-2 amplification occurs in more than 10% of gastric cancers, potential heterogeneity of HER-2 amplification and overexpression could represent a major drawback for anti-Her-2 therapy. To address the potential applicability of trastuzumab in gastric cancer, tissue microarray sections of 166 gastric adenocarcinomas and 69 lymph node metastases were analyzed for Her-2 overexpression and amplification using Food and Drug Administration-approved reagents for immunohistochemistry and fluorescence in situ hybridization. HER-2 amplification was seen in 27 (16%) of 166 gastric adenocarcinomas. Amplification was typically high level with more than 20 HER-2 copies per tumor cell and a HER-2/centromere 17 ratio >3. Amplification was associated with intestinal tumor phenotype but unrelated to survival, grading, pT, pN, or pM. Identical HER-2 status was found in primary tumor and their matched lymph node metastases. Moreover, HER-2 and Topoisomerase IIalpha coamplification analysis of 3 to 16 large sections from 8 Her-2-positive gastric cancers did not reveal any heterogeneity of the amplicon site. The high level of HER-2 amplification in combination with the homogeneity of its expression in primary and metastatic tumors argues for a possible therapeutic utility of trastuzumab in HER-2-amplified gastric adenocarcinomas.


Assuntos
Adenocarcinoma/genética , Genes erbB-2/genética , Neoplasias Gástricas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Antígenos de Neoplasias/genética , DNA Topoisomerases Tipo II/genética , Proteínas de Ligação a DNA/genética , Feminino , Amplificação de Genes , Humanos , Hibridização in Situ Fluorescente , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Receptor ErbB-2/imunologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Análise Serial de Tecidos , Trastuzumab
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