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1.
Clin Cancer Res ; 11(6): 2180-7, 2005 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-15788665

RESUMO

PURPOSE: Microsatellite instability (MSI) is found in 10% to 15% of sporadic colorectal tumors and is usually caused by defects in DNA mismatch repair (MMR). In 1997, a panel of microsatellite markers including mononucleotide and dinucleotide repeats was recommended by a National Cancer Institute workshop on MSI. We investigated the relationship between instability of these markers and MMR protein expression in a cohort of sporadic colorectal cancer patients. EXPERIMENTAL DESIGN: Paraffin sections of normal and tumor tissue from 262 colorectal cancer patients were examined for MSI status by PCR amplification and for MMR protein expression using antibodies against hMLH1, hPMS2, hMSH2, and hMSH6. RESULTS: Twenty-six (10%) of the patients studied had tumors with a high level of MSI (MSI-H). The frequencies of MSI were the same in African-American and Caucasian patients. Each of the MSI-H tumors had mutations in both mononucleotide and dinucleotide repeats and had loss of MMR protein expression, as did two tumors that had low levels of MSI (MSI-L). These two MSI-L tumors exhibited mutations in mononucleotide repeats only, whereas eight of the other nine MSI-L tumors had mutations in just a single dinucleotide repeat. There was not a statistically significant difference in outcomes between patients whose tumors were MMR-positive or MMR-negative, although there was a slight trend toward improved survival among those with MMR-deficient tumors. CONCLUSIONS: The choice of microsatellite markers is important for MSI testing. Examination of mononucleotide repeats is sufficient for detection of tumors with MMR defects, whereas instability only in dinucleotides is characteristic of MSI-L/MMR-positive tumors.


Assuntos
Adenosina Trifosfatases/genética , Pareamento Incorreto de Bases/genética , Neoplasias Colorretais/genética , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Repetições de Microssatélites/genética , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Adaptadoras de Transdução de Sinal , Adulto , Negro ou Afro-Americano , Idoso , Idoso de 80 Anos ou mais , Proteínas de Transporte , Estudos de Coortes , Colo/metabolismo , Colo/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Instabilidade Genômica , Humanos , Masculino , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento , Proteína 1 Homóloga a MutL , Proteína 2 Homóloga a MutS , Reto/metabolismo , Reto/patologia , Sensibilidade e Especificidade , População Branca
2.
Appl Immunohistochem Mol Morphol ; 13(1): 66-74, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15722796

RESUMO

SWI/SNF is a chromatin-remodeling complex important in gene regulation, cytokine responses, tumorigenesis, differentiation, and development. As a multitude of signaling pathways require SWI/SNF, loss of SWI/SNF function is expected to have an impact on cellular phenotypes. The SWI/SNF ATPase subunits, BRG1 and BRM, have been shown to be lost in a subset of human cancer cell lines and human primary cancers and may represent tumor suppressor proteins. To better understand the biology of these proteins, the authors examined the expression pattern of BRG1 and BRM in a variety of normal tissues. BRG1 expression was predominantly seen in cell types that constantly undergo proliferation or self-renewal; in contrast, BRM was preferentially expressed in brain, liver, fibromuscular stroma, and endothelial cell types, cell types not constantly engaged in proliferation or self-renewal. This differential expression suggests that these proteins serve distinct functions in human tissues.


Assuntos
Adenosina Trifosfatases/química , Proteínas de Ciclo Celular/metabolismo , Proteínas de Drosophila/metabolismo , Proteínas Nucleares/metabolismo , Subunidades Proteicas/metabolismo , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Anticorpos Monoclonais/metabolismo , Linhagem Celular , DNA Helicases , Ectoderma/metabolismo , Células HeLa , Humanos , Imuno-Histoquímica , Mesoderma/metabolismo , Distribuição Tecidual
3.
Cancer Res ; 63(3): 560-6, 2003 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-12566296

RESUMO

A role for the SWI/SNF complex in tumorigenesis based on its requirement for retinoblastoma induced growth arrest and p53-mediated transcription and the appearance of tumors in SWI/SNF-deficient mice. In addition, Western blot data have shown that the SWI/SNF ATPase subunits cell, BRG1 and BRM (BRG1/BRM), are lost in approximately 30% of human non-small lung cancer cell lines. To determine whether loss of expression of these proteins occurs in primary tumors, we examined their expression in 41 primary lung adenocarcinomas and 19 primary lung squamous carcinomas by immunohistochemistry. These analyses showed that 10% of tumors show a concomitant loss of BRG1 and BRM expression. Moreover, patients with BRG1/BRM-negative carcinomas, independent of stage, have a statistically significant decrease in survival compared with patients with BRG1/BRM. This report provides supportive evidence that BRG1 and BRM act as tumor suppressor proteins and implicates a role for their loss in the development of non-small cell lung cancers.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas Nucleares/deficiência , Fatores de Transcrição/deficiência , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , DNA Helicases , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/patologia , Proteínas Nucleares/biossíntese , Prognóstico , Fatores de Transcrição/biossíntese , Células Tumorais Cultivadas
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