RESUMO
PURPOSE: Brain metastases affect 25% of patients with non-small cell lung cancer (NSCLC). We hypothesized that the expression of genes in primary NSCLC tumors could predict brain metastasis and be used for identification of high-risk patients, who may benefit from prophylactic therapy. EXPERIMENTAL DESIGN: The expression of 12 genes was measured by real-time quantitative reverse transcriptase PCR in 142 frozen NSCLC tissue samples. Univariate and multivariate Cox regression analysis was used to analyze the correlation between gene expression and the occurrence of brain metastasis. Immunohistochemistry on independent samples was used to verify the findings. RESULTS: A score based on the expression levels of three genes, CDH2 (N-cadherin), KIFC1, and FALZ, was highly predictive of brain metastasis in early and advanced lung cancer. The probability of remaining brain metastasis-free at 2 years after diagnosis was 90.0+/-9.5% for patients with stage I/stage II tumors and low score compared with 62.7+/-12% for patients with high score (P<0.01). In patients with more advanced lung cancer, the brain metastasis-free survival at 24 months was 89% for patients with low score compared with only 37% in patients with high score (P<0.02). These results were confirmed by immunohistochemical detection of N-cadherin in independent cohort of primary NSCLC. CONCLUSIONS: The expression levels of three genes in primary NSCLC tumors may be used to identify patients at high risk for brain metastasis who may benefit from prophylactic therapy to the central nervous system.
Assuntos
Antígenos CD/genética , Antígenos Nucleares/genética , Neoplasias Encefálicas/diagnóstico , Caderinas/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Cinesinas/genética , Neoplasias Pulmonares/genética , Proteínas do Tecido Nervoso/genética , Fatores de Transcrição/genética , Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Adenocarcinoma/secundário , Antígenos CD/metabolismo , Antígenos Nucleares/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundário , Caderinas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/secundário , Feminino , Perfilação da Expressão Gênica , Humanos , Técnicas Imunoenzimáticas , Cinesinas/metabolismo , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/secundário , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/metabolismo , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/metabolismoRESUMO
Sil (SCL interrupting locus) was cloned from the most common chromosomal rearrangement in T-cell acute lymphoblastic leukemia. It is an immediate early gene whose expression is associated with cell proliferation. Sil protein levels are tightly regulated during the cell cycle, reaching peak levels in mitosis and disappearing on transition to G1. A recent study found Sil to be one of 17 genes whose overexpression in primary adenocarcinomas predicts metastatic spread. We hypothesized that Sil might have a role in carcinogenesis. To address this question, we utilized several approaches. Using a multitumor tissue array, we found that Sil protein expression was increased mostly in lung cancer, but also at lower levels, in a subset of other tumors. Microarray gene expression analysis and immunohistochemistry of lung cancer samples verified these observations. Sil gene expression in lung cancer correlated with the expression of several kinetochore check-point genes and with the histopathologic mitotic index. These observations suggest that overexpression of the Sil gene characterizes tumors with increased mitotic activity.
Assuntos
Neoplasias Pulmonares/metabolismo , Mitose , Proteínas de Fusão Oncogênica/biossíntese , Adenocarcinoma/metabolismo , Western Blotting , Diferenciação Celular , Divisão Celular , Linhagem Celular , Fase G1 , Genes Precoces , Células HeLa , Humanos , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intracelular , Cinetocoros/metabolismo , Metástase Neoplásica , Análise de Sequência com Séries de Oligonucleotídeos , RNA Mensageiro/metabolismoRESUMO
BACKGROUND: Asthma is an inflammatory airway disease caused by interaction between susceptibility genes and diverse environmental factors. In Israel, asthma seems to be familial and more severe in patients of Iraqi Jewish descent. On the other hand, asthma is less frequent in individuals with familial Mediterranean fever, an autoinflammatory disease prevalent in the Iraqi Jewish community and linked to mutations in the familial Mediterranean fever gene, designated MEFV. OBJECTIVES: To explore a possible role for mutated MEFV in the reduced susceptibility to asthma and to determine its expression in Israeli subjects of Iraqi origins. METHODS: Using a case-control approach, we studied the presence of the 3 most common MEFV mutations (M694V, V726A, and E148Q) in DNA samples from 75 patients with asthma and 45 asymptomatic first-degree relatives, all of Iraqi Jewish origin. The severity of asthma was evaluated using a published severity score. RESULTS: Eleven patients with asthma and 14 of their relatives carried 1 or 2 mutations in the MEFV gene, a carrier rate significantly lower in patients with asthma than in their first-degree relatives and in ethnically matched healthy individuals (P < .03 and P < .003, respectively). Carriers of MEFV mutations had less severe disease, compared with noncarriers (P < .002). CONCLUSION: These findings suggest that MEFV mutations may have a protective effect in the pathogenesis of asthma.