RESUMO
INTRODUCTION: Germ cell tumours (GCTs) of the testis show exquisite sensitivity to treatment with cisplatin. Despite the high cure rates provided by platinum-based chemotherapy, 10-20% of patients die from progressive disease. Although various cellular pathways may influence cisplatin efficacy, their actual impact has not been comprehensively investigated in advanced GCTs. The objective of the present study was to clarify the role of the expression status of proteins involved in the Rb and p53 tumour suppressor pathways in sensitivity and resistance of GCTs to cisplatin-based chemotherapy. MATERIALS AND METHODS: Paraffin-embedded tumour tissues from 84 patients with advanced GCT treated with cisplatin-based chemotherapy were analysed. Immunohistochemical expression of proteins p53 and mdm2, and the G1-phase cyclins D1 and D2 (CD1 and CD2) was assessed and correlated with the clinical course. RESULTS: The percentages of positive expression of p53, mdm2, CD1 and CD2 were 56, 57, 37.5 and 55%, respectively. From univariate analysis, there was no significant association between p53, mdm2 or CD1 expression and outcome. Instead, positive CD2 expression was found to be marginally associated with shorter median duration of progression-free survival (PFS) (p=0.06). In multivariate analysis, none of the molecular markers retained statistical significance with treatment response or survival. CONCLUSIONS: Tissular expression of p53, mdm2 and CD1 is not associated with prognosis or treatment response in patients with advanced GCT. Aberrant CD2 expression appears to further determine a shorter PFS. Larger and further studies are required to validate CD2 as a marker of cisplatin resistance.
Assuntos
Biomarcadores Tumorais/metabolismo , Cisplatino/administração & dosagem , Resistencia a Medicamentos Antineoplásicos , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Testiculares/tratamento farmacológico , Antígenos CD1/metabolismo , Antígenos CD2/metabolismo , Cisplatino/uso terapêutico , Intervalo Livre de Doença , Humanos , Imuno-Histoquímica , Masculino , Neoplasias Embrionárias de Células Germinativas/metabolismo , Neoplasias Embrionárias de Células Germinativas/patologia , Prognóstico , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Neoplasias Testiculares/metabolismo , Neoplasias Testiculares/patologia , Proteína Supressora de Tumor p53/metabolismoRESUMO
INTRODUCTION: Methylation of the promoter of the MGMT gene and MGMT protein expression are recognized as predictive markers for response to alkylating chemotherapy in glioblastoma (GB). MATERIAL AND METHODS: We have assessed MGMT methylation with the methylation-specific polymerase chain reaction (MSP) in tumor samples from 70 GB patients and in serum samples from 37 of these patients. We have also assessed MGMT protein expression by immunohistochemical (IHC) analysis in tissue samples from 63 of these patients. RESULTS: We found concordance between MGMT methylation status in tissue and serum (Cohen's Kappa = 0.586; p<0.0001). MSP for detection of non-methylated MGMT promoter in serum showed a sensitivity of 95.4% and a specificity of 60%, while the IHC methylation test showed a low specificity (8.9%). Patients whose MGMT promoter was methylated in tissue attained longer progression-free and overall survival. In the multivariate analysis, serum MGMT promoter methylation emerged as an independent factor for longer progression-free and overall survival. CONCLUSION: Serum-based MGMT methylation analysis offers a promising alternative to tumor-based MGMT analysis in cases where tissue samples are unavailable.
Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Metilases de Modificação do DNA/genética , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/genética , Enzimas Reparadoras do DNA/metabolismo , Glioblastoma/genética , Glioblastoma/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Análise Química do Sangue , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/mortalidade , Metilação de DNA/fisiologia , Metilases de Modificação do DNA/análise , Metilases de Modificação do DNA/sangue , Enzimas Reparadoras do DNA/análise , Enzimas Reparadoras do DNA/sangue , Feminino , Glioblastoma/sangue , Glioblastoma/mortalidade , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/genética , Neoplasias/metabolismo , Regiões Promotoras Genéticas/fisiologia , Estudos Retrospectivos , Soro/química , Soro/metabolismo , Análise de Sobrevida , Análise Serial de Tecidos , Proteínas Supressoras de Tumor/análise , Proteínas Supressoras de Tumor/sangueRESUMO
Key "driver" mutations have been discovered in specific subgroups of non-small-cell lung cancer (NSCLC) patients. Activating mutations in the form of deletions in exon 19 (del 19) or the missense mutation L858R in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) predict outcome to EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib. Pooled data from several phase II studies show that gefitinib and erlotinib induce responses in over 70% of NSCLC patients harbouring EGFR mutations, with progression-free survival (PFS) ranging from 9 to 13 months and median survival of around 23 months. Two studies in Caucasian and Asian patients have confirmed that these subgroups of patients attain response rates of 70% with erlotinib and ge- fitinib, including complete responses, PFS up to 14 months and median survival up to 27 months. These landmark outcomes have been accompanied by new challenges: the additional role of chemotherapy and the management of tumours with the secondary T790M mutation that confers resistance to EGFR TKIs. Mechanisms of resistance to reversible EGFR TKIs should be further clarified and could be related to modifications in DNA repair. The presence of double mutations (T790M plus either L858R or del 19) at the time of diagnosis could be much more frequent than originally thought. The sensitivity to EGFR TKIs could be greatly influenced by the expression of genes involved in the repair of DNA double-strand breaks by homologous recombination and non-homologous end joining.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/química , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Mutação , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Bases de Dados Genéticas , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Modelos Biológicos , Mutação/fisiologia , Fosfotransferases/química , Fosfotransferases/genética , Estrutura Terciária de Proteína/genética , EspanhaRESUMO
At the time of diagnosis, half of lung cancer patients have advanced incurable disease. Different chemotherapy combinations--with or without targeted therapies--yield similar results in spite of the continuous efforts of clinicians. However, molecular biological studies have already shed a great deal of light on the existence of multiple genetic aberrations that can be useful for customizing treatment. mRNA transcripts involved in DNA repair pathways, such as ERCC1 and BRCA1, confer selective resistance to cisplatin or taxanes. Polymorphisms in DNA repair genes and methylation of checkpoint genes in circulating serum DNA could become important predictive markers of survival to certain cisplatin-based regimens. EGFR tyrosine kinase mutations are the crux of targeted therapies.