RESUMO
UNLABELLED: Correction of misincorporated nucleotides during DNA replication (mismatch repair) distinguishes histologically similar cancers with distinct biological and clinical behavior. We investigated expression of two mismatch repair genes in testis cancer to determine the expression pattern in histologically distinct subtypes, correlate expression with genetic instability and correlate expression and genetic instability with clinical outcome. PATIENTS AND METHODS: 118 cases of testis cancer were analyzed. Immunohistochemical analysis of paraffin embedded specimens utilized monoclonal antibody for hMLH1 and hMSH2 mismatch repair proteins. Genetic instability was determined by comparing genomic DNA from microdissected matched normal and tumor cells. PCR amplification of 10 genetic markers assessed loss of heterozygosity and/or microsatellite instability. RESULTS: hMSH2 staining was associated with pathologic stage (p < 0.001) while hMLH1 staining was associated with cancer specific survival (p = 0.036). Genetic instability was detected in 94% of low hMLH1 and 92% of low hMSH2 staining tumors. Relapse and cancer specific death correlated with genetic instability (p = 0.01 and 0.04 respectively). Overall 9% of tumors exhibited reduced mismatch repair expression, microsatellite instability and an unfavorable clinical outcome. CONCLUSIONS: Mismatch repair expression and genetic instability define testis cancers with distinct molecular properties and clinical behavior. In conjunction with pathologic examination and serum tumor markers, mismatch repair expression may be an important determinant for clinical management of men with this malignancy.
Assuntos
Germinoma/genética , Neoplasias Testiculares/genética , Pareamento Incorreto de Bases/genética , Reparo do DNA/genética , Instabilidade Genômica/genética , Germinoma/metabolismo , Germinoma/patologia , Humanos , Imuno-Histoquímica , Masculino , Neoplasias Testiculares/metabolismo , Neoplasias Testiculares/patologiaRESUMO
La corrección de los nucleótidos mal incorporados durante la replicación del ADN (sistema de reparación de genes) puede determinar un potencial biológico y clínico diferente en los tumores. En este trabajo investigamos la expresión inmunohistoquímica de los genes de reparación en cáncer de testículo en los distintos tipos histológicos, correlacionando el grado de expresión con la presencia de inestabilidad microsatélite y correlacionando ambas con la evolución clínica. Pacientes y método: 118 casos de tumores testiculares fueron analizados molecularmente realizando inmunohistoquímica para hMLH1 y hMSH2. El análisis de inestabilidad microsatélite y LOH se realizó comparando ADN micro disecado de tejido tumoral y normal, el que fue amplificado mediante PCR con 10 marcadores preestablecidos. Resultados: El grado de expresión de hMSH2 se correlaciona con el estadio del tumor (p<0,001) mientras que la sobreviva cáncer específica se correlaciona con el grado de expresión de hMLH1 (p=0,036). Inestabilidad microsatélite se detectó en un 94% y 92% de los cánceres con baja expresión de hMLH1 y hMSH2 respectivamente. La recaída y muerte cáncer específica se correlacionan con el grado de inestabilidad genética (p=0,01, p=0,04). Un 9% de los tumores presentan una bajo grado de expresión de los genes de reparación, inestabilidad microsatélite y un mal pronóstico. Conclusiones: El grado de expresión de los genes de reparación así como la frecuencia de inestabilidad logran definir cánceres testiculares con diferentes propiedades moleculares y diferente pronóstico. Los genes de reparación usados en conjunto con la histología, los marcadores serológicos pueden ser determinantes en el manejo de los pacientes con tumores testiculares (AU)
Correction of misincorporated nucleotides during DNA replication (mismatch repair) distinguishes histologically similar cancers with distinct biological and clinical behavior. We investigated expression of two mismatch repair genes in testis cancer to determine the expression pattern in histologically distinct subtypes, correlate expression with genetic instability and correlate expression and genetic instability with clinical outcome. Patients and methods: 118 cases of testis cancer were analyzed. Immunohistochemical analysis of paraffin embedded specimens utilized monoclonal antibody for hMLH1 and hMSH2 mismatch repair proteins. Genetic instability was determined by comparing genomic DNA from microdissected matched normal and tumor cells. PCR amplification of 10 genetic markers assessed loss of heterozygosity and/or microsatellite instability. Results: hMSH2 staining was associated with pathologic stage (p<0.001) while hMLH1 staining was associated with cancer specific survival (p=0.036). Genetic instability was detected in 94% of low hMLH1 and 92% of low hMSH2 staining tumors. Relapse and cancer specific death correlated with genetic instability (p=0.01 and 0.04 respectively). Overall 9% of tumors exhibited reduced mismatch repair expression, microsatellite instability and an unfavorable clinical outcome. Conclusions: Mismatch repair expression and genetic instability define testis cancers with distinct molecular properties and clinical behavior. In conjunction with pathologic examination and serum tumor markers, mismatch repair expression may be an important determinant for clinical management of men with this malignancy (AU)
