RESUMO
BACKGROUND: The current biomarkers alpha-fetoprotein and human chorionic gonadotropin have limited sensitivity and specificity for diagnosing malignant germ-cell tumours (GCTs). MicroRNAs (miRNAs) from the miR-371-373 and miR-302/367 clusters are overexpressed in all malignant GCTs, and some of these miRNAs show elevated serum levels at diagnosis. Here, we developed a robust technical pipeline to quantify these miRNAs in the serum and cerebrospinal fluid (CSF). The pipeline was used in samples from a cohort of exclusively paediatric patients with gonadal and extragonadal malignant GCTs, compared with appropriate tumour and non-tumour control groups. METHODS: We developed a method for miRNA quantification that enabled sample adequacy assessment and reliable data normalisation. We performed qRT-PCR profiling for miR-371-373 and miR-302/367 cluster miRNAs in a total of 45 serum and CSF samples, obtained from 25 paediatric patients. RESULTS: The exogenous non-human spike-in cel-miR-39-3p and the endogenous housekeeper miR-30b-5p were optimal for obtaining robust serum and CSF qRT-PCR quantification. A four-serum miRNA panel (miR-371a-3p, miR-372-3p, miR-373-3p and miR-367-3p): (i) showed high sensitivity/specificity for diagnosing paediatric extracranial malignant GCT; (ii) allowed early detection of relapse of a testicular mixed malignant GCT; and (iii) distinguished intracranial malignant GCT from intracranial non-GCT tumours at diagnosis, using CSF and serum samples. CONCLUSIONS: The pipeline we have developed is robust, scalable and transferable. It potentially promises to improve clinical management of paediatric (and adult) malignant GCTs.
Assuntos
Biomarcadores Tumorais/sangue , Neoplasias do Sistema Nervoso Central/diagnóstico , MicroRNAs/sangue , Recidiva Local de Neoplasia/diagnóstico , Neoplasias Embrionárias de Células Germinativas/diagnóstico , Neoplasias Ovarianas/diagnóstico , Neoplasias Testiculares/diagnóstico , Adolescente , Biomarcadores Tumorais/líquido cefalorraquidiano , Carcinoma Embrionário/sangue , Carcinoma Embrionário/líquido cefalorraquidiano , Carcinoma Embrionário/diagnóstico , Neoplasias do Sistema Nervoso Central/sangue , Neoplasias do Sistema Nervoso Central/líquido cefalorraquidiano , Criança , Pré-Escolar , Coriocarcinoma não Gestacional/sangue , Coriocarcinoma não Gestacional/líquido cefalorraquidiano , Coriocarcinoma não Gestacional/diagnóstico , Gonadotropina Coriônica/sangue , Gonadotropina Coriônica/líquido cefalorraquidiano , Tumor do Seio Endodérmico/sangue , Tumor do Seio Endodérmico/líquido cefalorraquidiano , Tumor do Seio Endodérmico/diagnóstico , Feminino , Germinoma/sangue , Germinoma/líquido cefalorraquidiano , Germinoma/diagnóstico , Humanos , Lactente , Recém-Nascido , Masculino , MicroRNAs/líquido cefalorraquidiano , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/líquido cefalorraquidiano , Neoplasias Embrionárias de Células Germinativas/sangue , Neoplasias Embrionárias de Células Germinativas/líquido cefalorraquidiano , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/líquido cefalorraquidiano , Reação em Cadeia da Polimerase , Região Sacrococcígea , Sensibilidade e Especificidade , Neoplasias Testiculares/sangue , Neoplasias Testiculares/líquido cefalorraquidiano , alfa-Fetoproteínas/líquido cefalorraquidiano , alfa-Fetoproteínas/metabolismoAssuntos
Neoplasias Encefálicas/patologia , Carcinoma in Situ/patologia , Germinoma/patologia , Neoplasias Primárias Múltiplas/patologia , Neoplasias Testiculares/patologia , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/líquido cefalorraquidiano , Carcinoma in Situ/sangue , Carcinoma in Situ/líquido cefalorraquidiano , Gonadotropina Coriônica Humana Subunidade beta/sangue , Gonadotropina Coriônica Humana Subunidade beta/líquido cefalorraquidiano , Evolução Fatal , Germinoma/sangue , Germinoma/líquido cefalorraquidiano , Humanos , Masculino , Proteínas de Neoplasias/sangue , Proteínas de Neoplasias/líquido cefalorraquidiano , Neoplasias Primárias Múltiplas/sangue , Neoplasias Primárias Múltiplas/líquido cefalorraquidiano , Neoplasias Testiculares/sangue , Neoplasias Testiculares/líquido cefalorraquidiano , Adulto Jovem , alfa-Fetoproteínas/análise , alfa-Fetoproteínas/líquido cefalorraquidianoRESUMO
Serum values of alpha-fetoprotein (AFP) and human chorionic gonadotrophin (HCG) have been used to monitor disseminated testicular carcinoma. Serial measurements of these markers have been used to monitor the response to therapy, to follow the progress of disease, and to detect subclinical recurrences. With increasingly effective chemotherapy for systemic disease, central nervous system (CNS) metastases in testicular carcinoma are becoming increasingly important as a cause of treatment failure. Cerebrospinal fluid (CSF) values of AFP and HCG seem to be important ancillary acids in the neurosurgical management of CNS metastases from testicular cancer. Our preliminary experience with three cases suggests that these CSF markers (plus computerized tomograhic scanning) should be evaluated in patients with this disease.
Assuntos
Encefalopatias/líquido cefalorraquidiano , Carcinoma/líquido cefalorraquidiano , Coriocarcinoma/líquido cefalorraquidiano , Teratoma/líquido cefalorraquidiano , Neoplasias Testiculares/líquido cefalorraquidiano , Adulto , Gonadotropina Coriônica/líquido cefalorraquidiano , Humanos , Masculino , Metástase Neoplásica , alfa-Fetoproteínas/líquido cefalorraquidianoRESUMO
Ascending myelopathy developed in a previously irradiated 10-year-old boy after intraventricular methotrexate and cytosine arabinoside were given for central nervous system relapse of acute lymphoblastic leukemia. The course was fatal in 10 weeks. Cerebrospinal fluid myelin basic protein levels, indicating a demyelinative process, rose prior to the onset of clinical symptoms and remained at very high levels until death. Myelin basic protein may be useful as a predictor of chemotherapy-associated neurotoxicity.