RESUMEN
PURPOSE: Biomarkers can facilitate diagnosis, monitor treatment response, and assess prognosis in some patients with cancer. YKL-40 and matrix metalloproteinase-9 (MMP-9) are two proteins highly differentially expressed by malignant gliomas. We obtained prospective longitudinal serum samples from patients with gliomas to determine whether YKL-40 or MMP-9 could be used as serum markers. EXPERIMENTAL DESIGN: Serum samples were obtained concurrently with magnetic resonance imaging scans. YKL-40 and MMP-9 were determined by ELISA and the values correlated with the patient's radiographic status and survival. RESULTS: High-grade glioma patients who underwent a surgical resection of their tumor had transient increase of both YKL-40 and MMP-9 serum levels in the postoperative period. Glioblastoma multiforme (GBM) patients with no radiographic evidence of disease (n = 10 patients, 50 samples) had a significantly lower level of YKL-40 and MMP-9 than patients with active tumor (n = 66 patients, 209 samples; P = 0.0003 and 0.0002, respectively). Anaplastic glioma patients with no radiographic evidence of disease (n = 32 patients, 107 samples) also had a significantly lower level of YKL-40 compared with those patients with active tumor (n = 48 patients, 199 samples; P = 0.04). There was a significant inverse association between YKL-40 and survival in GBM, hazard ratio (hazard ratio, 1.4; P = 0.02), and anaplastic astrocytoma patients (hazard ratio, 2.2; P = 0.05). CONCLUSIONS: YKL-40 and MMP-9 can be monitored in patients' serum and help confirm the absence of active disease in GBM and YKL-40 in anaplastic glioma patients. YKL-40 can be used as predictor of survival in patients with high-grade glioma. Longitudinal studies with a larger patient population are needed to confirm these findings.
Asunto(s)
Biomarcadores de Tumor/sangre , Glioblastoma/sangre , Glicoproteínas/sangre , Metaloproteinasa 9 de la Matriz/sangre , Oligodendroglioma/sangre , Adipoquinas , Adulto , Anciano , Anciano de 80 o más Años , Autoantígenos/sangre , Estudios de Casos y Controles , Proteína 1 Similar a Quitinasa-3 , Femenino , Glioblastoma/patología , Glioblastoma/cirugía , Sustancias de Crecimiento/sangre , Humanos , Lectinas , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Oligodendroglioma/patología , Oligodendroglioma/cirugía , Pronóstico , Estudios Prospectivos , Tasa de SupervivenciaRESUMEN
PURPOSE: YKL-40 is a secreted glycoprotein (chitinase family). We compared YKL-40 with two ovarian cancer serum markers, CA125 and CA15-3, for the detection of early-stage ovarian cancer. MATERIALS AND METHODS: Serum YKL-40 levels were assayed by enzyme-linked immunosorbent assay for 46 healthy subjects, 61 high-risk individuals, 33 patients with benign gynecologic processes, and 50 preoperative patients subsequently diagnosed with predominantly early-stage ovarian cancer. Serum CA125 and CA15-3 values were obtained. RESULTS: Median YKL-40 level was 28 ng/mL (range, 15 to 166 ng/mL) for healthy subjects, 36 ng/mL (range, 9 to 69 ng/mL) for high-risk individuals without prior cancer, 44.5 ng/mL (range, 5 to 133 ng/mL) for high-risk patients with prior breast cancer, and 38 ng/mL (range, 5 to 67 ng/mL) for individuals with benign gynecologic processes (P = NS). Median preoperative YKL-40 level for ovarian cancer patients was 94 ng/mL (range, 17 to 517 ng/mL; P <.0001 compared with normal and high-risk). YKL-40 was elevated (>/= 62 ng/mL) in 36 (72%) of 50 patients compared with 23 (46%) of 50 and 13 (26%) of 50 patients for CA125 and CA15-3 (P <.008). Twenty (65%) of 31 early-stage patients had elevated serum YKL-40 levels compared with 11 (35%) of 31 and four (13%) of 31 patients for CA125 and CA15-3 (P =.039). YKL-40 levels increased with stage (P <.005), regardless of grade, histology, or patient age. Patients with early-stage tumors with YKL-40 values more than 80 ng/mL had a worse prognosis (71% recurrence v no recurrence [P =.034]). CONCLUSION: YKL-40 may represent a novel marker for the detection of early-stage ovarian cancer. YKL-40 levels in early-stage patients may also predict disease recurrence and survival. The utility of YKL-40 in detection of early-stage ovarian cancer deserves further investigation.
Asunto(s)
Biomarcadores de Tumor/análisis , Glicoproteínas/análisis , Recurrencia Local de Neoplasia , Estadificación de Neoplasias/métodos , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/patología , Adipoquinas , Adulto , Anciano , Anciano de 80 o más Años , Autoantígenos/análisis , Proteína 1 Similar a Quitinasa-3 , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Lectinas , Persona de Mediana Edad , Pronóstico , Sensibilidad y Especificidad , Análisis de SupervivenciaRESUMEN
Human serum contains a complex array of proteolytically derived peptides (serum peptidome) that may provide a correlate of biological events occurring in the entire organism; for instance, as a diagnostic for solid tumors (Petricoin, E. F.; Ardekani, A. M.; Hitt, B. A.; Levine, P. J.; Fusaro, V. A.; Steinberg, S. M.; Mills, G. B.; Simone, C.; Fishman, D. A.; Kohn, E. C.; Liotta, L. Lancet 2002, 359, 572-577). Here, we describe a novel, automated technology platform for the simultaneous measurement of serum peptides that is simple, scalable, and generates highly reproducible patterns. Peptides are captured and concentrated using reversed-phase (RP) batch processing in a magnetic particle-based format, automated on a liquid handling robot, and followed by a MALDI TOF mass spectrometric readout. The protocol is based on a detailed investigation of serum handling, RP ligand and eluant selection, small-volume robotics design, an optimized spectral acquisition program, and consistent peak extraction plus binning across a study set. The improved sensitivity and resolution allowed detection of 400 polypeptides (0.8-15-kDa range) in a single droplet (approximately 50 microL) of serum, and almost 2000 unique peptides in larger sample sets, which can then be analyzed using common microarray data analysis software. A pilot study indicated that sera from brain tumor patients can be distinguished from controls based on a pattern of 274 peptide masses. This, in turn, served to create a learning algorithm that correctly predicted 96.4% of the samples as either normal or diseased.
Asunto(s)
Proteínas Sanguíneas/análisis , Neoplasias Encefálicas/sangre , Materiales Biocompatibles Revestidos/química , Glioblastoma/sangre , Magnetismo , Péptidos/sangre , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Algoritmos , Automatización , Biomarcadores de Tumor/sangre , Neoplasias Encefálicas/diagnóstico , Glioblastoma/diagnóstico , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Proyectos PilotoRESUMEN
We have identified a potential serum marker for glioblastoma multiforme (GBM) using microarray analysis from samples of GBM. We compared the gene expression profile of 19 gliomas to pooled normal brain by competitive hybridization of RNA from each tumor sample to a pooled sample of RNA isolated from normal brain tissue using the Incyte 10,000 gene expression array. The most differentially expressed gene in this analysis encodes a secreted glycoprotein and is referred to as YKL-40. YKL-40 mRNA was detected in the GBM samples with a range of 3- to 62-fold elevation over normal brain. It has been reported previously that this protein is expressed in pathologic conditions of extracellular matrix degradation and angiogenesis, such as rheumatoid arthritis, severe osteoarthritis, hepatic fibrosis, primary colorectal cancer, and metastatic breast cancer. These data suggest YKL-40 may be involved in extracellular matrix degradation and/or angiogenesis. Western blot analysis of glioma samples for YKL-40 protein levels revealed substantial elevation in approximately 65% of GBMs and undetectable levels in lower-grade gliomas (grade II and III) or normal brain tissue. We performed ELISA analysis on serum samples of glioma patients to determine whether this protein would correlate with the presence of tumor and tumor grade or burden. YKL-40 serum levels were substantially elevated in many of the GBM patients. Statistical analysis of these data indicates that in patients with glioma, serum YKL-40 levels correlate with tumor grade and potentially tumor burden in GBM.