MAGE-A1 expression is associated with good prognosis in neuroblastoma tumors.
OBJECTIVE
Neuroblastoma is an embryonal tumor of neuroectodermal cells. Patients with metastatic neuroblastoma have a poor survival rate, which has led to numerous efforts to develop prognostic markers. Cancer/testis-specific antigens MAGE-A1 and MAGE-A3 genes were proposed as minimal residual disease (MRD) markers in neuroblastoma, but its usefulness for this purpose is rather limited.


METHODS
We studied 47 primary neuroblastoma tumors. RNA was extracted and cDNA was prepared by reverse transcription. Detection of the MAGE-A1 expression was done by hybridization of the RT-PCR products. We used methylation-specific-PCR to perform the epigenetic studies.


RESULTS
We studied the MAGE-A1 and MAGE-A3 expressions, and the MAGE-A1 expression showed significant association with tumor stage, absence of bone marrow infiltration and survival. A multivariate analysis enabled us to conclude that the MAGE-A1 expression represents a new independent predictive factor, which is independent of N-Myc amplification (P value = 0.000), age at diagnosis (P value = 0.002) or tumoral stage (P value = 0.024). Considering the epigenetic regulation of MAGE-A1, we analyzed its methylation profile, and found a significant association with its expression in tumor cells. Moreover, we found tumors that failed to show the MAGE-A1 expression despite the hypomethylated sequence, and corresponded to advanced neuroblastoma that might share another mechanism involved in MAGE-A1 silencing. Given the association described between genome-wide hypomethylation and microsatellite instability, we determined the MSI status of tumor samples, finding a significant correlation with the MAGE-A1 expression and, more specifically, with the hypomethylated status of this gene only in female patients.


CONCLUSIONS
We conclude that the MAGE-A1 expression is associated with good prognosis in neuroblastoma.
Grau
Elena
E
Unidad de Genética y Diagnóstico Prenatal, Hospital Universitario La Fe, Av/Campanar no. 21, 46009, Valencia, Spain. elena_grau@hotmail.com
Oltra
Silvestre
S
Martínez
Francisco
F
Orellana
Carmen
C
Cañete
Adela
A
Fernández
Jose María
JM
Hernández-Martí
Miguel
M
Castel
Victoria
V
D000951:Antigens, Neoplasm / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D018572:Disease-Free Survival; D015972:Gene Expression Regulation, Neoplastic; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases / Q000235:genetics; D006801:Humans; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins / Q000235:genetics*; D009367:Neoplasm Staging; D009447:Neuroblastoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D012334:RNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D012097:Repressor Proteins / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D017741:Survivors
D000951:Antigens, Neoplasm; D004273:DNA, Neoplasm; C072013:MAGEA3 protein, human; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D012097:Repressor Proteins; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases