CpG island methylator phenotype is a strong determinant of poor prognosis in neuroblastomas.
Neuroblastoma, one of the most common pediatric solid tumors, is characterized by two extreme disease courses, spontaneous regression and life-threatening progression. Here, we conducted a genome-wide search for differences in DNA methylation that distinguish between neuroblastomas of the two types. Three CpG islands (CGI) and two groups of CGIs were found to be methylated specifically in neuroblastomas with a poor prognosis. By quantitative analysis of 140 independent cases, methylation of all the five CGI (groups) was shown to be closely associated with each other, conforming to the CpG island methylator phenotype (CIMP) concept. The presence of CIMP was sensitively detected by methylation of the PCDHB CGIs and associated with significantly poor survival (hazard ratio, 22.1; 95% confidence interval, 5.3-93.4; P < 0.0001). Almost all cases with N-myc amplification (37 of 38 cases) exhibited CIMP. Even in 102 cases without N-myc amplification, the presence of CIMP (30 cases) strongly predicted poor survival (hazard ratio, 12.4; 95% confidence interval, 2.6-58.9; P = 0.002). Methylation of PCDHB CGIs, located in their gene bodies, did not suppress gene expression or induce histone modifications. However, CIMP was significantly associated with methylation of promoter CGIs of the RASSF1A and BLU tumor suppressor genes. The results showed that neuroblastomas with CIMP have a poor prognosis and suggested induction of silencing of important genes as an underlying mechanism.
Abe
Masanobu
M
Carcinogenesis Division, National Cancer Center Research Institute, University of Tokyo Graduate School of Medicine, 5-1-1 Tsikiji, Chuo-ku, Tokyo 104-0045, Japan.
Ohira
Miki
M
Kaneda
Atsushi
A
Yagi
Yukiko
Y
Yamamoto
Seiichiro
S
Kitano
Yoshihiro
Y
Takato
Tsuyoshi
T
Nakagawara
Akira
A
Ushijima
Toshikazu
T
D045744:Cell Line, Tumor; D002675:Child, Preschool; D018899:CpG Islands; D019175:DNA Methylation; D015894:Genome, Human; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D009447:Neuroblastoma / Q000235:genetics*; D011003:Ploidies; D011379:Prognosis; D011401:Promoter Regions, Genetic