Human Cancer Biology Mechanisms of CHD5 Inactivation in Neuroblastomas

Purpose:Neuroblastomas (NBs) have genomic, biological, and clinical heterogeneity. High-risk NBs are characterized by several genomic changes, includingMYCN amplification and 1p36 deletion.We identified the chromatin-remodeling gene CHD5 as a tumor suppressor gene that maps to 1p36.31. Low or absent CHD5 expression is associated with a 1p36 deletion and an unfavorable outcome, but the mechanisms of CHD5 inactivation in NBs are unknown. Experimental Design:We examined (i) the CHD5 sequence in 188 high-risk NBs investigated through the TARGET initiative, (ii) the methylation status of the CHD5 promoter in 108 NBs with or without 1p36 deletion and/orMYCN amplification, and (iii)mRNA expression ofCHD5 andMYCN in 814 representative NBs using TaqMan low-density array microfluidic cards. Results:Wefoundnoexamplesof somatically acquiredCHD5mutations, even in caseswith1p36deletion, indicating that homozygous genomic inactivation is rare. Methylation of the CHD5 promoter was common in the high-risk tumors, and it was generally associated with both 1p deletion and MYCN amplification. High CHD5 expression was a powerful predictor of favorable outcome, and it showed prognostic value even in multivariable analysis after adjusting for MYCN amplification, 1p36 deletion, and/or 11q deletion. Conclusions: We conclude that (i) somatically acquired CHD5 mutations are rare in primary NBs, so inactivation probably occurs by deletion and epigenetic silencing; (ii) CHD5 expression and promoter methylation are associated with MYCN amplification, suggesting a possible interaction between these 2 genes; and (iii) highCHD5 expression is strongly correlatedwith favorable clinical/biological features and outcome. Clin Cancer Res; 18(6); 1588–97. 2012 AACR.