Clinical application of the CpG island methylator phenotype to prognostic diagnosis in neuroblastomas

Clinical applications of aberrant DNA methylation to cancer diagnostics and therapeutics are accelerating. Especially, the CpG island methylator phenotype (CIMP), simultaneous methylation of multiple genes, provides information that cannot be obtained by other diagnostic methods and therapeutic opportunities. CIMP is known to be associated with poor or good prognosis depending upon cancer types. We identified that CIMP in neuroblastomas (NBLs) is strongly associated with poor prognosis in Japanese NBL cases (hazard ratio (HR) = 22). Almost all NBLs with MYCN amplification displayed CIMP, and even among NBLs without MYCN amplification, NBLs with CIMP had worse prognosis (HR = 12). The prognostic power was faithfully reproduced in German NBL cases by the same methods, and also in Italian and Swedish NBL cases with different analytical methods. Mechanistically, methylation silencing of different sets of tumor-suppressor genes is involved in poor prognosis of NBLs with CIMP, and the presence of CIMP is most sensitively detected by methylation of the PCDHB family. For therapeutic purposes, a combination of 5-aza-2'-deoxycytidine, a DNA-demethylating drug, with 13-cis-retinoic acid, a differentiating drug, has been shown to be effective for NBLs in vitro, and further development of a better combination(s) is awaited. Now, epigenetic diagnosis and therapeutics are becoming or have become an important choice for cancer patients.