Abstract
Approximately 20% of stage 4 high-risk neuroblastoma patients are alive and disease-free 5 years after disease onset while the remaining experience rapid and fatal progression. Numerous findings underline the prognostic role of methylation of defined target genes in neuroblastoma without taking into account the clinical and biological heterogeneity of this disease. In this report we have investigated the methylation of the PCDHB cluster, the most informative member of the “Methylator Phenotype” in neuroblastoma, hypothesizing that if this epigenetic mark can predict overall and progression free survival in high-risk stage 4 neuroblastoma, it could be utilized to improve the risk stratification of the patients, alone or in conjunction with the previously identified methylation of the SFN gene (14.3.3sigma) that can accurately predict outcome in these patients. We have utilized univariate and multivariate models to compare the prognostic power of PCDHB methylation in terms of overall and progression free survival, quantitatively determined by pyrosequencing, with that of other markers utilized for the patients' stratification utilizing methylation thresholds calculated on neuroblastoma at stage 1–4 and only on stage 4, high-risk patients. Our results indicate that PCDHB accurately distinguishes between high- and intermediate/low risk stage 4 neuroblastoma in agreement with the established risk stratification criteria. However PCDHB cannot predict outcome in the subgroup of stage 4 patients at high-risk whereas methylation levels of SFN are suggestive of a “methylation gradient” associated with tumor aggressiveness as suggested by the finding of a higher threshold that defines a subset of patients with an extremely severe disease (OS <24 months). Because of the heterogeneity of neuroblastoma we believe that clinically relevant methylation markers should be selected and tested on homogeneous groups of patients rather than on patients at all stages.
Highlights
Neuroblastoma (NB), a neoplasia derived from ganglionic precursors of the sympathetic nervous system, is the most common extra cranial solid tumor of infancy
In view of a possible translational application of methylation of Protocadherin B cluster (PCDHB) cluster to improve risk stratification in stage 4 NB patients at high risk, we have evaluated the predictive power of PCDHB methylation by quantitative analysis in stage 4 NB at high risk, the most common mode of presentation of this disease which represents a clinically relevant problem in terms of accurate patients stratification and improvement of outcome
Within the stage 4 high-risk group we considered the patients as ‘‘short survivors’’ (HR-SS) if they died for disease within 60 months (N = 83) from diagnosis and as ‘‘long survivors’’ (HR-LS) if they survived more than 60 months (N = 23)
Summary
Neuroblastoma (NB), a neoplasia derived from ganglionic precursors of the sympathetic nervous system, is the most common extra cranial solid tumor of infancy This tumor is highly heterogeneous and its clinical behavior ranges from spontaneous regression to rapid and aggressive progression, metastatic spreading and poor outcome [1]. The guidelines set for by the International Neuroblastoma Risk Group (INRG) subdivide these patients into three categories (high, intermediate and low risk) depending on clinical and biological criteria [3] This risk stratification is part of the clinical decisional tree and helps to choose the most suitable treatment. In stage 4, high-risk NB approximately 80% of the patients experience rapid and fatal disease while the remaining subgroup performs well with most of the patients alive and free of disease 5 years after diagnosis [1] This dramatic difference suggests that the prediction of outcome for these patients is still inaccurate. The identification of predictive biomarkers in NB is made difficult because of its clinical and biological heterogeneity
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