OR02-1 DNA Methylation Profiling in Pediatric Adrenocortical Tumors Reveals Distinct Methylation Signatures with Prognostic Significance: A Report from the International Pediatric Adrenocortical Tumor Registry

Pediatric adrenocortical tumors (ACTs) are heterogeneous and have a poor prognosis. Overall survival is around 60%. In pediatric ACT that is managed only with surgery, features associated with adverse outcome include age greater than 3 years, non-functioning tumors, and metastatic (Stage IV) or residual tumor after surgery (Stage III). These factors individually do not account for most treatment failures, however. As current histopathologic classification systems are hindered by poor reproducibility and lack of predictive value, new prognostic markers are critically needed. In adults, methylation profiling can distinguish benign from malignant ACT, but similar data on pediatric ACT have not been reported. We performed DNA methylation profiling (MethylationEPIC BeadChip Array) on 52 pediatric ACTs and 13 normal pediatric adrenocortical tissue samples. The median age of 38 girls and 14 boys was 2.8 years (range, 0.3-17). ACTs were histologically classified as carcinoma (n=29), adenoma (n=10), and indeterminate (n=13). Overall survival was used as a primary endpoint. Unsupervised analysis of the 20,000 most variably methylated probes segregated cases into two distinct subgroups (designated A1 and A2). Differentially methylated genes (q-value 4 years (HR = 16.8, p = 0.008) and A1 methylation group (HR 7.7, p=0.0011) were each significantly correlated with overall survival. A1 subgroup remained significantly associated with overall survival in a series of models that adjusted for features including: clinical diagnosis, histopathologic characteristics, Ki67 index, and advanced stage. Methylation profiling provides prognostic significance that is independent of most current predictive variables, and in the future, may serve as a powerful biomarker in the prognostication of pediatric ACT.