Differential DNA methylation in the brain is associated with many psychiatric diseases, but access to brain tissues is essentially limited to postmortem samples. The use of surrogate tissues has become common in identifying methylation changes associated with psychiatric disease. In this study, we determined the extent to which peripheral tissues can be used as surrogates for DNA methylation in the brain. Blood, saliva, buccal, and live brain tissue samples from 27 patients with medically intractable epilepsy undergoing brain resection were collected (age range 5–61 years). Genome-wide methylation was assessed with the Infinium HumanMethylation450 (n = 12) and HumanMethylationEPIC BeadChip arrays (n = 21). For the EPIC methylation data averaged for each CpG across subjects, the saliva–brain correlation (r = 0.90) was higher than that for blood–brain (r = 0.86) and buccal–brain (r = 0.85) comparisons. However, within individual CpGs, blood had the highest proportion of CpGs correlated to brain at nominally significant levels (20.8%), as compared to buccal tissue (17.4%) and saliva (15.1%). For each CpG and each gene, levels of brain-peripheral tissue correlation varied widely. This indicates that to determine the most useful surrogate tissue for representing brain DNA methylation, the patterns specific to the genomic region of interest must be considered. To assist in that objective, we have developed a website, IMAGE-CpG, that allows researchers to interrogate DNA methylation levels and degree of cross-tissue correlation in user-defined locations across the genome.

Posterior fossa ependymoma comprises two distinct molecular variants termed EPN_PFA and EPN_PFB that have a distinct biology and natural history. The therapeutic value of cytoreductive surgery and radiation therapy for posterior fossa ependymoma after accounting for molecular subgroup is not known. MethodsFour independent nonoverlapping retrospective cohorts of posterior fossa ependymomas (n = 820) were profiled using genome-wide methylation arrays. Risk stratification models were designed based on known clinical and newly described molecular biomarkers identified by multivariable Cox proportional hazards analyses. ResultsMolecular subgroup is a powerful independent predictor of outcome even when accounting for age or treatment regimen. Incompletely resected EPN_PFA ependymomas have a dismal prognosis, with a 5-year progression-free survival ranging from 26.1% to 56.8% across all four cohorts. Although first-line (adjuvant) radiation is clearly beneficial for completely resected EPN_PFA, a substantial proportion of patients with EPN_PFB can be cured with surgery alone, and patients with relapsed EPN_PFB can often be treated successfully with delayed external-beam irradiation. ConclusionThe most impactful biomarker for posterior fossa ependymoma is molecular subgroup affiliation, independent of other demographic or treatment variables. However, both EPN_PFA and EPN_PFB still benefit from increased extent of resection, with the survival rates being particularly poor for subtotally resected EPN_PFA, even with adjuvant radiation therapy. Patients with EPN_PFB who undergo gross total resection are at lower risk for relapse and should be considered for inclusion in a randomized clinical trial of observation alone with radiation reserved for those who experience recurrence. INTRODUCTIONEpendymoma is the third most common posterior fossa tumor of childhood and a major cause of morbidity and mortality in pediatric oncology, occurring across the entire age spectrum. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] Current therapy for posterior fossa ependymoma in children is aggressive surgical resection followed by involved-field radiation, resulting in 7-year event free-survival of 65%. 12,15 Despite the high mortality rate, trials of cytotoxic chemotherapy have failed to reveal a clear survival benefit for chemotherapy over surgery and radiation alone, although definitive pediatric randomized trials of maintenance chemotherapy are still recruiting through cooperative groups (ClinicalTrials.gov identifiers: NCT01096368 and NCT02265770). 1,5,17 In adults, posterior fossa ependymoma is frequently treated with surgery alone. 18Numerous publications have suggested that the most powerful prognostic factor for posterior fossa ependymoma is the extent of surgical resection or, more appropriately, the amount of residual tumor after surgery. This has entailed an aggressive surgical approach, with some oncologists and surgeons tolerating serious neurologic deficits, including the need for tracheostomies and gastrostom...