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Neuroblastoma Super Enhancer Profiles Pinpoint Four Epigenetic Subtypes

NEW YORK – A new super enhancer study suggests there may be previously unappreciated epigenetic subtypes for neuroblastoma, including epigenetic features associated with particularly poor clinical outcomes in children with the peripheral sympathetic nervous system tumors.

"[W]e identified four major super-enhancer-driven epigenetic subtypes and their underlying master regulatory networks," co-senior and co-corresponding authors Frank Westermann, a researcher affiliated with Hopp Children's Cancer Center Heidelberg and the German Cancer Research Center, and Carl Herrmann, a health data science researcher at Medical Faculty Heidelberg and BioQuant, and their colleagues wrote.

In an effort to overlay regulatory features on top of new and known gene mutations in neuroblastoma, the researchers relied on chromatin immunoprecipitation (ChIP) sequencing-based H3 lysine 27 acetylation (H3K27ac) histone enhancer profiling, whole-genome sequencing, RNA sequencing, allele-specific copy number estimation sequencing (ACE-seq), ATAC-seq, and other approaches to profile genomic and regulatory features in dozens of neuroblastoma tumors.

The analyses encompassed 49 newly profiled primary neuroblastoma tumors, eight tumors from relapsed neuroblastoma cases, and three metastatic neuroblastoma tumors, as well as super enhancer expression profiles on hundreds of neuroblastoma tumors. The data was considered in combination with available genomic and epigenomic data, including H3K27ac histone profiles on another 23 neuroblastomas and two related cell lines.

"[I]t remains unclear how distinct cell identities impact [neuroblastoma] tumor development, progression, and relapse," the authors explained, noting that "we determine super enhancer-driven subtypes and their corresponding transcriptional core regulatory circuitries in [neuroblastoma] tumors and cells lines."

The findings, appearing online in Nature Cancer, suggested that three of the four super enhancer-based subtypes tracked with known clinical subtypes. Even so, the team noted that more than half of the specific super enhancers identified in the study appeared to be tumor-specific, underscoring the importance of profiling patient samples as well as available cell lines.

"While previous work carried out mainly in cell lines has broadly identified mesenchymal and adrenergic/MYCN-amplified epigenetic signatures," the authors wrote, "our work on patient samples has further resolved the adrenergic group into MYCN-amplified, MYCN non-amplified high-risk, and MYCN non-amplified low-risk signatures."

Along with analyses aimed at understanding the regulatory landscape and related gene mutations in the epigenetic subtypes, the researchers' analyses indicated that the super enhancer profiles and other regulatory features might lend a hand in distinguishing between neuroblastoma cases with better or worse clinical outcomes.

In particular, they noted that a RAS signaling pathway activation-related subtype with mesenchymal-type features tended to be over-represented in tumor samples from individuals with relapsed neuroblastoma. That subtype shared features with Schwann precursor cells, though the presence of normal, infiltrating Schwann cells in other neuroblastoma tumors tended to turn up in cases with better clinical outcomes.

Based on these and other results, the authors concluded that the study "opens up translational avenues for therapeutic interventions targeting the spectrum of cellular identities that drive [neuroblastoma], ranging from adrenergic to mesenchymal cells."