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| Status |
Public on Feb 01, 2024 |
| Title |
5-Hydroxymethylcytosine Profiling of Cell-Free DNA Identifies Bivalent Genes That Are Prognostic of Survival in High-Risk Neuroblastoma [KAS-Seq] |
| Organism |
Homo sapiens |
| Experiment type |
Other
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| Summary |
Purpose: Neuroblastoma is the most common extracranial solid tumor in childhood. We previously showed that circulating cell-free DNA (cfDNA) and tumor biopsy derived 5-hydroxymethylcytosime (5-hmC) profiles identified patients with neuroblastoma who experienced subsequent relapse. Here, we hypothesized that 5-hmC modifications selectively enriched in cfDNA compared with tumor biopsy samples would identify epigenetic changes associated with aggressive tumor behavior and identify novel biomarkers of outcome in patients with high- risk neuroblastoma.
Methods: 5-hmC profiles from cfDNA (n = 64) and tumor biopsies (n = 48) were compared. Two neuroblastoma cell lines underwent chromatin immunopre- cipitation followed by sequencing (ChIP-Seq) for H3K27me3, H3K4me3, and H3K27ac; kethoxal-associated single-stranded DNA sequencing; hmC-Seal for 5-hmC; and RNA-sequencing (RNA-Seq). Genes enriched for both H3K27me3 and H3K4me3 in the included cell lines were defined as bivalent. Using bivalent genes defined in vitro, a bivalent signature was established in three publicly available cohorts of patients with neuroblastoma through gene set variation analysis. Differences between tumors with high or low bivalent signatures were assessed by the Kaplan-Meier method and Cox proportional hazards models.
Results: In cfDNA compared with tumor biopsy derived 5-hmC profiles, we found in- creased 5-hmC deposition on Polycomb Repressive Complex 2 target genes, a finding previously described in the context of bivalent genes. We identified 313 genes that bore bivalent chromatin marks, were enriched for mediators of neuronal differentiation, and were transcriptionally repressed across a panel of heterogeneous neuroblastoma cell lines. In three distinct clinical cohorts, low bivalent signature was significantly and independently associated with worse clinical outcome in patients with high-risk neuroblastoma.
Conclusion: Low expression of bivalent genes is a biomarker of worse outcome in patients with high-risk neuroblastoma.
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| Overall design |
Kethoxal-assisted single-stranded DNA sequencing (KAS-Seq) performed in 8 neuroblastoma cell lines
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| Contributor(s) |
Chennakesavalu M, Moore K, Chaves G, Veeravalli S, TerHaar R, Wu T, Lyu R, Chlenski A, He C, Piunti A, Applebaum M |
| Citation(s) |
38295320 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| R37 CA262781 |
Liquid biopsy approaches to inform neuroblastoma prognosis and disease monitoring |
UNIVERSITY OF CHICAGO |
Mark Andrew Applebaum |
| R00 CA234434 |
A molecular informed therapy for Diffuse Intrinsic Pontine Gliomas (DIPG) |
UNIVERSITY OF CHICAGO |
Andrea Piunti |
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| Submission date |
Sep 07, 2022 |
| Last update date |
Feb 02, 2024 |
| Contact name |
Mark Applebaum |
| E-mail(s) |
mapplebaum@bsd.uchicago.edu
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| Organization name |
University of Chicago
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| Department |
Pediatrics, Section of Hematology/Oncology
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| Street address |
900 E 57th St
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| City |
Chicago |
| State/province |
IL |
| ZIP/Postal code |
60637 |
| Country |
USA |
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| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
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| Samples (16)
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| GSM6560475 |
55N, KAS-Seq, biol rep2 |
| GSM6560476 |
BE2, KAS-Seq, biol rep1 |
| GSM6560477 |
BE2, KAS-Seq, biol rep2 |
| GSM6560478 |
NBLS, KAS-Seq, biol rep1 |
| GSM6560479 |
NBLS, KAS-Seq, biol rep2 |
| GSM6560480 |
SHEP, KAS-Seq, biol rep1 |
| GSM6560481 |
SHEP, KAS-Seq, biol rep2 |
| GSM6560482 |
SY5Y, KAS-Seq, biol rep1 |
| GSM6560483 |
SY5Y, KAS-Seq, biol rep2 |
| GSM6560484 |
WN, KAS-Seq, biol rep1 |
| GSM6560485 |
WN, KAS-Seq, biol rep2 |
| GSM6560486 |
WS, KAS-Seq, biol rep1 |
| GSM6560487 |
WS, KAS-Seq, biol rep2 |
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| This SubSeries is part of SuperSeries: |
| GSE212882 |
5-Hydroxymethylcytosine Profiling of Cell-Free DNA Identifies Bivalent Genes That Are Prognostic of Survival in High-Risk Neuroblastoma |
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| Relations |
| BioProject |
PRJNA877688 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE212881_RAW.tar |
1.7 Gb |
(http)(custom) |
TAR (of BIGWIG) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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