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Research article
Ki Woong Sung
Corresponding Author
ORCiD: https://orcid.org/0000-0001-5989-4772
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Background MYCN amplification is the most important genomic feature in neuroblastoma (NB). However, limited studies have been conducted on the MYCN non-amplified NB including low- and intermediate-risk NB. Here, the genomic characteristics of MYCN non-amplified NB were studied to allow for the identification of biomarkers for molecular stratification.
Results Fifty-eight whole exome sequencing (WES) and 48 whole transcriptome sequencing (WTS) samples of MYCN non-amplified NB were analysed. Forty-one patients harboured WES and WTS pairs. In the MYCN non-amplified NB WES data, maximum recurrent mutations were found in MUC4 (26%), followed by RBMXL3 (19%), ALB (17%), and MUC16 and SEPD8 (14% each). Two gene fusions, CCDC32-CBX3 (10%) and SAMD5-SASH1 (6%), were recurrent in WTS analysis, and these fusions were detected mostly in non-high-risk patients with ganglioneuroblastoma histology. Analysis of risk-group-specific biomarkers showed that several genes and gene sets were differentially expressed between the risk groups, and some immune-related pathways tended to be activated in the high-risk group. Mutational signatures 6 and 18, which represent DNA mismatch repair (MMR) associated mutations, were commonly detected in 60% of the patients. In the tumour mutation burden (TMB) analysis, four patients showed high TMB (> 3 mutations/Mb), and had mutations in genes related to either MMR or homologous recombination. Excluding four outlier samples with TMB > 3 Mb, high-risk patients had significantly higher levels of TMB compared with the non-high-risk patients.
Conclusions This study provides novel insights into the genomic background of MYCN non-amplified NB. Activation of immune-related pathways in the high-risk group and the results of TMB and mutational signature analyses collectively suggest the need for further investigation to discover potential immunotherapeutic strategies for NB.
Keywords
MYCN non-amplified neuroblastoma, tumour mutation burden, mutational signature, genomic profile, immunotherapy
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CURRENT STATUS: Published
View the published article at BMC Medical Genomics.
No community comments so far
Editorial decision: Accept
On 30 Oct, 2020
Editor assigned
On 13 Oct, 2020
Submission checks complete
On 12 Oct, 2020
Editor invited
On 12 Oct, 2020
No comments provided
Submission checks complete
On 30 Sep, 2020
Editorial decision: Minor revision
On 29 Sep, 2020
No comments provided
Reviewer #2 agreed
On 19 Sep, 2020
Review #2 received
Received 19 Sep, 2020
Review #1 received
Received 11 Sep, 2020
Reviewer #1 agreed
On 08 Sep, 2020
Editor assigned
On 28 Aug, 2020
Reviewers invited
Invitations sent on 28 Aug, 2020
Submission checks complete
On 27 Aug, 2020
Editor invited
On 27 Aug, 2020
Version 1
Posted 10 May, 2020
No comments provided
Review #2 received
Received 30 Jun, 2020
Editorial decision: Major revision
On 30 Jun, 2020
Reviewer #2 agreed
On 23 Jun, 2020
Review #1 received
Received 18 May, 2020
Reviewer #1 agreed
On 11 May, 2020
Reviewers invited
Invitations sent on 08 May, 2020
First submitted
On 28 Apr, 2020
Editor assigned
On 28 Apr, 2020
Submission checks complete
On 27 Apr, 2020
Editor invited
On 27 Apr, 2020
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Subject Areas
Epigenetics & Genomics
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A new preprint design is coming!
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See the published version of this preprint at BMC Medical Genomics.
This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research article
Ki Woong Sung
Corresponding Author
ORCiD: https://orcid.org/0000-0001-5989-4772
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
View the published article at BMC Medical Genomics.
No community comments so far
Editorial decision: Accept
On 30 Oct, 2020
Editor assigned
On 13 Oct, 2020
Submission checks complete
On 12 Oct, 2020
Editor invited
On 12 Oct, 2020
No comments provided
Submission checks complete
On 30 Sep, 2020
Editorial decision: Minor revision
On 29 Sep, 2020
No comments provided
Reviewer #2 agreed
On 19 Sep, 2020
Review #2 received
Received 19 Sep, 2020
Review #1 received
Received 11 Sep, 2020
Reviewer #1 agreed
On 08 Sep, 2020
Editor assigned
On 28 Aug, 2020
Reviewers invited
Invitations sent on 28 Aug, 2020
Submission checks complete
On 27 Aug, 2020
Editor invited
On 27 Aug, 2020
Version 1
Posted 10 May, 2020
No comments provided
Review #2 received
Received 30 Jun, 2020
Editorial decision: Major revision
On 30 Jun, 2020
Reviewer #2 agreed
On 23 Jun, 2020
Review #1 received
Received 18 May, 2020
Reviewer #1 agreed
On 11 May, 2020
Reviewers invited
Invitations sent on 08 May, 2020
First submitted
On 28 Apr, 2020
Editor assigned
On 28 Apr, 2020
Submission checks complete
On 27 Apr, 2020
Editor invited
On 27 Apr, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Epigenetics & Genomics
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published article at BMC Medical Genomics.
Background MYCN amplification is the most important genomic feature in neuroblastoma (NB). However, limited studies have been conducted on the MYCN non-amplified NB including low- and intermediate-risk NB. Here, the genomic characteristics of MYCN non-amplified NB were studied to allow for the identification of biomarkers for molecular stratification.
Results Fifty-eight whole exome sequencing (WES) and 48 whole transcriptome sequencing (WTS) samples of MYCN non-amplified NB were analysed. Forty-one patients harboured WES and WTS pairs. In the MYCN non-amplified NB WES data, maximum recurrent mutations were found in MUC4 (26%), followed by RBMXL3 (19%), ALB (17%), and MUC16 and SEPD8 (14% each). Two gene fusions, CCDC32-CBX3 (10%) and SAMD5-SASH1 (6%), were recurrent in WTS analysis, and these fusions were detected mostly in non-high-risk patients with ganglioneuroblastoma histology. Analysis of risk-group-specific biomarkers showed that several genes and gene sets were differentially expressed between the risk groups, and some immune-related pathways tended to be activated in the high-risk group. Mutational signatures 6 and 18, which represent DNA mismatch repair (MMR) associated mutations, were commonly detected in 60% of the patients. In the tumour mutation burden (TMB) analysis, four patients showed high TMB (> 3 mutations/Mb), and had mutations in genes related to either MMR or homologous recombination. Excluding four outlier samples with TMB > 3 Mb, high-risk patients had significantly higher levels of TMB compared with the non-high-risk patients.
Conclusions This study provides novel insights into the genomic background of MYCN non-amplified NB. Activation of immune-related pathways in the high-risk group and the results of TMB and mutational signature analyses collectively suggest the need for further investigation to discover potential immunotherapeutic strategies for NB.
Figure 1
Figure 2
Figure 3
This is a list of supplementary files associated with this preprint. Click to download.
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