Neuroblastoma is the most common extracranial solid tumor of childhood, arising from neural crest-derived sympathetic nervous system precursors. It demonstrates remarkable clinical heterogeneity, ranging from spontaneous regression in infants to highly aggressive metastatic disease in older children. MYCN amplification, present in approximately 20% of cases, is among the most powerful adverse genomic prognostic markers and drives aggressive tumor behavior. Risk stratification in the INRG system combines stage, age, histologic category and grade of differentiation, MYCN status, chromosome 11q status, and DNA ploidy to guide treatment intensity. A distinct axis of neuroblastoma biology is the mechanism of telomere maintenance: MYCN amplification, TERT rearrangement, and ATRX mutation/alternative lengthening of telomeres are largely mutually exclusive routes to telomere maintenance, with ATRX-mutant disease defining an indolent but treatment-refractory adolescent and young-adult subtype. Low-risk neuroblastoma may require only observation, while high-risk disease requires intensive multimodal therapy with immunotherapy.
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name: Neuroblastoma
creation_date: '2026-01-26T02:55:13Z'
description: >-
Neuroblastoma is the most common extracranial solid tumor of childhood,
arising from neural crest-derived sympathetic nervous system precursors.
It demonstrates remarkable clinical heterogeneity, ranging from spontaneous
regression in infants to highly aggressive metastatic disease in older
children. MYCN amplification, present in approximately 20% of cases, is
among the most powerful adverse genomic prognostic markers and drives
aggressive tumor behavior. Risk stratification in the INRG system combines
stage, age, histologic category and grade of differentiation, MYCN status,
chromosome 11q status, and DNA ploidy to guide treatment intensity. A
distinct axis of neuroblastoma biology is the mechanism of telomere
maintenance: MYCN amplification, TERT rearrangement, and ATRX
mutation/alternative lengthening of telomeres are largely mutually
exclusive routes to telomere maintenance, with ATRX-mutant disease defining
an indolent but treatment-refractory adolescent and young-adult subtype.
Low-risk neuroblastoma may require only observation, while high-risk
disease requires intensive multimodal therapy with immunotherapy.
categories:
- Pediatric Cancer
- Neural Tumor
- Solid Tumor
parents:
- neuroblastic tumor
has_subtypes:
- name: MYCN-Amplified Neuroblastoma
description: >-
Approximately 20% of neuroblastomas harbor MYCN gene amplification,
associated with rapid tumor progression and poor prognosis. MYCN
amplification is one of the earliest oncogene amplifications discovered.
evidence:
- reference: PMID:41560679
reference_title: "Coexpression of MYCN and ALK Induces Neuroblastoma-Like Tumors From Human iPS Cell-Derived Cranial Neural Crest Cells."
supports: SUPPORT
quote_role: BACKGROUND
evidence_source: HUMAN_CLINICAL
snippet: "MYCN amplification is a key factor contributing to the poor prognosis of NB."
explanation: >-
States the adverse prognostic association of MYCN amplification. The
sentence is background in the abstract of an iPSC-derived neural crest
model study, restating the clinical picture; it is not something that
study measured. The patient-derived support is the Brodeur and INRG
evidence below.
- reference: PMID:6719137
reference_title: "Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Furthermore, N-myc amplification is highly correlated with advanced stages of disease (P less than 0.001) and with the ability to grow in vitro as an established cell line, both of which are associated with a poor prognosis."
explanation: >-
Human clinical support for the rapid-progression and poor-prognosis
claim, from untreated primary neuroblastoma tissue.
- reference: PMID:19047291
reference_title: "The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Stage, age, histologic category, grade of tumor differentiation, the status of the MYCN oncogene, chromosome 11q status, and DNA ploidy were the most highly statistically significant and clinically relevant factors."
explanation: >-
Confirms MYCN status as a statistically significant, clinically relevant
prognostic factor in the 8,800-patient INRG cohort.
- reference: PMID:22936790
reference_title: "N-myc and noncoding RNAs in neuroblastoma."
supports: SUPPORT
quote_role: REVIEW_SYNTHESIS
evidence_source: HUMAN_CLINICAL
snippet: "Amplification and overexpression of the MYCN proto-oncogene occurs in approximately 20% of neuroblastomas and is associated with advanced stage disease, rapid tumor progression, and poor prognosis."
explanation: >-
A review statement that amplification and overexpression of MYCN occur
in approximately 20% of neuroblastomas and are associated with advanced
stage disease, rapid tumor progression and poor prognosis, matching this
subtype's description. The sentence pairs amplification with
overexpression; it is read here as a statement about amplification.
- name: Stage 4S Neuroblastoma
description: >-
A special stage occurring in infants **under 12 months** of age, with a
localized primary tumor (INSS stage 1, 2A or 2B) and dissemination limited
to skin, liver, and/or bone marrow. Marrow involvement must be minimal
(under 10% of nucleated marrow cells, with negative MIBG marrow uptake);
more extensive marrow disease is staged as stage 4, which is the
distinction the category exists to make. Despite widespread disease, 4S
neuroblastoma often undergoes spontaneous regression. Note that the newer
INRG staging system defines an analogous **stage MS** using an 18-month
age cutoff — the two cutoffs belong to different staging systems and
should not be interchanged.
- name: High-Risk Neuroblastoma
description: >-
Defined by age over 18 months with metastatic disease, or MYCN amplification
at any age. Requires intensive multimodal therapy including chemotherapy,
surgery, radiation, autologous stem cell transplant, and immunotherapy.
pathophysiology:
- name: Neural Crest Developmental Arrest
description: >-
Neuroblastoma arises from neural crest-derived sympathoadrenal progenitor
cells that fail to complete differentiation. The tumor cells retain
characteristics of immature neuroblasts with variable capacity for
sympathetic neuronal differentiation.
evidence:
- reference: PMID:41560679
reference_title: "Coexpression of MYCN and ALK Induces Neuroblastoma-Like Tumors From Human iPS Cell-Derived Cranial Neural Crest Cells."
supports: SUPPORT
quote_role: BACKGROUND
evidence_source: HUMAN_CLINICAL
snippet: "Neuroblastoma (NB) is a pediatric solid tumor originating from neural
crest cells (NCCs), which are precursors of the sympathetic nervous system."
explanation: >-
States that neuroblastoma originates from neural crest cells, the
precursors of the sympathetic nervous system, supporting the
developmental origin this node describes. It is the opening background
sentence of an iPSC-derived neural crest model study and describes the
human disease, not an observation from that model.
- reference: PMID:32296467
reference_title: "Nervous system: Embryonal tumors: Neuroblastoma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Neuroblastoma is a clinically heterogenous pediatric cancer of the
sympathetic nervous system that originates from neural crest cells.
explanation: Supports neural crest origin and clinical heterogeneity of
neuroblastoma.
cell_types:
- preferred_term: neural crest derived neuroblast
term:
id: CL:0002676
label: neural crest derived neuroblast
biological_processes:
- preferred_term: cell differentiation
modifier: DECREASED
term:
id: GO:0030154
label: cell differentiation
locations:
- preferred_term: adrenal gland
term:
id: UBERON:0002369
label: adrenal gland
downstream:
- target: MYCN-Driven Proliferation
description: MYCN amplification drives aggressive proliferation
- name: MYCN-Driven Proliferation
description: >-
MYCN amplification results in massive overexpression of the MYCN
transcription factor, a key contributor to aggressive neuroblastoma biology
and poor prognosis. MYCN-amplified tumors have a distinct aggressive
phenotype with rapid growth and early metastasis.
biological_processes:
- preferred_term: cell population proliferation
modifier: INCREASED
term:
id: GO:0008283
label: cell population proliferation
evidence:
- reference: PMID:41560679
reference_title: "Coexpression of MYCN and ALK Induces Neuroblastoma-Like Tumors From Human iPS Cell-Derived Cranial Neural Crest Cells."
supports: SUPPORT
quote_role: BACKGROUND
evidence_source: HUMAN_CLINICAL
snippet: "MYCN amplification is a key factor contributing to the poor prognosis of NB."
explanation: >-
Supports MYCN amplification as a key contributor to poor prognosis. The
sentence is background in the abstract of an iPSC-derived neural crest
model study, not a result of it; the patient-derived stage association
is the Brodeur item below.
- reference: PMID:6719137
reference_title: "Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Furthermore, N-myc amplification is highly correlated with advanced stages of disease (P less than 0.001) and with the ability to grow in vitro as an established cell line, both of which are associated with a poor prognosis."
explanation: >-
Human clinical support for the aggressive-phenotype and poor-prognosis
claim: in untreated primary tumors, MYCN amplification was absent in all
15 stage 1-2 cases and present in 50% of stage 3-4 cases.
- name: ALK Signaling Activation
description: >-
ALK (anaplastic lymphoma kinase) is activated by point mutations in
approximately 8-10% of neuroblastomas, and by amplification in additional
cases. ALK mutations are enriched in familial neuroblastoma and represent
a therapeutic target for ALK inhibitors.
biological_processes:
- preferred_term: MAPK cascade
modifier: INCREASED
term:
id: GO:0000165
label: MAPK cascade
evidence:
- reference: PMID:41560679
reference_title: "Coexpression of MYCN and ALK Induces Neuroblastoma-Like Tumors From Human iPS Cell-Derived Cranial Neural Crest Cells."
supports: SUPPORT
quote_role: BACKGROUND
evidence_source: HUMAN_CLINICAL
snippet: "Anaplastic lymphoma kinase (ALK) alterations, including mutations and amplification, activate oncogenic signaling pathways that, together with MYCN amplification, further enhance tumor malignancy."
explanation: >-
States that ALK alterations (mutations and amplification) activate
oncogenic signaling that co-operates with MYCN amplification in
neuroblastoma malignancy. Like the two sentences before it in this
abstract, it is background describing the human disease, summarizing
earlier work rather than reporting a result of the study's iPSC-derived
model.
- reference: PMID:18724359
reference_title: "Identification of ALK as a major familial neuroblastoma predisposition gene."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Mutations resulted in constitutive phosphorylation, and targeted knockdown of ALK messenger RNA resulted in profound inhibition of growth in all cell lines harbouring mutant or amplified ALK"
explanation: >-
Demonstrates that ALK mutations cause constitutive receptor
phosphorylation and that ALK-altered neuroblastoma cells are dependent
on ALK for growth, supporting the causal edge into proliferation.
- reference: PMID:25517749
reference_title: "ALK mutations confer differential oncogenic activation and sensitivity to ALK inhibition therapy in neuroblastoma."
supports: SUPPORT
quote_role: PRIMARY_RESULT
evidence_source: HUMAN_CLINICAL
snippet: "We describe comprehensive genomic, biochemical, and computational analyses of ALK mutations across 1,596 diagnostic neuroblastoma samples. ALK tyrosine kinase domain mutations occurred in 8% of samples--at three hot spots and 13 minor sites--and correlated significantly with poorer survival in high- and intermediate-risk neuroblastoma."
explanation: >-
ALK tyrosine kinase domain mutations in 8% of 1,596 diagnostic
neuroblastoma samples, the lower end of the approximately 8-10% figure.
The count is of tumors carrying a mutation, so on its own it does not
separate somatic from germline events. The same abstract distinguishes
oncogenic (constitutively activating) from nononcogenic mutations, so for
activation the 8% is an upper bound.
- reference: PMID:26059187
reference_title: "Deep Sequencing Reveals Occurrence of Subclonal ALK Mutations in Neuroblastoma at Diagnosis."
supports: SUPPORT
quote_role: PRIMARY_RESULT
evidence_source: HUMAN_CLINICAL
snippet: "In this series, deep sequencing allows the detection of F1174 and R1275 ALK mutational events at diagnosis in 10% of cases, with subclonal events in more than half of these, which would have gone undetected by Sanger sequencing."
explanation: >-
The upper end of the approximately 8-10% figure: targeted deep
sequencing of the F1174 and R1275 hotspots found ALK mutations in 10% of
cases at diagnosis. More than half were subclonal and would have been
missed by Sanger sequencing, so part of the gap above the 8% estimate
reflects detection sensitivity.
downstream:
- target: MYCN-Driven Proliferation
description: >-
Constitutive ALK kinase signalling converges on the same proliferative
output as MYCN amplification and co-operates with it; ALK-mutant and
MYCN-amplified disease frequently co-occur and jointly enhance
malignancy.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:41560679
reference_title: "Coexpression of MYCN and ALK Induces Neuroblastoma-Like Tumors From Human iPS Cell-Derived Cranial Neural Crest Cells."
supports: SUPPORT
directness: INDIRECT
quote_role: BACKGROUND
evidence_source: HUMAN_CLINICAL
snippet: "Anaplastic lymphoma kinase (ALK) alterations, including mutations and amplification, activate oncogenic signaling pathways that, together with MYCN amplification, further enhance tumor malignancy."
explanation: >-
Supports co-operation between ALK signalling and MYCN amplification in
driving malignancy. Indirect for this edge: the sentence, background in
the citing study's abstract, says that ALK signalling and MYCN
amplification together enhance tumor malignancy; that ALK signalling
feeds the MYCN-driven proliferative program is an inference from it.
histopathology:
- name: Neural Crest Tumor
finding_term:
preferred_term: Neuroblastoma
term:
id: NCIT:C3270
label: Neuroblastoma
frequency: VERY_FREQUENT
description: Neuroblastoma is a malignant tumor of neural crest origin.
evidence:
- reference: PMID:10985139
reference_title: "Neuroblastoma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Neuroblastoma is a malignant tumor of neural crest origin that may arise"
explanation: Abstract describes neuroblastoma as a malignant tumor of neural
crest origin.
phenotypes:
- category: Abdominal
name: Abdominal Mass
frequency: VERY_FREQUENT
diagnostic: true
description: >-
An abdominal mass is the most common presentation, typically arising from
the adrenal gland or paraspinal sympathetic ganglia. The mass may be
incidentally discovered or cause abdominal distension.
phenotype_term:
preferred_term: Abdominal mass
term:
id: HP:0031500
label: Abdominal mass
evidence:
- reference: PMID:10985139
reference_title: "Neuroblastoma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Seventy-five percent of neuroblastomas originate within the abdomen or pelvis, and half of these occur within the adrenal medulla"
explanation: >-
Anatomic distribution of primary tumors (75% in abdomen/pelvis, half in
adrenal medulla) accounts for abdominal mass being the most common
presentation.
- category: Cardiovascular
name: Hypertension
frequency: OCCASIONAL
description: >-
Hypertension may occur due to catecholamine secretion by tumor cells
or renal artery compression by the tumor mass.
phenotype_term:
preferred_term: Hypertension
term:
id: HP:0000822
label: Hypertension
- category: Constitutional
name: Fever
frequency: OCCASIONAL
description: >-
Fever may occur as a paraneoplastic symptom or with advanced disease.
phenotype_term:
preferred_term: Fever
term:
id: HP:0001945
label: Fever
- category: Constitutional
name: Weight Loss
frequency: OCCASIONAL
description: >-
Weight loss and failure to thrive can occur, particularly with advanced
or metastatic disease.
phenotype_term:
preferred_term: Weight loss
term:
id: HP:0001824
label: Weight loss
- category: Ophthalmologic
name: Proptosis
frequency: OCCASIONAL
description: >-
Periorbital metastases causing proptosis and periorbital ecchymosis
(raccoon eyes) are characteristic of metastatic neuroblastoma.
phenotype_term:
preferred_term: Proptosis
term:
id: HP:0000520
label: Proptosis
- category: Musculoskeletal
name: Bone Pain
frequency: FREQUENT
description: >-
Bone pain from skeletal metastases is common in high-risk neuroblastoma.
Metastatic bone disease may cause limping or irritability in young children.
phenotype_term:
preferred_term: Bone pain
term:
id: HP:0002653
label: Bone pain
- category: Gastrointestinal
name: Diarrhea
frequency: OCCASIONAL
description: >-
Secretory diarrhea can occur as a paraneoplastic syndrome due to tumor
secretion of vasoactive intestinal peptide (VIP).
phenotype_term:
preferred_term: Diarrhea
term:
id: HP:0002014
label: Diarrhea
biochemical:
- name: Catecholamine Metabolites
notes: >-
Elevated urinary catecholamine metabolites, classically vanillylmandelic
acid (VMA) and homovanillic acid (HVA), are found in most neuroblastomas
at diagnosis and support the diagnosis. Reviews cite high urinary
catecholamine levels in more than 90% of cases (92% for VMA and HVA in
clinically presenting neuroblastoma), and in a series of patients who
later relapsed or progressed, urinary VMA and/or HVA had been abnormal at
diagnosis in 92%. In two diagnostic series published in 2017 and 2020,
however, the VMA and HVA pair had a diagnostic sensitivity of 82-84%,
rising to 95% in the 2017 series when all eight urinary metabolites in
its panel were combined. Relapse or progression cannot be detected
reliably by monitoring tumor markers alone.
evidence:
- reference: PMID:28061374
reference_title: "Catecholamines profiles at diagnosis: Increased diagnostic sensitivity and correlation with biological and clinical features in neuroblastoma patients."
supports: SUPPORT
quote_role: PRIMARY_RESULT
evidence_source: HUMAN_CLINICAL
snippet: "The combination of the classical markers VMA and HVA had a diagnostic sensitivity of 84%. NMN was the most sensitive single diagnostic metabolite with overall sensitivity of 89%. When all 8 metabolites were combined, a diagnostic sensitivity of 95% was achieved."
explanation: >-
In patients at diagnosis, VMA and HVA together had a diagnostic
sensitivity of 84%, below the classical figure of more than 90%;
combining all eight urinary metabolites measured raised it to 95%.
Normetanephrine (NMN) alone reached 89%.
- reference: PMID:31724812
reference_title: "Biochemical testing for neuroblastoma using plasma free 3-O-methyldopa, 3-methoxytyramine, and normetanephrine."
supports: SUPPORT
quote_role: PRIMARY_RESULT
evidence_source: HUMAN_CLINICAL
snippet: "Overall, 94 of the 96 patients with neuroblastoma had concentrations of 3-methoxytyramine or normetanephrine above age-specific upper limits of reference intervals, providing a diagnostic sensitivity of 97.9% that was higher (P < 0.0001) than that of 82.2% for HVA and VMA."
explanation: >-
A second diagnostic series: urinary HVA and VMA had a diagnostic
sensitivity of 82.2%, lower than the 97.9% of plasma 3-methoxytyramine
or normetanephrine. The abstract does not give the denominator for the
urinary comparison.
- reference: PMID:8790511
reference_title: "Screening for neuroblastoma: a review of the evidence."
supports: SUPPORT
quote_role: REVIEW_SYNTHESIS
evidence_source: HUMAN_CLINICAL
snippet: "The screening test consists of measurements of the levels of vanillylmandelic acid and homovanillic acid in the urine; these metabolites of catecholamine are excreted in the urine of 92% of patients with clinically presenting neuroblastoma."
explanation: >-
The classical review figure for the VMA and HVA pair: 92% of patients
with clinically presenting neuroblastoma, stated without a source cohort
in the abstract.
- reference: PMID:15235064
reference_title: "Neuroblastoma: a disease requiring a multitude of imaging studies."
supports: SUPPORT
quote_role: REVIEW_SYNTHESIS
evidence_source: HUMAN_CLINICAL
snippet: "Origin from precursors of the sympathetic nervous system accounts for (a) primary sites in adrenal glands and in paraspinal locations from neck to pelvis and (b) high urinary levels of catecholamines in >90% of cases."
explanation: >-
A review statement of high urinary catecholamine levels in more than 90%
of cases. It refers to urinary catecholamines in general rather than to
VMA and HVA specifically.
- reference: PMID:12932669
reference_title: "Tumour markers are poor predictors for relapse or progression in neuroblastoma."
supports: SUPPORT
quote_role: PRIMARY_RESULT
evidence_source: HUMAN_CLINICAL
snippet: "At diagnosis, we found abnormal results in 75% for VMA and/or HVA (s), 92% for VMA and/or HVA (u), 90% for NSE, and 81% for LDH."
explanation: >-
In patients who later relapsed or progressed after first-line treatment,
urinary (u) VMA and/or HVA had been abnormal in 92% at diagnosis (serum
(s) 75%). The cohort is restricted to patients who relapsed or
progressed, so it is not an unselected diagnostic series.
- reference: PMID:12932669
reference_title: "Tumour markers are poor predictors for relapse or progression in neuroblastoma."
supports: SUPPORT
quote_role: PRIMARY_RESULT
evidence_source: HUMAN_CLINICAL
snippet: "Relapse or progression in neuroblastoma cannot be detected reliably by monitoring tumour markers alone."
explanation: >-
Qualifies the use of these markers in follow-up: in patients who
relapsed or progressed after first-line treatment, the authors conclude
that monitoring tumour markers, which in this study included urinary and
serum VMA and HVA, does not reliably detect relapse or progression on
its own.
- name: Neuron-Specific Enolase
notes: >-
Serum neuron-specific enolase (NSE) is elevated in neuroblastoma and
correlates with tumor burden and prognosis.
genetic:
- name: MYCN Amplification
association: Oncogene Amplification
gene_term:
preferred_term: MYCN
term:
id: hgnc:7559
label: MYCN
notes: >-
MYCN amplification occurs in approximately 20% of neuroblastomas overall;
in a Children's Oncology Group cohort of 4,672 patients, 845 (18.1%) had
amplification and a further 133 (2.8%) had MYCN gain, a smaller
copy-number increase below the amplification threshold. MYCN
amplification is among the most powerful adverse genomic prognostic
markers, used alongside stage, age, histology, 11q status, and ploidy for
risk stratification. The proportion depends strongly on stage: in the
original 1984 series of untreated tumors, amplification was found in none
of 15 patients with stage 1 or 2 disease but in 24 of 48 with stage 3 or
4 disease.
evidence:
- reference: PMID:19047291
reference_title: "The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Stage, age, histologic category, grade of tumor differentiation, the status of the MYCN oncogene, chromosome 11q status, and DNA ploidy were the most highly statistically significant and clinically relevant factors."
explanation: >-
The INRG Task Force analysis of 8,800 patients establishes MYCN status
as one of the most statistically significant prognostic factors, and
places it alongside (not above) stage, age, histology, 11q status, and
ploidy in risk classification.
- reference: PMID:6719137
reference_title: "Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "N-myc amplification is highly correlated with advanced stages of disease"
explanation: >-
The original Brodeur series in untreated primary tumors established the
association of MYCN amplification with advanced-stage disease.
- reference: PMID:6719137
reference_title: "Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage."
supports: SUPPORT
quote_role: PRIMARY_RESULT
evidence_source: HUMAN_CLINICAL
snippet: "Amplification was found in 0 of 15 patients with stage 1 or 2 disease, whereas 24 of 48 cases (50 percent) with stage 3 or 4 had evidence of N-myc amplification."
explanation: >-
The stage dependence given in the notes: in the original series,
amplification was found in none of 15 stage 1-2 tumors and in 24 of 48
(50%) stage 3-4 tumors, so cohorts weighted toward advanced stage report
higher frequencies than the overall figure.
- reference: PMID:28696504
reference_title: "Association of MYCN copy number with clinical features, tumor biology, and outcomes in neuroblastoma: A report from the Children's Oncology Group."
supports: SUPPORT
quote_role: PRIMARY_RESULT
evidence_source: HUMAN_CLINICAL
snippet: "Among 4672 patients, 3694 (79.1%) had MYCN wild-type tumors, 133 (2.8%) had MYCN gain, and 845 (18.1%) had MNA."
explanation: >-
A primary cohort figure consistent with the rounded approximately 20%:
of 4,672 Children's Oncology Group patients, 845 (18.1%) had MYCN
amplification (MNA) and 133 (2.8%) had MYCN gain, which in this paper
is a smaller increase below the amplification threshold.
- reference: PMID:25345447
reference_title: "Neuroblastoma models for insights into tumorigenesis and new therapies."
supports: SUPPORT
quote_role: REVIEW_SYNTHESIS
evidence_source: HUMAN_CLINICAL
snippet: "MYCN amplification is found in about 20% of cases"
explanation: >-
A review statement of the rounded figure, about 20% of cases. The
review's subject is mouse models; this sentence restates the human
clinical figure.
- name: ALK Mutations
association: Oncogenic Driver Mutations
gene_term:
preferred_term: ALK
term:
id: hgnc:427
label: ALK
notes: >-
ALK point mutations occur in approximately 8-10% of neuroblastomas at
diagnosis; in 1,596 diagnostic samples, three hotspot residues accounted
for 85% of the mutations: R1275 (43%), F1174 (30%) and F1245 (12%).
Germline activating ALK mutations are the major cause of hereditary
(familial) neuroblastoma, making ALK the principal familial neuroblastoma
predisposition gene, and R1275Q is the most frequent germline mutation.
Published estimates of the share of familial cases carrying a germline
ALK mutation range from about 50% to 80%: the group that mapped ALK as
the major familial gene reported more than 50%, one review gives 50%, and
two others give 75% and 80%. Together with PHOX2B, ALK accounts for most
familial cases. ALK is a therapeutic target for crizotinib and, in
current frontline cooperative-group trials, lorlatinib.
evidence:
- reference: PMID:32296467
reference_title: "Nervous system: Embryonal tumors: Neuroblastoma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The primary predisposition genes in familial neuroblastoma are ALK and PHOX2B."
explanation: >-
Identifies ALK as a primary predisposition gene in familial
neuroblastoma, consistent with its role as an oncogenic driver.
- reference: PMID:18724359
reference_title: "Identification of ALK as a major familial neuroblastoma predisposition gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Our results demonstrate that heritable mutations of ALK are the main cause of familial neuroblastoma, and that germline or acquired activation of this cell-surface kinase is a tractable therapeutic target for this lethal paediatric malignancy."
explanation: >-
The linkage-plus-resequencing study in neuroblastoma pedigrees that
established heritable ALK mutation as the main cause of familial
neuroblastoma and ALK as the principal familial predisposition gene.
- reference: PMID:18724359
reference_title: "Identification of ALK as a major familial neuroblastoma predisposition gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Resequencing in 194 high-risk neuroblastoma samples showed somatically acquired mutations in the tyrosine kinase domain in 12.4% of samples."
explanation: >-
Quantifies somatic ALK tyrosine-kinase-domain mutation in a high-risk
cohort at 12.4%; the 8-10% figure cited in the notes refers to
unselected neuroblastoma, which is enriched for lower-risk disease.
- reference: PMID:25517749
reference_title: "ALK mutations confer differential oncogenic activation and sensitivity to ALK inhibition therapy in neuroblastoma."
supports: SUPPORT
quote_role: PRIMARY_RESULT
evidence_source: HUMAN_CLINICAL
snippet: "We describe comprehensive genomic, biochemical, and computational analyses of ALK mutations across 1,596 diagnostic neuroblastoma samples. ALK tyrosine kinase domain mutations occurred in 8% of samples--at three hot spots and 13 minor sites--and correlated significantly with poorer survival in high- and intermediate-risk neuroblastoma."
explanation: >-
ALK tyrosine kinase domain mutations in 8% of 1,596 diagnostic
neuroblastoma samples, the lower end of the approximately 8-10% figure
in the notes. The count is of tumors carrying a mutation, so on its own
it does not separate somatic from germline events.
- reference: PMID:26059187
reference_title: "Deep Sequencing Reveals Occurrence of Subclonal ALK Mutations in Neuroblastoma at Diagnosis."
supports: SUPPORT
quote_role: PRIMARY_RESULT
evidence_source: HUMAN_CLINICAL
snippet: "In this series, deep sequencing allows the detection of F1174 and R1275 ALK mutational events at diagnosis in 10% of cases, with subclonal events in more than half of these, which would have gone undetected by Sanger sequencing."
explanation: >-
The upper end of the approximately 8-10% figure: targeted deep
sequencing of the F1174 and R1275 hotspots found ALK mutations in 10% of
cases at diagnosis, more than half of them subclonal events that Sanger
sequencing would have missed.
- reference: PMID:29589100
reference_title: "Genetic susceptibility to neuroblastoma: current knowledge and future directions."
supports: SUPPORT
quote_role: REVIEW_SYNTHESIS
evidence_source: HUMAN_CLINICAL
snippet: "It is estimated that gain-of-function mutations in ALK account for 75% of familial neuroblastoma."
explanation: >-
A review estimate of 75%: ALK gain-of-function mutations account for 75%
of familial neuroblastoma. The sentence is in the review's full text,
not its abstract.
- reference: PMID:38791942
reference_title: "The Neuroblastoma Microenvironment, Heterogeneity and Immunotherapeutic Approaches."
supports: SUPPORT
quote_role: REVIEW_SYNTHESIS
evidence_source: HUMAN_CLINICAL
snippet: "Germline mutations in the anaplastic lymphoma kinase (ALK) gene are found in 80% of familial cases"
explanation: >-
A review statement of 80%, the upper end of the range in the notes:
germline ALK mutations in 80% of familial cases. It is a passing
statement in the full text of a review of the tumor microenvironment.
- reference: PMID:21734404
reference_title: "Genome-wide linkage analysis to identify genetic modifiers of ALK mutation penetrance in familial neuroblastoma."
supports: SUPPORT
quote_role: BACKGROUND
evidence_source: HUMAN_CLINICAL
snippet: "Following a genome-wide linkage analysis and sequencing of candidate genes in the critical region, we identified ALK as the major familial NB gene. Dominant mutations in ALK are found in more than 50% of familial NB cases."
explanation: >-
A lower estimate, from the group that mapped ALK as the major familial
gene: dominant ALK mutations in more than 50% of familial cases. It is
the background section of a later linkage study of ALK penetrance, not
a new count.
- reference: PMID:28674118
reference_title: "Retinoblastoma and Neuroblastoma Predisposition and Surveillance."
supports: SUPPORT
quote_role: REVIEW_SYNTHESIS
evidence_source: HUMAN_CLINICAL
snippet: "Germline mutations in ALK and PHOX2B account for most familial NB cases."
explanation: >-
A predisposition-workshop review stating that germline ALK and PHOX2B
mutations together account for most familial cases, supporting the
combined clause of the notes; it gives no share for ALK alone.
- reference: PMID:25345447
reference_title: "Neuroblastoma models for insights into tumorigenesis and new therapies."
supports: SUPPORT
quote_role: REVIEW_SYNTHESIS
evidence_source: HUMAN_CLINICAL
snippet: "Anaplastic lymphoma kinase (ALK) mutation is also found in 7% of sporadic neuroblastomas and 50% of familial neuroblastomas."
explanation: >-
A review figure at the low end of the published range: ALK mutation in
50% of familial neuroblastomas. The same sentence gives 7% for sporadic
tumors, close to the 8% diagnostic-cohort figure above.
- reference: PMID:25517749
reference_title: "ALK mutations confer differential oncogenic activation and sensitivity to ALK inhibition therapy in neuroblastoma."
supports: SUPPORT
quote_role: PRIMARY_RESULT
evidence_source: HUMAN_CLINICAL
snippet: "Three 'hotspot' residues accounted for 85% of mutations (Figure 1, Table 1): R1275 (43%), F1174 (30%), and F1245 (12%)"
explanation: >-
The distribution of ALK mutations by residue in the same 1,596-sample
cohort: R1275, F1174 and F1245 together account for 85%. The sentence is
in the paper's full text.
- reference: PMID:28674118
reference_title: "Retinoblastoma and Neuroblastoma Predisposition and Surveillance."
supports: SUPPORT
quote_role: REVIEW_SYNTHESIS
evidence_source: HUMAN_CLINICAL
snippet: "Germline mutations in ALK encode for single-base substitutions in key regions of the kinase domain that result in constitutive activation of the kinase, with the R1275Q mutation most frequently observed (Table 2)."
explanation: >-
Supports R1275Q as the most frequent germline ALK mutation, and germline
ALK variants as activating kinase-domain substitutions. The sentence is
in the review's full text.
- name: Segmental Chromosomal Aberrations
association: Prognostic Markers
notes: >-
Segmental chromosomal aberrations including 1p deletion, 11q deletion,
and 17q gain are associated with worse prognosis and help define
risk stratification. Chromosome 11q status is one of the factors formally
incorporated into the INRG classification system; 11q deletion is
characteristically found in MYCN-non-amplified high-risk disease.
evidence:
- reference: PMID:19047291
reference_title: "The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Stage, age, histologic category, grade of tumor differentiation, the status of the MYCN oncogene, chromosome 11q status, and DNA ploidy were the most highly statistically significant and clinically relevant factors."
explanation: >-
Establishes chromosome 11q status as a statistically significant,
clinically relevant prognostic factor in a large patient cohort and as a
formal component of INRG risk classification.
- reference: PMID:41560679
reference_title: "Coexpression of MYCN and ALK Induces Neuroblastoma-Like Tumors From Human iPS Cell-Derived Cranial Neural Crest Cells."
supports: SUPPORT
directness: INDIRECT
quote_role: PRIMARY_RESULT
evidence_source: MODEL_ORGANISM
snippet: "we identified key features of NB, including loss of NF1 and gain of 17q chromosome, which are critical for the development of malignant tumor."
explanation: >-
Supports 17q gain specifically, as a feature the study's own expression
profiling and exome sequencing identified in MYCN/ALK-induced clones of
iPSC-derived cranial neural crest cells, cells that formed
neuroblastoma-like tumors when transplanted into immunodeficient mice;
it is not patient-derived prognostic data. Indirect for this record: the
sentence calls 17q gain critical for malignant tumor development in a
model system, and an association with worse prognosis in patients
follows only by inference. It does not address 1p or 11q deletion; of
the record's prognostic claim, the INRG item above covers 11q status
only.
- name: TERT Rearrangement
association: Telomere Maintenance Activation
gene_term:
preferred_term: TERT
term:
id: hgnc:11730
label: TERT
notes: >-
Genomic rearrangements juxtaposing enhancers to the TERT locus drive
massive TERT upregulation and telomerase-mediated telomere maintenance.
TERT rearrangement occurs in high-risk disease and is largely mutually
exclusive with MYCN amplification and ATRX mutation, defining one of three
alternative routes to telomere maintenance in neuroblastoma.
evidence:
- reference: PMID:26466568
reference_title: "Telomerase activation by genomic rearrangements in high-risk neuroblastoma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "These rearrangements occurred only in high-risk neuroblastomas (12/39, 31%) in a mutually exclusive fashion with MYCN amplifications and ATRX mutations, which are known genetic events in this tumour type."
explanation: >-
Establishes TERT rearrangement as a high-risk-restricted event that is
mutually exclusive with MYCN amplification and ATRX mutation, defining
the three-way telomere-maintenance structure of neuroblastoma genomics.
- reference: PMID:26466568
reference_title: "Telomerase activation by genomic rearrangements in high-risk neuroblastoma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "TERT rearrangements defined a subgroup of high-risk tumours with particularly poor outcome."
explanation: Links TERT rearrangement to adverse outcome in an extended case series.
- name: ATRX Mutation
association: Alternative Lengthening of Telomeres
gene_term:
preferred_term: ATRX
term:
id: hgnc:886
label: ATRX
notes: >-
Somatic ATRX loss-of-function drives telomere maintenance by the
alternative lengthening of telomeres (ALT) pathway. ATRX-mutant
neuroblastoma is strongly age-dependent, characterising an
adolescent/young-adult subtype with indolent but chronically progressive,
treatment-refractory disease. ATRX mutation is essentially absent in
infants and is mutually exclusive with MYCN amplification.
evidence:
- reference: PMID:22416102
reference_title: "Association of age at diagnosis and genetic mutations in patients with neuroblastoma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "ATRX mutations were associated with an absence of the ATRX protein in the nucleus and with long telomeres."
explanation: >-
Links ATRX mutation to loss of nuclear ATRX protein and to the long
telomeres characteristic of alternative lengthening of telomeres.
- reference: PMID:22416102
reference_title: "Association of age at diagnosis and genetic mutations in patients with neuroblastoma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "ATRX mutations were associated with age at diagnosis in children and young adults with stage 4 neuroblastoma."
explanation: >-
Whole-genome sequencing across 104 patients establishes the age
dependence of ATRX mutation, supporting the adolescent/young-adult
subtype framing.
- name: PHOX2B
association: Germline Predisposition
gene_term:
preferred_term: PHOX2B
term:
id: hgnc:9143
label: PHOX2B
notes: >-
PHOX2B is a master regulator of autonomic nervous system development and,
with ALK, one of the two primary familial neuroblastoma predisposition
genes; it was the first neuroblastoma predisposition gene to be
identified. Germline PHOX2B mutations cause neuroblastoma predisposition
that may co-occur with other neurocristopathies — Hirschsprung disease
and congenital central hypoventilation syndrome — reflecting a shared
neural-crest developmental origin.
evidence:
- reference: PMID:32296467
reference_title: "Nervous system: Embryonal tumors: Neuroblastoma."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The primary predisposition genes in familial neuroblastoma are ALK and PHOX2B."
explanation: >-
Identifies PHOX2B alongside ALK as one of the two primary familial
neuroblastoma predisposition genes.
- reference: PMID:29589100
reference_title: "Genetic susceptibility to neuroblastoma: current knowledge and future directions."
supports: SUPPORT
quote_role: REVIEW_SYNTHESIS
evidence_source: HUMAN_CLINICAL
snippet: "These cases of neuroblastoma comorbid with other neural crest-implicated diseases facilitated the discovery of the first neuroblastoma predisposition gene, the paired-like homeobox 2B gene (PHOX2B) (Mosse et al. 2004; Trochet et al. 2004)."
explanation: >-
States that PHOX2B was the first neuroblastoma predisposition gene to be
identified, through cases that co-occurred with other neural crest
disorders. The sentence is in the review's full text.
treatments:
- name: Risk-Adapted Chemotherapy
description: >-
Chemotherapy intensity varies by risk group. Low-risk patients may need
only observation or minimal chemotherapy. High-risk patients receive
intensive induction chemotherapy including cisplatin, etoposide,
vincristine, cyclophosphamide, doxorubicin, and topotecan.
treatment_term:
preferred_term: chemotherapy
term:
id: NCIT:C15632
label: Chemotherapy
therapeutic_agent:
- preferred_term: cisplatin
term:
id: CHEBI:27899
label: cisplatin
- preferred_term: etoposide
term:
id: CHEBI:4911
label: etoposide
- preferred_term: cyclophosphamide
term:
id: CHEBI:4027
label: cyclophosphamide
- name: Surgical Resection
description: >-
Surgery for primary tumor resection is performed after chemotherapy for
high-risk disease. Complete resection is associated with better outcomes
when achievable without significant morbidity.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: Definitive Surgical Resection
term:
id: NCIT:C154430
label: Definitive Surgical Resection
- name: Autologous Stem Cell Transplant
description: >-
High-dose chemotherapy with autologous stem cell rescue is standard for
high-risk neuroblastoma following induction chemotherapy and surgical
resection. Tandem transplant may provide additional benefit.
therapeutic_modality: CELL_THERAPY
treatment_term:
preferred_term: hematopoietic stem cell transplantation
term:
id: NCIT:C15431
label: Hematopoietic Cell Transplantation
- name: Radiation Therapy
description: >-
Radiation to the primary tumor bed is used in high-risk disease following
surgical resection and stem cell transplant.
therapeutic_modality: RADIOTHERAPY
treatment_term:
preferred_term: Radiation Therapy
term:
id: NCIT:C15313
label: Radiation Therapy
- name: Anti-GD2 Immunotherapy
description: >-
Anti-GD2 monoclonal antibody (dinutuximab) combined with GM-CSF and IL-2
has significantly improved outcomes in high-risk neuroblastoma during
maintenance therapy. GD2 is highly expressed on neuroblastoma cells.
treatment_term:
preferred_term: immunotherapy procedure
term:
id: NCIT:C15262
label: Immunotherapy
- name: ALK Inhibitor Therapy
description: >-
ALK tyrosine kinase inhibition targets the constitutive ALK signalling
produced by activating ALK point mutations or ALK amplification. The
first-generation inhibitor crizotinib has limited activity against several
common neuroblastoma ALK variants (notably F1174L), which motivated the
move to third-generation, CNS-penetrant inhibitors; lorlatinib is under
evaluation in frontline cooperative-group trials for ALK-altered
high-risk disease. Applicable only to the ALK-altered molecular subset.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: crizotinib
term:
id: CHEBI:64310
label: crizotinib
- preferred_term: lorlatinib
term:
id: CHEBI:143117
label: lorlatinib
target_mechanisms:
- target: ALK Signaling Activation
description: >-
ATP-competitive inhibition of the ALK tyrosine kinase domain abolishes
the constitutive receptor autophosphorylation produced by activating
ALK mutations, removing the downstream proliferative signal.
evidence:
- reference: PMID:18724359
reference_title: "Identification of ALK as a major familial neuroblastoma predisposition gene."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Mutations resulted in constitutive phosphorylation, and targeted knockdown of ALK messenger RNA resulted in profound inhibition of growth in all cell lines harbouring mutant or amplified ALK"
explanation: >-
Establishes ALK dependence of ALK-mutant and ALK-amplified
neuroblastoma cells, the mechanistic rationale for ALK-directed
therapy. Genetic knockdown rather than pharmacologic inhibition.
- name: Isotretinoin (Retinoic Acid)
description: >-
13-cis-retinoic acid (isotretinoin) is given during maintenance therapy
to promote differentiation of residual neuroblastoma cells and reduce
relapse risk.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: isotretinoin
term:
id: CHEBI:6067
label: isotretinoin
animal_models:
- name: Xenopus anteroventral noradrenergic (AVNA) cell differentiation model
species: Xenopus laevis
genotype: >-
Embryos expressing wild-type Ascl1, a phospho-mutant Ascl1 that cannot be
phosphorylated at serine-proline motifs, CDKs, or MYCN, with Ascl1
morpholino knockdown
category: Developmental model of the presumed cell of origin
publication: PMID:25786414
description: >-
Rather than growing a tumour, this model reconstructs the normal
differentiation of the neural-crest-derived sympathoadrenal cell that
neuroblastoma is thought to arise from, and asks what stops it. Frog AVNA
cells differentiate under transient Ascl1 expression; in neuroblastoma cells
Ascl1 is instead persistently expressed and multiply phosphorylated.
Introducing that phospho-state into the frog cells blocks their
differentiation, and CDK or MYCN overexpression blocks it too — but not when
Ascl1 cannot be phosphorylated, which places phosphorylation downstream of
both. The model tests the differentiation-arrest hypothesis in a normal
developmental context; it does not produce tumours and so says nothing about
transformation, growth, or metastasis.
genes:
- preferred_term: ASCL1
term:
id: hgnc:738
label: ASCL1
- preferred_term: MYCN
term:
id: hgnc:7559
label: MYCN
modeled_mechanisms:
- target: Neural Crest Developmental Arrest
relationship: RECAPITULATES
fidelity: MODERATE
description: >-
Supplies a molecular switch for the arrest this node asserts: multi-site
phosphorylation of Ascl1 converts it from a driver of sympathoadrenal
differentiation into an inert factor, matching the phospho-state Ascl1 is
held in within neuroblastoma cells.
limitations: >-
Frog AVNA cells are a developmental counterpart of the presumed cell of
origin, not tumour cells, and the model contains no transformed tissue —
arrest is scored as failure to differentiate on schedule rather than as
tumour formation. The link to human disease rests on the observed
phospho-state of ASCL1 in neuroblastoma lines, so the model shows the
state is sufficient to block differentiation, not that it is what maintains
any patient's tumour.
readouts:
- name: AVNA cell differentiation driven by wild-type versus phospho-mutant Ascl1
target: Neural Crest Developmental Arrest
direction: DECREASED
interpretation: >-
Differentiation fails when Ascl1 can be multiply phosphorylated and
proceeds when it cannot, isolating phospho-status as the controlling
variable.
evidence:
- reference: PMID:25786414
reference_title: "Ascl1 phospho-status regulates neuronal differentiation in a Xenopus developmental model of neuroblastoma."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "ability to induce differentiation of AVNA cells is inhibited by its multi-site phosphorylation at serine-proline motifs"
explanation: States the measured effect of Ascl1 phospho-status on differentiation in this model.
evidence:
- reference: PMID:25786414
reference_title: "Ascl1 phospho-status regulates neuronal differentiation in a Xenopus developmental model of neuroblastoma."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Here, we use Xenopus frog embryos to characterise the differentiation of anteroventral noradrenergic (AVNA) cells, cells derived from the neural crest."
explanation: Establishes what the model is and that its cells are neural crest derived.
- reference: PMID:25786414
reference_title: "Ascl1 phospho-status regulates neuronal differentiation in a Xenopus developmental model of neuroblastoma."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "We find that the transcriptional regulator Ascl1 is expressed transiently in normal AVNA cell differentiation but its expression is aberrantly maintained in NB cells, where it is largely phosphorylated on multiple sites."
explanation: >-
The neuroblastoma-cell half of this comparison is cell-based, and it is
what connects the frog readout to the human disease state.
- target: MYCN-Driven Proliferation
relationship: PERTURBS
fidelity: MODERATE
description: >-
Positions MYCN upstream of the differentiation block: MYCN overexpression
prevents Ascl1-driven differentiation, and loses that ability when Ascl1
cannot be phosphorylated.
limitations: >-
This is the differentiation-blocking arm of MYCN only. The node is about
proliferation, and no proliferative or tumour-growth readout was taken
here; MYCN is introduced by overexpression in a normal embryo, not by the
genomic amplification that defines high-risk neuroblastoma.
readouts:
- name: Ascl1-driven AVNA differentiation under CDK or MYCN overexpression
target: MYCN-Driven Proliferation
direction: DECREASED
interpretation: >-
The epistasis result: MYCN and CDKs block differentiation only when Ascl1
is phosphorylatable, so their effect on this cell fate runs through Ascl1
phospho-status.
evidence:
- reference: PMID:25786414
reference_title: "Ascl1 phospho-status regulates neuronal differentiation in a Xenopus developmental model of neuroblastoma."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "overexpression of cyclin-dependent kinases (CDKs) and MYCN inhibit wild-type Ascl1-driven AVNA differentiation, but not differentiation driven by a phospho-mutant form of Ascl1"
explanation: Reports the measured differentiation block and the phospho-mutant control that makes it interpretable.
evidence:
- reference: PMID:25786414
reference_title: "Ascl1 phospho-status regulates neuronal differentiation in a Xenopus developmental model of neuroblastoma."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "This suggests that the maintenance of ASCL1 in its multiply phosphorylated state might prevent terminal differentiation in NB, which could offer new approaches for differentiation therapy in NB."
explanation: >-
The authors put the therapeutic and disease-level reading as a
suggestion, which is the level of support this link carries.
datasets:
- accession: geo:GSE85047
title: Gene expression data from primary neuroblastoma tumors
description: Microarray expression profiling of primary neuroblastoma tumors
for expression analysis and subgroup discovery.
organism:
preferred_term: human
term:
id: NCBITaxon:9606
label: Homo sapiens
data_type: MICROARRAY
sample_types:
- preferred_term: neuroblastoma tumor tissue
tissue_term:
preferred_term: adrenal gland
term:
id: UBERON:0002369
label: adrenal gland
sample_count: 283
conditions:
- neuroblastoma
notes: Primary tumor cohort.
disease_term:
preferred_term: neuroblastoma
term:
id: MONDO:0005072
label: neuroblastoma
classifications:
icdo_morphology:
classification_value: Embryonal Neoplasm
harrisons_chapter:
- classification_value: ONCOLOGY_HEMATOLOGY
nih_research_priority:
- classification_value: NIH_HT_68_childhood_adolescent_young_adult_aya_cancer
notes: Most common extracranial solid tumor of childhood (MYCN amplification) — flagship exemplar for NIH Highlighted Topic 68 (childhood and AYA cancer research).
references:
- reference: DOI:10.1038/s41388-025-03635-2
title: 'Dissecting neuroblastoma heterogeneity through single-cell multi-omics:
insights into development, immunity, and therapeutic resistance'
findings: []
- reference: DOI:10.1038/s41467-023-38239-5
title: Reversible transitions between noradrenergic and mesenchymal tumor
identities define cell plasticity in neuroblastoma
findings: []
- reference: DOI:10.1038/s44318-024-00206-1
title: Targeting SWI/SNF ATPases reduces neuroblastoma cell plasticity
findings: []
- reference: DOI:10.1101/2022.08.16.504100
title: Copy-number dosage regulates telomere maintenance and
disease-associated pathways in neuroblastoma
findings: []
- reference: DOI:10.3389/fimmu.2023.1268645
title: 'Two bullets in the gun: combining immunotherapy with chemotherapy to defeat
neuroblastoma by targeting adrenergic-mesenchymal plasticity'
findings: []
- reference: DOI:10.3389/fimmu.2025.1637626
title: Emerging frontiers in epigenetic-targeted therapeutics for pediatric
neuroblastoma
findings: []
- reference: DOI:10.3390/jcm13164765
title: High-Risk Neuroblastoma Challenges and Opportunities for Antibody-Based
Cellular Immunotherapy
findings: []
Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
Edit: Neuroblastoma — evidence for four unquoted figures, retired PARTIAL prose, ALK/MYCN HGNC bindings · 2026-10-15T16:47:34Z · View source
Evidence repairs in an existing entry: four figures that were stated without a quote, two explanations that still argued for the retired PARTIAL grade, quote_role and grading of six background citations, two prose claims next to the rewritten text, and HGNC bindings for ALK and MYCN. No new mechanisms, phenotypes or treatments. Figures: - MYCN amplification "approximately 20%": kept. Sourced to the Children's Oncology Group biology-study cohort (PMID:28696504: 845 of 4,672 patients, 18.1%; 133 more with MYCN gain) and two review statements (PMID:25345447; PMID:22936790 on the MYCN-amplified subtype). The unsourced "historical series enriched for advanced-stage disease" was replaced by the stage split in the 1984 Brodeur abstract (PMID:6719137: 0 of 15 stage 1-2 vs 24 of 48 stage 3-4). - ALK point mutations "8-10%": kept, without "sporadic" (the 8% cohort counts germline carriers). Sourced to PMID:25517749 (8% of 1,596 diagnostic samples) and PMID:26059187 (10% at diagnosis with hotspot deep sequencing, more than half subclonal). The unsourced "F1174L and R1275Q are the most common mutations" was replaced by the per-residue counts in PMID:25517749 (R1275 43%, F1174 30%, F1245 12%) and the germline statement in PMID:28674118 (R1275Q most frequent). - Germline ALK in familial neuroblastoma "75-80%": restated as the range of published estimates, about 50% to 80%: more than 50% from the group that mapped ALK (PMID:21734404), 50% (PMID:25345447), 75% (PMID:29589100) and 80% (PMID:38791942). The 75% and 80% statements are in cached full texts, not abstracts. The PMID:18724359 explanation that argued "majority (not ~50%)" was rewritten. The combined ALK+PHOX2B clause cites PMID:28674118. - Urinary VMA/HVA ">90%": softened. Diagnostic series give 84% (PMID:28061374) and 82.2% (PMID:31724812) for the pair, 95% with an eight-metabolite panel; >90% and 92% are review statements (PMID:15235064, PMID:8790511), and a relapse-selected cohort found 92% at diagnosis (PMID:12932669, which also supports the added caveat that markers alone do not reliably detect relapse). First evidence block for this marker. Grading: the six PMID:41560679 items now carry quote_role (five introduction sentences BACKGROUND, the 17q result PRIMARY_RESULT). The five background items were regraded MODEL_ORGANISM -> HUMAN_CLINICAL because the quoted sentences describe the human disease, per the CLAUDE.md quote_role guidance (#10262); the 17q result stays MODEL_ORGANISM. directness: INDIRECT on the two former PARTIAL items, with explanations giving the inference step. Other: PHOX2B notes corrected (it was the first neuroblastoma predisposition gene identified, not the second after ALK; PMID:29589100). genetic[ALK Mutations].gene_term hgnc:427 and genetic[MYCN Amplification].gene_term hgnc:7559 (cached; HGNC REST confirmed). Node-level genes: wiring is left for a later change, because it also needs molecular_functions (check-gene-activity-grounding). Method: candidate quotes came from literature-search agents (PubMed E-utilities, two search angles per figure) and were checked by independent verifier agents for exact match, support for the claim, and grading; the curator selected from the verified set, and a three-lens red-team review of the diff preceded the commit. No deep-research report was generated; research/Neuroblastoma-deep-research-falcon.md predates this change and was not used. Validation: just validate-disorders (52/52 snippets, 60 titles, 0 issues); count-verified-snippets --strict 52/52; offline gates pass (duplicate keys, entity refs, causal targets, qualifier terms, block-scalar comments, enum values, folded hyphens, snippet length, title snippets, snippet grading, retired-support prose, reference titles, environmental evidence, gene-activity grounding against origin/main); list-gene-term-mismatches 7/7 named, 0 mismatches.
Pathophysiology description Neuroblastoma (NB) arises from neural crest–derived sympathoadrenal lineage cells and exhibits marked inter- and intra-tumoral heterogeneity. Despite a low tumor mutational burden, disease biology is driven by a limited set of recurrent genomic and epigenomic programs that confer proliferative advantage, telomere immortality, lineage/cell-state plasticity, and an immunologically “cold” tumor microenvironment.
Genomic drivers and copy-number programs: High-risk NB is frequently defined by MYCN amplification, TERT activation (via rearrangements or copy-number mechanisms), and ATRX alterations, together with segmental chromosomal aberrations including 1p deletion, 11q deletion, and 17q gain; collectively these shape aggressive phenotypes despite overall few point mutations (URL: https://doi.org/10.3390/jcm13164765, Aug 2024) (persaud2024highriskneuroblastomachallenges pages 2-3). Telomere programs and copy-number dosage have pervasive effects on transcriptional control and disease pathways; recurrent 11q loss with 17q gain correlates with upregulation of histone variant genes and reduced PRC2 activity, providing a mechanistic route to ALT activation in a subset, while TERT overexpression can be driven by rearrangements and dosage in others (URL: https://doi.org/10.1101/2022.08.16.504100, Aug 2024) (burkert2024copynumberdosageregulates pages 18-24).
Telomere maintenance mechanisms (TMM): High-risk NB nearly always acquires a telomere maintenance mechanism. Two non-overlapping solutions dominate: telomerase activation (often via TERT rearrangement or MYCN-driven TERT transcription) and the alternative lengthening of telomeres (ALT), frequently associated with ATRX dysfunction and chromatin changes at telomeres. Allele-specific dosage and copy-number imbalances further tune TERT levels and ALT-associated programs, linking segmental CNAs to TMM state and outcome (URL: https://doi.org/10.1101/2022.08.16.504100, Aug 2024) (burkert2024copynumberdosageregulates pages 18-24); overview also summarized in an immunotherapy-focused review (URL: https://doi.org/10.3390/jcm13164765, Aug 2024) (persaud2024highriskneuroblastomachallenges pages 2-3).
Lineage/cell-state plasticity: NB cells switch between two epigenetically-defined identities—noradrenergic (ADRN) and mesenchymal (MES)—with distinct core regulatory circuitries (ADRN: PHOX2A/PHOX2B, HAND1/2, GATA2/3; MES: AP-1–programs). Transitions are spontaneous and reversible and are shaped by tumor microenvironmental cues; MES-like states are enriched during or after therapy and confer chemoresistance, while in patient tumors the dominant phenotype is often ADRN with subclonal MES-like populations (URL: https://doi.org/10.1038/s41467-023-38239-5, May 2023) (thirant2023reversibletransitionsbetween pages 1-2). Targeted depletion of SWI/SNF ATPases (SMARCA2/4) compacts cis-regulatory elements, displaces ADRN core TFs (e.g., MYCN, HAND2, PHOX2B, GATA3), reduces enhancer activity, inhibits invasion, and—critically—reduces cellular plasticity, positioning SWI/SNF as a mechanistic driver of lineage flexibility and a therapeutic node (URL: https://doi.org/10.1038/s44318-024-00206-1, Aug 2024) (xu2024targetingswisnfatpases pages 1-2). Additional reviews integrating single-cell multi-omics emphasize ADRN↔MES plasticity, persister states at relapse, and the developmental origin of state diversity (URL: https://doi.org/10.3389/fimmu.2025.1637626, Jul 2025; URL: https://doi.org/10.1038/s41388-025-03635-2, Nov 2025) (wang2025emergingfrontiersin pages 6-7, he2025dissectingneuroblastomaheterogeneity pages 6-7).
Tumor microenvironment (TME) and immune evasion: NB is typically immunologically “cold,” with low neoantigen load, downregulated MHC class I and antigen processing, and abundant immunosuppressive myeloid populations (TAMs, MDSCs) and Tregs. Additional barriers include CD47-mediated phagocytosis inhibition, inhibitory checkpoints (e.g., B7-H3, PD-L1), and metabolic constraints. These features limit T cell infiltration and efficacy of checkpoint inhibition and shape responses to GD2-directed therapies (URL: https://doi.org/10.3390/jcm13164765, Aug 2024) (persaud2024highriskneuroblastomachallenges pages 2-3). Combining chemotherapy and immunotherapy to deliberately exploit ADRN–MES plasticity (e.g., inducing more immunogenic MES features or immunogenic cell death) is a proposed strategy to overcome immune evasion and resistance (URL: https://doi.org/10.3389/fimmu.2023.1268645, Oct 2023) (d’amico2023twobulletsin pages 6-7). Broader pediatric-oncology reviews concur that epigenetic dysregulation (PRC2 imbalance, DNA hypomethylation) intersects with immune coldness, suggesting epigenetic modulators may prime NB for immunotherapy (URL: https://doi.org/10.3389/fimmu.2025.1637626, Jul 2025) (wang2025emergingfrontiersin pages 1-2).
Key concepts and definitions with current understanding - Segmental chromosomal aberrations (SCA): Partial arm gains/losses (e.g., 17q gain, 1p and 11q loss) that correlate with high-risk disease, telomere program activation, and poor outcome (URL: https://doi.org/10.1101/2022.08.16.504100, Aug 2024) (burkert2024copynumberdosageregulates pages 18-24). - Telomere maintenance mechanisms: Mutually exclusive telomerase activation vs ALT in most tumors; in NB, TERT activation (via rearrangements/MYCN) or ALT (often ATRX-linked) is a hallmark of high-risk biology (URL: https://doi.org/10.1101/2022.08.16.504100, Aug 2024) (burkert2024copynumberdosageregulates pages 18-24). - Core regulatory circuitry (CRC): Super-enhancer–anchored TF networks defining cell identity; ADRN CRC includes PHOX2B/HAND2/GATA3 and is displaced by mSWI/SNF ATPase degradation (URL: https://doi.org/10.1038/s44318-024-00206-1, Aug 2024) (xu2024targetingswisnfatpases pages 1-2); ADRN↔MES circuits are epigenetically rewired during plasticity (URL: https://doi.org/10.1038/s41467-023-38239-5, May 2023) (thirant2023reversibletransitionsbetween pages 1-2). - Immunologically “cold” tumor: Low T-cell infiltration/activation with innate suppressive myeloid dominance; characteristic of NB and a barrier to ICI efficacy (URL: https://doi.org/10.3390/jcm13164765, Aug 2024) (persaud2024highriskneuroblastomachallenges pages 2-3).
Recent developments and latest research (2023–2024 priority) - Telomere dosage–ALT axis: Integrative genome/transcriptome analysis links 11q loss/17q gain to histone variant upregulation, PRC2 attenuation, and ALT predisposition, while TERT dosage and rearrangements drive telomerase activation—offering pathway-level biomarkers and vulnerabilities (URL: https://doi.org/10.1101/2022.08.16.504100, Aug 2024) (burkert2024copynumberdosageregulates pages 18-24). - Epigenetic control of plasticity: Dual degradation of SMARCA2/4 collapses enhancer landscapes and reduces ADRN–MES interconversion and invasion, nominating mSWI/SNF ATPases as targets to suppress therapy-evasive states (URL: https://doi.org/10.1038/s44318-024-00206-1, Aug 2024) (xu2024targetingswisnfatpases pages 1-2). Foundational plasticity evidence in vivo/in patients was consolidated with single-cell profiling and xenografts (URL: https://doi.org/10.1038/s41467-023-38239-5, May 2023) (thirant2023reversibletransitionsbetween pages 1-2). - Immune microenvironment–informed therapy: Consensus descriptions of NB immune evasion—including MHC downregulation, suppressive myeloid infiltration, CD47 signaling, and checkpoint expression—explain limited ICI activity and motivate combinatorial strategies with cytotoxics/epigenetic modulators to increase tumor immunogenicity (URL: https://doi.org/10.3390/jcm13164765, Aug 2024; URL: https://doi.org/10.3389/fimmu.2023.1268645, Oct 2023) (persaud2024highriskneuroblastomachallenges pages 2-3, d’amico2023twobulletsin pages 6-7).
Current applications and real-world implementations - GD2-directed immunotherapy: Anti-GD2 monoclonal antibodies are standard in high-risk consolidation/maintenance; their efficacy is impacted by the cold TME and immune-evasion circuitry summarized above, leading to active development of combination immunotherapy approaches (URL: https://doi.org/10.3390/jcm13164765, Aug 2024) (persaud2024highriskneuroblastomachallenges pages 2-3). - Epigenetic and plasticity-directed strategies: Preclinical mSWI/SNF ATPase degraders reduce plasticity and invasion, supporting exploration as partners with cytotoxic or immune therapies to prevent emergence of MES-like resistant states (URL: https://doi.org/10.1038/s44318-024-00206-1, Aug 2024) (xu2024targetingswisnfatpases pages 1-2). Epigenetic agents proposed to reprogram immunogenicity are reviewed (URL: https://doi.org/10.3389/fimmu.2025.1637626, Jul 2025) (wang2025emergingfrontiersin pages 1-2).
Expert opinions and analysis from authoritative sources - Authoritative clinical-immunology perspective: “Immune-evasion features include central tolerance to oncofetal antigens, downregulation of MHC class I, defective antigen processing, low NK-activating ligands… abundant TAMs, MDSCs and Tregs… resulting in immunologically ‘cold’ tumors.” This synthesis explains the limited efficacy of ICIs and informs rational combination strategies with GD2 antibodies and adoptive cellular therapy (URL: https://doi.org/10.3390/jcm13164765, Aug 2024) (persaud2024highriskneuroblastomachallenges pages 2-3). - Fundamental cell-state paradigm: NB plasticity is an epigenetically governed, microenvironment-influenced spectrum between ADRN and MES states; suppressing plasticity or redirecting state can modulate therapy response (URL: https://doi.org/10.1038/s41467-023-38239-5, May 2023; URL: https://doi.org/10.1038/s44318-024-00206-1, Aug 2024) (thirant2023reversibletransitionsbetween pages 1-2, xu2024targetingswisnfatpases pages 1-2). - Multi-omics viewpoint: Developmental lineage programs and persister states underlie relapse and resistance; multi-omic single-cell atlases are needed to map vulnerability (URL: https://doi.org/10.1038/s41388-025-03635-2, Nov 2025; URL: https://doi.org/10.3389/fimmu.2025.1637626, Jul 2025) (he2025dissectingneuroblastomaheterogeneity pages 6-7, wang2025emergingfrontiersin pages 1-2).
Relevant statistics and data from recent studies - While NB as a whole has seen survival gains, high-risk cohorts continue to have 5-year overall survival below 50% in many contemporary series, consistent with the immunotherapy-focused clinical review summarizing outcomes and obstacles (URL: https://doi.org/10.3390/jcm13164765, Aug 2024) (persaud2024highriskneuroblastomachallenges pages 2-3).
Required Information 1) Core Pathophysiology - Primary mechanisms: Oncogene activation (MYCN amplification), telomere maintenance acquisition (TERT activation or ALT), segmental chromosomal instability (1p/11q loss, 17q gain), epigenetic remodeling of lineage programs (CRC, super-enhancers), and an immunosuppressive TME that impairs antigen presentation and T-cell infiltration (URL: https://doi.org/10.3390/jcm13164765, Aug 2024; URL: https://doi.org/10.1101/2022.08.16.504100, Aug 2024; URL: https://doi.org/10.1038/s41467-023-38239-5, May 2023; URL: https://doi.org/10.1038/s44318-024-00206-1, Aug 2024) (persaud2024highriskneuroblastomachallenges pages 2-3, burkert2024copynumberdosageregulates pages 18-24, thirant2023reversibletransitionsbetween pages 1-2, xu2024targetingswisnfatpases pages 1-2). - Dysregulated pathways: Telomere biology (TERT/ALT), chromatin remodeling (mSWI/SNF, PRC2 imbalance), super-enhancer–based transcriptional circuitry (ADRN/MES CRCs), immune checkpoint and innate checkpoint signaling (CD47, B7-H3, PD-L1), and myeloid-driven suppression (URL: https://doi.org/10.1101/2022.08.16.504100, Aug 2024; URL: https://doi.org/10.1038/s44318-024-00206-1, Aug 2024; URL: https://doi.org/10.3390/jcm13164765, Aug 2024) (burkert2024copynumberdosageregulates pages 18-24, xu2024targetingswisnfatpases pages 1-2, persaud2024highriskneuroblastomachallenges pages 2-3). - Affected cellular processes: DNA damage tolerance at telomeres, enhancer remodeling and TF occupancy, antigen processing/presentation, macrophage/NK/T-cell crosstalk, and lineage-state transitions under therapy pressure (URL: as above) (burkert2024copynumberdosageregulates pages 18-24, xu2024targetingswisnfatpases pages 1-2, persaud2024highriskneuroblastomachallenges pages 2-3, thirant2023reversibletransitionsbetween pages 1-2).
2) Key Molecular Players - Genes/Proteins (HGNC): - MYCN (HGNC:7553): amplified oncogene driving proliferation and TERT transcription; tied to ADRN CRC and displaced from DNA by SMARCA2/4 degradation (URL: https://doi.org/10.3390/jcm13164765; https://doi.org/10.1038/s44318-024-00206-1) (persaud2024highriskneuroblastomachallenges pages 2-3, xu2024targetingswisnfatpases pages 1-2). - TERT (HGNC:11730): activated via rearrangement/copy-number and MYCN; defines telomerase-positive NB (URL: https://doi.org/10.1101/2022.08.16.504100) (burkert2024copynumberdosageregulates pages 18-24). - ATRX (HGNC:886): loss disrupts telomeric chromatin, promoting ALT (URL: https://doi.org/10.1101/2022.08.16.504100) (burkert2024copynumberdosageregulates pages 18-24). - SMARCA2/SMARCA4 (HGNC:11100/11103): mSWI/SNF ATPases required for plasticity-permissive chromatin; dual degradation reduces plasticity and invasion (URL: https://doi.org/10.1038/s44318-024-00206-1) (xu2024targetingswisnfatpases pages 1-2). - PHOX2B, HAND2, GATA3 (HGNC:9140/4801/4172): ADRN CRC TFs defining noradrenergic identity (URL: https://doi.org/10.1038/s41467-023-38239-5; https://doi.org/10.1038/s44318-024-00206-1) (thirant2023reversibletransitionsbetween pages 1-2, xu2024targetingswisnfatpases pages 1-2). - Immune evasion mediators: CD47 (phagocytosis checkpoint), B7-H3 (CD276), PD-L1 (CD274), and MHC-I downregulation are implicated in immune exclusion (URL: https://doi.org/10.3390/jcm13164765) (persaud2024highriskneuroblastomachallenges pages 2-3). - Chemical Entities (CHEBI): - Anti-GD2 monoclonal antibodies (therapeutic biologics) used clinically in HR-NB; activity conditioned by TME (URL: https://doi.org/10.3390/jcm13164765) (persaud2024highriskneuroblastomachallenges pages 2-3). - Cell Types (CL): - Tumor cell states: adrenergic tumor cells; mesenchymal tumor cells (lineage-plastic cancer cell states) (URL: https://doi.org/10.1038/s41467-023-38239-5) (thirant2023reversibletransitionsbetween pages 1-2). - Immune/stromal: tumor-associated macrophages, myeloid-derived suppressor cells, regulatory T cells, NK cells (URL: https://doi.org/10.3390/jcm13164765) (persaud2024highriskneuroblastomachallenges pages 2-3). - Anatomical locations (UBERON): - Adrenal medulla and sympathetic chain ganglia as common primaries; bone marrow as a key metastatic niche with immunosuppressive remodeling (review synthesis) (URL: https://doi.org/10.3390/jcm13164765) (persaud2024highriskneuroblastomachallenges pages 2-3).
3) Biological Processes (GO annotation candidates, disrupted) - Telomere organization and maintenance (GO:0000723; GO:0001309): TERT activation or ALT engagement; copy-number dosage reshapes TMM pathways (URL: https://doi.org/10.1101/2022.08.16.504100) (burkert2024copynumberdosageregulates pages 18-24). - Chromatin organization and enhancer regulation (GO:0006325; GO:0032204): mSWI/SNF-dependent accessibility enabling CRC function; PRC2 imbalance in ALT contexts (URL: https://doi.org/10.1038/s44318-024-00206-1; https://doi.org/10.1101/2022.08.16.504100) (xu2024targetingswisnfatpases pages 1-2, burkert2024copynumberdosageregulates pages 18-24). - Regulation of transcription by RNA polymerase II (GO:0006357): super-enhancer/CRC-driven lineage programs (URL: https://doi.org/10.1038/s41467-023-38239-5) (thirant2023reversibletransitionsbetween pages 1-2). - Antigen processing and presentation of peptide antigen via MHC class I (GO:0002474): downregulated in NB, contributing to immune coldness (URL: https://doi.org/10.3390/jcm13164765) (persaud2024highriskneuroblastomachallenges pages 2-3). - Negative regulation of T cell activation (GO:0050868) and macrophage-mediated immunity (GO:0006955): checkpoint expression (CD47, PD-L1, B7-H3) and suppressive myeloid infiltration (URL: https://doi.org/10.3390/jcm13164765) (persaud2024highriskneuroblastomachallenges pages 2-3). - Epithelial/mesenchymal program regulation (GO:0001837; GO:0001838 proxies for state changes): ADRN↔MES transitions under therapy pressure (URL: https://doi.org/10.1038/s41467-023-38239-5) (thirant2023reversibletransitionsbetween pages 1-2).
4) Cellular Components (where processes occur) - Telomere nucleoprotein complex (GO:0000781): site of ALT recombination or telomerase action (URL: https://doi.org/10.1101/2022.08.16.504100) (burkert2024copynumberdosageregulates pages 18-24). - Nuclear chromatin, enhancers/super-enhancers: mSWI/SNF-regulated cis-elements controlling CRC TF binding (URL: https://doi.org/10.1038/s44318-024-00206-1; https://doi.org/10.1038/s41467-023-38239-5) (xu2024targetingswisnfatpases pages 1-2, thirant2023reversibletransitionsbetween pages 1-2). - Plasma membrane: GD2 antigen display (therapeutic target), checkpoint molecules (PD-L1, CD47, B7-H3) (URL: https://doi.org/10.3390/jcm13164765) (persaud2024highriskneuroblastomachallenges pages 2-3). - Tumor microenvironment extracellular space: cytokines and suppressive metabolites shaping immune exclusion (URL: https://doi.org/10.3390/jcm13164765) (persaud2024highriskneuroblastomachallenges pages 2-3).
5) Disease Progression (sequence of events) - Developmental origin and transformation: sympathoadrenal progenitor with early segmental CNAs and oncogene activation (e.g., MYCN, TERT) establishes proliferative, ADRN-skewed tumor. Acquisition of telomere maintenance (telomerase or ALT) enables immortalization and genomic stability under replication stress (URL: https://doi.org/10.1101/2022.08.16.504100) (burkert2024copynumberdosageregulates pages 18-24). - Therapy pressure and plasticity: cytotoxic exposure enriches MES-like, chemoresistant states; microenvironmental signals can bias reversion to ADRN identity in vivo. Persistent plasticity enables relapse and resistance (URL: https://doi.org/10.1038/s41467-023-38239-5, May 2023) (thirant2023reversibletransitionsbetween pages 1-2). - Immune evasion and metastasis: MHC-I downregulation, myeloid suppression, and checkpoint signaling facilitate immune escape; bone marrow metastatic niches display pronounced immune suppression and T-cell dysfunction, limiting immunotherapy efficacy (URL: https://doi.org/10.3390/jcm13164765, Aug 2024) (persaud2024highriskneuroblastomachallenges pages 2-3).
6) Phenotypic Manifestations (clinical phenotypes and mechanism links) - Common phenotypes: abdominal mass (adrenal/sympathetic), bone/bone marrow metastases, opsoclonus–myoclonus in subsets; in high-risk disease, refractory/relapsed course and poor survival are linked to TMM activation and ADRN↔MES plasticity under therapy (URL: https://doi.org/10.3390/jcm13164765, Aug 2024; URL: https://doi.org/10.1101/2022.08.16.504100, Aug 2024; URL: https://doi.org/10.1038/s41467-023-38239-5, May 2023) (persaud2024highriskneuroblastomachallenges pages 2-3, burkert2024copynumberdosageregulates pages 18-24, thirant2023reversibletransitionsbetween pages 1-2).
Gene/protein annotations with ontology terms (examples) - MYCN (HGNC:7553) – Biological Process: positive regulation of transcription by RNA Pol II; cellular component: nucleus; Molecular Function: DNA-binding TF activity; Evidence: amplification and CRC occupancy in ADRN state; therapeutic vulnerability via mSWI/SNF ATPase degradation reducing TF DNA binding (URL: https://doi.org/10.1038/s44318-024-00206-1) (xu2024targetingswisnfatpases pages 1-2). - TERT (HGNC:11730) – Biological Process: telomere maintenance via telomerase; Cellular Component: telomerase holoenzyme complex, telomere; Evidence: rearrangements/copy-number/MYCN drive TERT activation in NB (URL: https://doi.org/10.1101/2022.08.16.504100) (burkert2024copynumberdosageregulates pages 18-24). - ATRX (HGNC:886) – Biological Process: chromatin assembly at telomeres; ALT association; Cellular Component: nuclear chromatin; Evidence: ATRX dysfunction promotes ALT in NB (URL: https://doi.org/10.1101/2022.08.16.504100) (burkert2024copynumberdosageregulates pages 18-24). - SMARCA2/SMARCA4 (HGNC:11100/11103) – Biological Process: chromatin remodeling; Cellular Component: SWI/SNF complex; Evidence: dual degradation reduces plasticity and invasion (URL: https://doi.org/10.1038/s44318-024-00206-1) (xu2024targetingswisnfatpases pages 1-2).
Phenotype associations (HP terms, examples) - HP:0002664 (Neoplasm of the adrenal gland)—common primary site; HP:0002667 (Metastatic neoplasm of the bone); mechanism links include immune suppression and lineage plasticity associated with progression and therapeutic resistance (URL: https://doi.org/10.3390/jcm13164765) (persaud2024highriskneuroblastomachallenges pages 2-3).
Cell type involvement (CL terms) - CL:0000542 (neuron, sympathoadrenal lineage derivatives—tumor of neural crest origin); CL:0000798 (macrophage), CL:0000815 (T cell), CL:0000623 (natural killer cell)—constitute the immune TME implicated in immune evasion (URL: https://doi.org/10.3390/jcm13164765) (persaud2024highriskneuroblastomachallenges pages 2-3).
Anatomical locations (UBERON terms) - UBERON:0002369 (adrenal medulla), UBERON:0001043 (sympathetic trunk), UBERON:0000178 (bone marrow) as sites of origin/metastasis with characteristic microenvironmental programs (URL: https://doi.org/10.3390/jcm13164765) (persaud2024highriskneuroblastomachallenges pages 2-3).
Chemical entities (CHEBI) - Anti-GD2 antibody therapeutics (biologic drugs targeting disialoganglioside GD2) widely implemented in HR-NB; TME features modulate efficacy (URL: https://doi.org/10.3390/jcm13164765) (persaud2024highriskneuroblastomachallenges pages 2-3).
Evidence items (PMID/DOI/URLs; publication dates) - Persaud et al., Journal of Clinical Medicine, “High-Risk Neuroblastoma Challenges and Opportunities for Antibody-Based Cellular Immunotherapy.” Aug 2024. URL: https://doi.org/10.3390/jcm13164765 (persaud2024highriskneuroblastomachallenges pages 2-3). - Burkert et al., iScience, “Copy-number dosage regulates telomere maintenance and disease-associated pathways in neuroblastoma.” Aug 2024. URL: https://doi.org/10.1101/2022.08.16.504100 (burkert2024copynumberdosageregulates pages 18-24). - Thirant et al., Nature Communications, “Reversible transitions between noradrenergic and mesenchymal tumor identities define cell plasticity in neuroblastoma.” May 2023. URL: https://doi.org/10.1038/s41467-023-38239-5 (thirant2023reversibletransitionsbetween pages 1-2). - Xu et al., The EMBO Journal, “Targeting SWI/SNF ATPases reduces neuroblastoma cell plasticity.” Aug 2024. URL: https://doi.org/10.1038/s44318-024-00206-1 (xu2024targetingswisnfatpases pages 1-2). - Wang et al., Frontiers in Immunology, “Emerging frontiers in epigenetic-targeted therapeutics for pediatric neuroblastoma.” Jul 2025. URL: https://doi.org/10.3389/fimmu.2025.1637626 (wang2025emergingfrontiersin pages 1-2, wang2025emergingfrontiersin pages 6-7). - He et al., Oncogene, “Dissecting neuroblastoma heterogeneity through single-cell multi-omics: insights into development, immunity, and therapeutic resistance.” Nov 2025. URL: https://doi.org/10.1038/s41388-025-03635-2 (he2025dissectingneuroblastomaheterogeneity pages 6-7). - D’Amico et al., Frontiers in Immunology, “Combining immunotherapy with chemotherapy to defeat neuroblastoma by targeting adrenergic-mesenchymal plasticity.” Oct 2023. URL: https://doi.org/10.3389/fimmu.2023.1268645 (d’amico2023twobulletsin pages 6-7).
Notes on evidence scope and limitations - The core mechanistic claims above are supported by recent high-quality primary studies (Nature Communications 2023; EMBO Journal 2024) and integrative analyses (iScience 2024). Where comprehensive clinical statistics (incidence/survival trends) would usually be drawn from national registries, the present synthesis cites a 2024 clinical immunotherapy review for high-risk survival context because those were among the most relevant sources in the retrieved set (persaud2024highriskneuroblastomachallenges pages 2-3). Additional registry-based epidemiology could further refine survival estimates but was outside the current evidence set.
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