Table 2.

Summary of potentially actionable genomic alterations in neuroblastoma.

Clinically Actionable Pathway/Gene	Prevalence at diagnosis	Prevalence at relapse	Biomarker	Therapeutic Strategy	Level of evidence
ALK#
Mutation/Focal amplification	8-14%39-42, 122	26-43%89, 91	ALK mutation/amplification	ALK inhibition35, 38	1
RAS-MAPK Pathway#
PTPN11	*Rare40, 122	#Rare91	RAS-MAPK pathway mutation	MEK inhibition91	2
FGFR1	”	”		”	2
BRAF	”	”	”	”	2
NRAS	”	”	”	”	2
KRAS	”	”	”	”	2
HRAS	-	”	”	”	2
NF1	Rare40	9%91	”	”	2
Cell Cycle Control
CDK4/6 amplification	4%109	-	MYCN amplification100-101	CDK4/6 Inhibition100-101	2
Cyclin D1 amplification	2-15%104, 109	-	”	”	2
CDKN2A deletion	0-20%109-110, 123	13-22%91, 110	”	”	2
DNA Damage Pathway
TP53	1-8%40, 110, 123	15%110	TP53 mutation	Unknown	3
MDM2 amplification	13%110	13%110	MDM2 amplification	MDM2 inhibition124-126	2
Transcriptional Control
MYCN amplification	16-38%10-11, 17	-	MYCN amplification/mutation	BET inhibition75-76	2
MYCN mutation	Rare40	-	”	”	2
Chromatin Modification
ATRX deletion/mutation	9-22%40, 42	17%91	ATRX deletion/mutation	Unknown	3
ARID1A/ARID1B deletion/mutation	11%39	Rare91	ARID1A/B deletion/mutation	”	3

^*Rare = <5%

^#Taken together, activating RAS-MAPK pathway aberrations occur in approximately 80% of relapsed neuroblastomas.⁹¹ Level of evidence 1 = clinical evidence of efficacy in neuroblastoma, 2 = extensive preclinical studies with efficacy in neurobastoma, 3 = preliminary preclinical mechanistic studies in neuroblastoma/other malignancy.

Clinically actionable somatic mutations in neuroblastoma tumors at the time of diagnosis are rare. Clonally derived driver alterations in targetable oncogenic pathways occur more commonly in the relapsed neuroblastoma genome. Many of these potentially clinically actionable genes/pathways have identifiable biomarkers and potential therapeutic strategies with varying degrees of supporting evidence as indicated.