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Exonic variants in neuroblastoma (including ALK variants and amplification)
Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.
Source updated: April 30, 2025 · Captured 2026-09-09.
Selected source text with whitespace normalised. This Triangle page is not an NCI PDQ summary. Independent clinical review is pending.
Context: Neuroblastoma / Molecular features of neuroblastoma
Compared with adult cancers, pediatric neuroblastoma tumors show a low number of variants per genome that affect protein sequence (10–20 per genome).[39] The most common gene variant is ALK, which is altered in approximately 10% of patients (see below). Other genes with even lower frequencies of variants include ATRX, PTPN11, ARID1A, and ARID1B.[26,27,30,40-43] As shown in Figure 9, most neuroblastoma cases lack variants in genes that are altered in a recurrent manner.
The ALK gene provides instructions for making a cell surface receptor tyrosine kinase, expressed at significant levels only in developing embryonic and neonatal brains. ALK is the exonic variant found most commonly in neuroblastoma. Germline pathogenic variants in ALK have been identified as the major cause of hereditary neuroblastoma. Somatically acquired ALK-activating exonic variants are also found as oncogenic drivers in neuroblastoma.[42]
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Two large cohort studies examined the clinical correlates and prognostic significance of ALK alterations. One study from the COG examined ALK status in 1,596 diagnostic neuroblastoma samples across all risk groups.[42] Another study from SIOPEN evaluated 1,092 patients with high-risk neuroblastoma.[44]
ALK tyrosine kinase domain variants occurred primarily at three hot spots (F1174, R1275, and F1245 positions), with 10% to 15% of variants occurring at other kinase domain positions.
In the COG cohort, the frequency of ALK variants was 10% in the high-risk neuroblastoma group, 8% in the intermediate-risk neuroblastoma group, and 6% in the low-risk neuroblastoma group.
In the SIOPEN high-risk population, ALK variants were divided into clonal (>20% variant allele frequency [VAF]) and subclonal (0.1%–20% VAF). Clonal ALK variants were detected in 10% of cases, and subclonal variants were found in 3.9% of patients. A total of 13.9% of the cases had an ALK variant.
ALK variants were found at higher rates in patients with MYCN-amplified tumors compared with those without MYCN amplification: 10.9% versus 7.2%, respectively, for the COG cohort and 14% versus 6.5%, respectively, for the SIOPEN cohort (for clonal ALK variants).
For patients with high-risk neuroblastoma, the ALK amplification was observed in approximately 4% of cases in both the COG and the SIOPEN cohorts. ALK amplification occurred almost exclusively in cases that also had MYCN amplification.
ALK alterations were associated with inferior prognoses for patients with high-risk neuroblastoma in both the COG and the SIOPEN studies:
ALK alterations were associated with inferior prognoses for patients with high-risk neuroblastoma in both the COG and the SIOPEN studies:
In the SIOPEN cohort, a statistically significant difference in OS was observed between cases with ALK amplification (ALKa) or clonal ALK variant (ALKm) versus subclonal ALKm or no ALK alterations (5-year OS rate: ALKa, 26% [95% CI, 10%–47%]; clonal ALKm, 33% [95% CI, 21%–44%]; subclonal ALKm, 48% [95% CI, 26%–67%]; and no alteration, 51% [95% CI, 46%–55%], respectively; P = .001). In a multivariate model, ALK amplification (HR, 2.38; P = .004) and clonal ALK variant (HR, 1.77; P = .001) were independent predictors of poor outcome.
ALK alterations were associated with inferior prognoses for patients with high-risk neuroblastoma in both the COG and the SIOPEN studies:
In the COG high-risk neuroblastoma population, inferior prognoses, similar to those seen in the SIOPEN cohort, were observed for cases with ALK variants and ALK amplifications.
In a study that compared the genomic data of primary diagnostic neuroblastomas originating in the adrenal gland (n = 646) with that of neuroblastomas originating in the thoracic sympathetic ganglia (n = 118), 16% of thoracic tumors harbored ALK variants.[45]
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Small-molecule ALK kinase inhibitors such as lorlatinib (added to conventional therapy) are being tested in patients with recurrent ALK-altered neuroblastoma (NCT03107988) and in patients with newly diagnosed high-risk neuroblastoma with activated ALK (COG ANBL1531).[42] For more information, see the sections on Treatment of High-Risk Neuroblastoma and Treatment of Recurrent or Refractory Neuroblastoma in Neuroblastoma Treatment.
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