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Genomic evolution of exonic variants
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.
There are limited data regarding the genomic evolution of exonic variants from diagnosis to relapse for neuroblastoma. Whole-genome sequencing was applied to 23 paired diagnostic and relapsed neuroblastoma tumor samples to define somatic genetic alterations associated with relapse,[46] while a second study evaluated 16 paired diagnostic and relapsed specimens.[47] Both studies identified an increased number of variants in the relapsed samples compared with the samples at diagnosis. This has been confirmed in a study of neuroblastoma tumor samples sent for NGS.[48]
In the first study, an increased incidence of variants in genes associated with RAS-MAPK signaling was found in tumors at relapse compared with tumors from the same patient at diagnosis; 15 of 23 relapse samples contained somatic variants in genes involved in this pathway, and each variant was consistent with pathway activation.[46] In addition, three relapse samples showed structural alterations involving MAPK pathway genes consistent with pathway activation, so aberrations in this pathway were detected in 18 of 23 (78%) relapse samples. Aberrations were found in ALK (n = 10), NF1 (n = 2), and one each in NRAS, KRAS, HRAS, BRAF, PTPN11, and FGFR1. Even with deep sequencing, 7 of the 18 alterations were not detectable in the primary tumor, highlighting the evolution of variants presumably leading to relapse and the importance of genomic evaluations of tissues obtained at relapse.
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In the second study, ALK variants were not observed in either diagnostic or relapse specimens, but relapse-specific recurrent single-nucleotide variants were observed in 11 genes, including the putative CHD5 neuroblastoma tumor suppressor gene located at chromosome 1p36.[47]
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A third retrospective variant-sequencing study used data from Foundation Medicine to compare tumor samples from patients with newly diagnosed neuroblastoma with tumor samples from patients with refractory and relapsed neuroblastoma. The study found a higher percentage of variants that were targetable with current drugs in the relapsed and refractory group.[48]
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A fourth study evaluated the frequency of ALK alterations at diagnosis and relapse. There were significantly higher rates of ALK variants at relapse than at diagnosis (17.7% at relapse vs. 10.5% at diagnosis). The rate of ALK amplifications did not differ between diagnosis and relapse.[49]
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Given the widespread metastatic nature of high-risk and relapsed neuroblastoma, use of circulating tumor DNA (ctDNA) technologies may reveal additional genomic alterations not found in conventional tumor biopsies. Moreover, these approaches have demonstrated the ability to detect resistant variants in patients with neuroblastoma who were treated with ALK inhibitors.[50][Level of evidence C1] In one analysis of serial ctDNA samples from patients treated with lorlatinib, ALK VAF tracked with disease burden in most but not all patients.[51] In subsets of patients who progressed while taking lorlatinib, second compound variants in ALK or variants in other genes, including RAS pathway genes and TP53, have been reported.[51,52]
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In a deep-sequencing study, 276 neuroblastoma samples (comprised of all stages and from patients of all ages at diagnosis) underwent very deep (33,000X) sequencing of just two amplified ALK variant hot spots, which revealed 4.8% clonal variants and an additional 5% subclonal variants. This finding suggests that subclonal ALK gene variants are common.[53] Thus, deep sequencing can reveal the presence of variants in tiny subsets of neuroblastoma tumor cells that may be able to survive during treatment and grow to constitute a relapse.
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