Genomic Profiling of High-Risk Pediatric Tumors Reveals Actionable Alterations in Nearly One-Quarter of Patients
核心洞察
A retrospective analysis of 97 high-risk/hard-to-treat pediatric cancer (搜索) patients at Sheba Medical Center (2016–2021) identified 386 variants, with TP53 (搜索) and ATM (搜索) as the most frequently mutated genes.
Nearly one in four patients (23.7%) received therapeutic or monitoring recommendations based on NGS results, and 70% of those treated with precision medicine in the first line required no additional therapy.
Seven of the 17 most prevalent variants were actionable, including ATM (搜索) p.P604S (Olaparib), EWSR1-FLI1 fusion (TK216), and TP53 (搜索) p.G245S (MDM2 inhibitor AMGMDS3 (搜索)).
A retrospective analysis of next-generation sequencing (NGS) data from 97 high-risk and hard-to-treat pediatric cancer (搜索) patients at Sheba Medical Center has characterized the genetic landscape of childhood tumors in Israel, revealing actionable genomic alterations that expanded treatment options for nearly one in four patients. The study, published in Pediatric Research by Cohen, Kventsel, Caspi and colleagues, examined cases referred for advanced genetic testing between 2016 and 2021, a cohort representing 8.6% of all oncologic patients admitted or consulted in the Hemato-oncology unit during that period.
The cohort comprised 46% female and 54% male patients (a male-to-female ratio of 1.17), with ages ranging from 2 days to 23 years and 15% diagnosed before age 2. The largest proportion (37.8%) of patients were between 3 and 10 years old. The patient population was heterogeneous, encompassing solid tumors (49%), central nervous system (CNS) tumors (30%), hematological malignancies (4%), benign tumors (9%), and carcinomas (8%).
A Heterogeneous Mutational Landscape
Across the cohort, 386 variants were identified. Ten genes demonstrated recurrent alterations, each observed in eight or more cases. TP53 (搜索) was the most frequently mutated gene, with 32 distinct variants detected across 19 different tumor types, including single nucleotide variants (SNVs) and fusions, six of which were classified as pathogenic or likely pathogenic. ATM (搜索) was the second most frequently mutated gene, with 23 distinct variants across 15 tumor types, primarily SNVs with a few frame-shift pathogenic variants. Both ATM and TP53 were mutated in 34 tumors.
Other recurrently altered genes included TSC2, KMT2D, NOTCH1, ARID2, SETD2, APC, BRCA2, and MYC, each appearing more than eight times. The authors noted two exceptions among these genes: ARID2 and SETD2, which are known to play a role in adult cancer but had not been studied in childhood cancer until recently.
Pathway enrichment analysis using the DAVID tool and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database revealed significant overrepresentation of pathways related to cell cycle regulation, kinase activity, MAPK signaling, cytokine-mediated signaling, regulation of cell proliferation and gene expression, and p53-mediated signal transduction. Of the 62 recurrently mutated genes, 22 were found to be involved in key cancer pathways, including AKT, APC, BRAF, GNAS, HRAS, MDM2, MYC, CSF1R, CCNE1, CDK4, CDK6, FGFR1, IL6ST, MSH2, NOTCH1, PTEN, PIK3CA, RET, RUNX1T1, TGFBR2, TP53 (搜索), and TRAF3.
Actionable Alterations and Precision Medicine Impact
Among the 97-patient cohort, 23 patients (23.7%) received therapeutic interventions or monitoring recommendations based on genetic profiling results. Of the 17 most prevalent variants in the cohort, seven were considered actionable genomic alterations—variants associated with targeted anti-cancer therapies that are either approved or under investigation in active registered clinical trials. These included Olaparib for ATM (搜索) p.P604S; kinase inhibitors, CDK2 inhibitors, or AURKA inhibitors for CCNE1 overexpression; TK216 for the EWSR1-FLI1 fusion; immune checkpoint inhibitors for germline MSH; BET inhibitors for MYCN amplification; micro-RNA-based molecules (GSK2636771, AZD8186) for PTEN deletion; and the MDM2 inhibitor AMGMDS3 (搜索) for TP53 (搜索) p.G245S.
To assess the impact of precision medicine (PM) on treatment outcomes, the researchers compared the duration of effective treatment between PM and conventional therapies. For each patient receiving PM as a subsequent line of treatment, they calculated the ratio of the best PM treatment duration to the best conventional treatment duration, using a ratio of 0.67 as the threshold for equivalence to conventional therapy.
Out of 10 patients who received PM treatment as a first line of therapy, 7 (70%) did not require any additional treatment and were therefore considered to benefit from treatment. The authors cautioned that this notably high success rate likely reflects several factors, including favorable tumor biology in patients harboring highly actionable driver mutations (such as BRAF V600E in pilocytic astrocytoma and ALK rearrangement in juvenile xanthogranuloma), the inclusion of locally aggressive but histologically benign tumors, and variable follow-up durations.
Population-Specific Mutational Signatures
The study identified potential population-specific mutations within the Israeli pediatric population. One patient (PMS-055) diagnosed with acute lymphoblastic leukemia (搜索) (ALL) exhibited a distinct pathogenic variant profile, with seven uniquely mutated genes (CPS1, FLT1, HDAC7, MAP3K6, PC, POT1, TSHR) that were not reported as common in a larger cohort of 950 ALL patients studied by Ma et al.
Similarly, in osteosarcoma (搜索) patients, of the 15 genes listed in the Ma et al. cohort (89 patients), 10 genes (PTEN, ATRX, ASXL1, CREBBP, SETD2, BCOR, MGA, NIPBL, STAG2, CDKN2A) were not found in the Israeli osteosarcoma patients. When comparing Ewing sarcoma (搜索) samples to 107 Ewing sarcoma tumor samples in PedcBioPortal, the researchers identified 27 uniquely mutated genes, including EWSR1, MSI, MSH6, TGFBR2, and TSHR.
These findings raise the possibility of population-specific mutations reflecting unique genetic backgrounds, founder effects, or environmental influences. The authors emphasized that such differences "highlight the importance of including diverse populations in genomic studies to ensure that precision medicine approaches are equitable and broadly applicable."
The Evolving Nature of Variant Interpretation
The study also underscored the dynamic nature of genomic interpretation. When the pathogenicity status of variants occurring more than once in the cohort (n = 62) was re-evaluated, a change in status was detected in 21 variants. Eighteen variants of unknown significance changed to pathogenic (n = 3), likely benign (n = 10), or benign (n = 4), while three variants changed from likely benign to likely pathogenic, benign, or VUS.
A notable example involved a PALB2 (搜索) mutation (p.P864S) identified in patient PMS-057, who was diagnosed with optic glioma (搜索) in June 2015. At the time of NGS, the variant was classified as "likely benign." However, recent literature suggests that mutated PALB2 should be considered pathogenic specifically in high-grade glioma and is potentially actionable—for example, with Niraparib, a PARP inhibitor that has shown significantly improved survival in patients with newly diagnosed glioblastoma in a phase 2 study and is currently being investigated in a phase 3 study (Gliofocus Study, NCT06388733, Ivy Brain Tumor Center, 2025).
Clinical Implications and Study Limitations
The authors concluded that the finding that nearly one-quarter of patients benefited from NGS-informed treatment supports "the routine implementation of NGS early in the treatment course, rather than reserving it solely for patients who have exhausted standard therapeutic options." They also noted that identification of a pathogenic finding in a cancer predisposition gene on a somatic panel constitutes a criterion for referral to germline testing, which may reveal a cancer predisposition syndrome, help adjust treatment, initiate surveillance, and prompt cascade screening in family members.
The study has several acknowledged limitations. The retrospective design and use of multiple NGS platforms with varying gene coverage limits direct comparison across patients. For 13 patients, the specific platform used was not documented. The inclusion of both malignant and clinically aggressive benign tumors introduces heterogeneity, and treatment duration was used as a surrogate for time to progression, which may not fully capture clinical benefit.
The researchers emphasized that future studies should expand the cohort size and include long-term follow-up to better assess the impact of NGS-informed therapies on clinical outcomes, and that collaborative efforts across institutions in Israel and internationally will be essential to validate variant interpretations, identify rare actionable mutations, and support the development of targeted therapies suitable for children.