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PubMed2026

Parental Perspectives and Experiences with Genetic Testing and Surveillance for Cancer Predisposition in Healthy Young Children.

OBJECTIVES: To evaluate parental experiences following diagnosis of a cancer predisposition syndrome (CPS) in childhood and to assess parental perspectives on population-based genomic newborn screening (gNBS) for CPS. STUDY DESIGN: Participants were guardians of children diagnosed with a CPS by age 8, for whom cancer surveillance was recommended, and who had no history of cancer before the CPS diagnosis. Participants completed a demographic survey, genetic knowledge assessment, and a semistructured qualitative interview. Thematic analysis was performed on interview transcripts. Clinical data were abstracted from medical records. RESULTS: We enrolled 25 parents of children with 7 different CPS, including Li-Fraumeni syndrome (43%), familial adenomatous polyposis (14%), nevoid basal cell carcinoma syndrome (11%), and Beckwith-Wiedemann syndrome (11%). Parents characterized receiving a CPS diagnosis as emotionally challenging but also felt empowered by engagement in proactive cancer surveillance. They identified logistical, emotional, physical, and financial burdens of surveillance; however, most perceived that these burdens were outweighed by the medical and emotional advantages. The majority endorsed implementation of gNBS for pediatric cancer risk. CONCLUSIONS: Parents of presymptomatic children with a CPS experience both psychological distress and benefits following a genetic diagnosis. Despite the burdens of surveillance, parents express support for early genomic identification of cancer risk. These findings have implications for the care of children with CPS and inform implementation of population-based gNBS for CPS.

Humans↗

PubMed2026

A PMS2-deficient pediatric high-grade glioma with PI3K-pathway mutations and adjacent developmental venous anomaly suggestive of CMMRD.

PURPOSE: Constitutional mismatch repair deficiency (CMMRD) is a rare hereditary cancer predisposition syndrome that frequently manifests with pediatric high-grade gliomas. However, recognition remains challenging, particularly in the absence of a clear family history. We report a pediatric high-grade glioma with PMS2 deficiency and complex molecular alterations to highlight key diagnostic clues and the importance of routine mismatch repair assessment. METHODS: Clinical, radiological, histopathological, immunohistochemical, and molecular findings of an 8-year-old girl presenting with a high-grade glioma were retrospectively evaluated. Immunohistochemistry included glial and mismatch repair markers. Targeted next-generation sequencing was performed to assess tumor mutational burden and pathogenic variants. RESULTS: Neuroimaging revealed a right frontoparietal mass associated with an adjacent developmental venous anomaly. Histopathology demonstrated a diffuse pediatric-type high-grade glioma with pseudopapillary architecture and marked mitotic activity. Immunohistochemistry showed diffuse p53 overexpression in tumor cells and complete loss of PMS2 expression in both tumor and non-neoplastic cells, supporting constitutional mismatch repair deficiency. Molecular analysis revealed an ultra-hypermutated profile with a tumor mutational burden of 117.4 mutations/Mb, a pathogenic PMS2 frameshift variant, and co-occurring alterations in TP53, PIK3CA, PIK3R1, and PTEN. The presence of PI3K-pathway mutations alongside a venous anomaly suggested a potential biological association. CONCLUSION: This case illustrates the characteristic clinicopathological and molecular features of CMMRD-associated pediatric high-grade glioma and underscores the critical role of routine mismatch repair immunohistochemistry. Integrated histological and genomic evaluation is essential for accurate diagnosis, appropriate genetic counseling, and potential therapeutic implications. Key Points • This case represents a pediatric high-grade glioma arising in the setting of PMS2-related constitutional mismatch repair deficiency (CMMRD). • The tumor exhibited an ultra-hypermutated profile with co-occurring TP53, PIK3CA, PIK3R1, and PTEN mutations. • Loss of PMS2 expression in both tumor and non-neoplastic cells was critical in establishing the diagnosis of CMMRD. • The presence of a developmental venous anomaly may relate to underlying PIK3R1 pathway alterations. • Routine mismatch repair immunohistochemistry is essential in pediatric high-grade gliomas, even in the absence of a family history.

Humans↗

PubMed2019

Pediatric Cancer Variant Pathogenicity Information Exchange (PeCanPIE): a cloud-based platform for curating and classifying germline variants.

Variant interpretation in the era of massively parallel sequencing is challenging. Although many resources and guidelines are available to assist with this task, few integrated end-to-end tools exist. Here, we present the Pediatric Cancer Variant Pathogenicity Information Exchange (PeCanPIE), a web- and cloud-based platform for annotation, identification, and classification of variations in known or putative disease genes. Starting from a set of variants in variant call format (VCF), variants are annotated, ranked by putative pathogenicity, and presented for formal classification using a decision-support interface based on published guidelines from the American College of Medical Genetics and Genomics (ACMG). The system can accept files containing millions of variants and handle single-nucleotide variants (SNVs), simple insertions/deletions (indels), multiple-nucleotide variants (MNVs), and complex substitutions. PeCanPIE has been applied to classify variant pathogenicity in cancer predisposition genes in two large-scale investigations involving >4000 pediatric cancer patients and serves as a repository for the expert-reviewed results. PeCanPIE was originally developed for pediatric cancer but can be easily extended for use for nonpediatric cancers and noncancer genetic diseases. Although PeCanPIE's web-based interface was designed to be accessible to non-bioinformaticians, its back-end pipelines may also be run independently on the cloud, facilitating direct integration and broader adoption. PeCanPIE is publicly available and free for research use.

Child↗

PubMed2024

Genomes for Nurses: Understanding and Overcoming Barriers to Nurses Utilizing Genomics.

Background: Genomic testing is an increasingly important technology within pediatric oncology that aids in cancer diagnosis, provides prognostic information, identifies therapeutic targets, and reveals underlying cancer predisposition. However, nurses lack basic knowledge of genomics and have limited self-assurance in using genomic information in their daily practice. This single-institution project was carried out at an academic pediatric cancer hospital in the United States with the aim to explore the barriers to achieving genomics literacy for pediatric oncology nurses. Method: This project assessed barriers to genomic education and preferences for receiving genomics education among pediatric oncology nurses, nurse practitioners, and physician assistants. An electronic survey with demographic questions and 15 genetics-focused questions was developed. The final survey instrument consisted of nine sections and was pilot-tested prior to administration. Data were analyzed using a ranking strategy, and five focus groups were conducted to capture more-nuanced information. The focus group sessions lasted 40 min to 1 hour and were recorded and transcribed. Results: Over 50% of respondents were uncomfortable with or felt unprepared to answer questions from patients and/or family members about genomics. This unease ranked as the top barrier to using genomic information in clinical practice. Discussion: These results reveal that most nurses require additional education to facilitate an understanding of genomics. This project lays the foundation to guide the development of a pediatric cancer genomics curriculum, which will enable the incorporation of genomics into nursing practice.

Humans↗

PubMed2026

Human-AI Interaction With AI-Assisted Tumor Overlays in Pediatric Whole-Body Magnetic Resonance Imaging: Exploratory Reader Study.

BACKGROUND: AI tools have the potential to enhance personalized clinical care, particularly in radiology. However, their integration into clinical workflows remains complex, especially in pediatric oncology, where early cancer detection is critical. Children with Li-Fraumeni syndrome (LFS), a rare cancer predisposition disorder, undergo regular surveillance whole-body magnetic resonance imaging (wbMRI), which presents an opportunity for AI-assisted tumor detection. OBJECTIVE: We evaluated the feasibility of an AI-assisted overlay for highlighting tumor-like regions in pediatric surveillance wbMRI and explored how access to the overlay influenced radiologist workflow, candidate-lesion marking behavior, follow-up recommendations, and perceived workload. METHODS: We developed a patch-based AI segmentation model trained on augmented 2D slices from 675 surveillance wbMRI volumes of pediatric patients with LFS. The model was designed to highlight regions with high tumor probability. A reader study was conducted with 2 radiologists who independently reviewed wbMRI cases both with and without AI assistance. We measured evaluation time, number and location of reader-marked candidate lesions, type of follow-up recommendation, and subjective feedback using structured questionnaires. RESULTS: AI assistance altered interpretation workflows for both radiologists, with mixed effects. On average, the time required to evaluate each case increased when using the AI tool for both radiologists. However, one radiologist had an increase in the number of candidate lesion locations selected with the tool, and one had a decrease in the number of candidate lesion locations selected with the tool. Subjective feedback indicated that one of the radiologists reported lower mental demand with the AI tool, while both radiologists reported lower stress with the AI tool. Interrater variability was evident, underscoring the need for personalized calibration of AI tools. CONCLUSIONS: AI-assisted wbMRI interpretation can improve tumor detection in pediatric cancer surveillance by reducing false negatives. However, its influence on workflow efficiency and interradiologist variability highlights the importance of careful implementation. Successful integration requires addressing challenges such as improving the predictive precision of AI models, offering intuitive end-user designs and instructions, and building trust in AI outputs. AI outputs can influence workflow and behavior in reader-specific ways. Clinical translation will require larger, randomized, multireader studies and model refinement to reduce false positives and quantify lesion-level reader performance. This can help ensure better patient outcomes in addition to reduced clinician burnout.

Humans↗

PubMed2026

Novel Germline ELP1 Splice-Acceptor Variant in NF1-Negative Optic Pathway Glioma: Expanding the Clinical Spectrum Associated With ELP1 Variation.

We report a 7-year-old boy with NF1-negative optic pathway glioma harboring a novel germline ELP1 splice-acceptor variant (NM_003640.5:c.2205-2A>G) identified by whole-exome sequencing. The variant was likely pathogenic (ACMG/AMP: PVS1, PM2) and inherited from an asymptomatic father, consistent with incomplete penetrance, expanding the limited evidence linking germline ELP1 variation to gliomas.

Humans↗

PubMed2026

Establishing a Multicenter Personalized Medicine Program in Childhood, Adolescent, and Young Adult Cancer in Spain: The SEHOP-PENCIL Project.

Pediatric cancer care in Spain lacked a national personalized medicine program. The SEHOP-PENCIL initiative, established by the SEHOP, was designed to address this gap. A national survey identified the genomic sequencing needs of hospitals treating pediatric patients with cancer. Results showed improved access to targeted next-generation sequencing panels but revealed persistent variability in implementation, limited availability of advanced sequencing (whole-exome sequencing, whole-genome sequencing, RNA sequencing, and DNA methylation profiling), and gaps in cancer predisposition clinics and molecular tumor boards (MTBs). SEHOP-PENCIL is organized as a network of 10 specialized genomic centers serving 45 hospitals through a centralized inclusion system. The program standardizes patient eligibility, genomic workflows, and result interpretation, supported by a national MTB. This framework enables informed clinical decision making, ensures access to molecular diagnosis and innovative therapies, and supports systematic data collection to advance pediatric cancer research and personalized care. SEHOP-PENCIL represents a pioneering national model for integrating precision oncology into pediatric cancer care in Spain. By fostering collaboration, standardizing genomic practices, and promoting equitable access, it aims to reduce disparities and improve outcomes, offering a scalable example for other decentralized health care systems.

Humans↗

PubMed2024

Adult-Onset Cancer Predisposition Syndromes in Children and Adolescents-To Test or not to Test?

With the increasing use of comprehensive germline genetic testing of children and adolescents with cancer, it has become evident that pathogenic variants (PV) in adult-onset cancer predisposition genes (aoCPG) underlying adult-onset cancer predisposition syndromes, such as Lynch syndrome or hereditary breast and ovarian cancer, are enriched and reported in 1% to 2% of children and adolescents with cancer. However, the causal relationship between PVs in aoCPGs and childhood cancer is still under investigation. The best-studied examples include heterozygous PVs in mismatch repair genes associated with Lynch syndrome in children with mismatch repair deficient high-grade glioma, heterozygous PVs in BARD1 in childhood neuroblastoma, and heterozygous PVs in BRCA2 in children with rhabdomyosarcoma. The low penetrance for pediatric cancers is considered to result from a combination of the low baseline risk of cancer in childhood and the report of only a modest relative risk of disease in childhood. Therefore, we do not advise that healthy children empirically be tested for PVs in an aoCPG before adulthood outside a research study. However, germline panel testing is increasingly being performed in children and adolescents with cancer, and exome and genome sequencing may be offered more commonly in this population in the future. The precise pediatric cancer risks and spectra associated with PVs in aoCPGs, underlying cellular mechanisms and somatic mutational signatures, as well as treatment response, second neoplasm risks, and psycho-oncological aspects require further research.

Adolescent↗

PubMed2026

T-rex: standardized analysis of germline variants in whole-exome sequencing trios.

Whole-exome sequencing (WES) enables the identification of rare germline variants contributing to pediatric diseases. Trio-based sequencing, comparing affected children with their parents, is particularly effective for rare disease genetics. However, WES data analysis requires bioinformatics expertise, varies across institutions, and is often incompatible with clinical workflows. We developed T-Rex (Trio Rare variant analysis of EXomes), a cross-platform desktop application that enables the standardized and local analysis of WES germline Trio data without the need for programming knowledge. T-Rex integrates state-of-the-art tools for alignment, dual-variant calling (GATK HaplotypeCaller + VarScan2), annotation (SNPEff/SNPSift), rare-variant filtering based on population frequencies (gnomAD), and family-based statistical testing, including the Transmission Disequilibrium Test with multiple-testing correction. Benchmarking of the dual-caller strategy on the Genome in a Bottle Ashkenazim Trio demonstrates high precision (99.2%) while maintaining robust sensitivity (91.1%). User testing (n = 13) confirmed quick learning across clinicians and researchers. Application to a cohort of n = 121 pediatric cancer Trio datasets, filtering for rare protein-coding variants (MAF ≤ 0.1% in gnomAD v4.1), validated all assessable previously reported pathogenic variants. Overall, T-Rex enables clinicians to robustly analyze WES Trio data in compliance with data protection regulations without requiring additional software licenses. As one of the first platforms for comprehensive WES Trio analysis that requires no programming expertise while providing reproducible, end-to-end workflows for clinical genomics, T-Rex facilitates collaborative research between clinics and reduces reliance on external providers.

Humans↗

PubMed2026

Harnessing Polygenic Risk Scores to Refine Venous Thromboembolism Risk Stratification.

BACKGROUND: Venous thromboembolism (VTE) is a major cause of morbidity in patients of all ages. Despite growing interest in polygenic risk scores (PRS) for VTE, their utility remains understudied. Our objective was to evaluate the independent impact of a PRS on VTE susceptibility in adults and children. METHODS: We completed a retrospective, case-control study of two separate cohorts with evaluation of three VTE PRS models, with the primary analysis focused on a 293 single nucleotide polymorphism (SNP) PRS. The adult cohort included 597 VTE cases and 31 998 controls, and the pediatric cohort included 109 cases and 448 controls, both obtained from a de-identified databank with linked genetic data. Separate adult and pediatric multivariable logistic regressions were performed to measure the association of risk factors with VTE. RESULTS: Higher PRS in adults was significantly associated with increased odds of VTE, with each 1-standard deviation increase in PRS conferring an adjusted odds ratio of 1.25 (OR = 1.25, 95% CI 1.15-1.36, p < 0.001). Leading risk factors for adults were cancer (OR = 2.43, 95% CI: 2.04-2.89, p < 0.001) and recent surgery (OR = 2.16, 95% CI: 1.83-2.54, p < 0.001). The standardized PRS also exhibited increased risk for VTE in children (OR = 1.38, 95% CI 1.10-1.74, p = 0.003). Central venous catheterization (OR = 5.65, 95% CI 3.40-9.50, p < 0.001) was the foremost risk factor for pediatric VTE. CONCLUSION: VTE in adults and children is multifactorial, with clinical and genome-wide risk factors contributing. PRS may serve as a valuable adjunct to clinical risk factors for VTE risk stratification.

Humans↗

PubMed2026

Genetic variants in IGF2BP family genes are associated with glioma risk in Chinese children.

BACKGROUND: Glioma is a highly prevalent malignant tumor of the central nervous system in children and is driven by complex genetic and environmental factors. IGF2BP family genes (IGF2BP1, IGF2BP2, and IGF2BP3) encode critical RNA epigenetic "readers" that participate in posttranscriptional gene regulation and modulate various cellular processes. However, the contributions of these gene variants to glioma risk remain unclear. METHODS: A multicenter case-control study was conducted, enrolling 360 patients with glioma and 547 cancer-free controls. Genotyping of 11 potentially functional polymorphisms within IGF2BP family genes was performed using the TaqMan assay. Unconditional logistic regression models were employed to estimate odds ratios and 95% confidence intervals. Furthermore, expression quantitative trait loci (eQTL) and The Cancer Genome Atlas (TCGA) clinical database analyses were conducted to investigate the potential regulatory mechanisms and clinical significance of the identified variants. RESULTS: We found that the IGF2BP1 rs2270575 polymorphism was significantly associated with a decreased risk of glioma. Conversely, the IGF2BP2 rs17289925 and rs7646419 polymorphisms were linked to increased glioma risk. Stratification and cumulative effect analyses revealed that harboring multiple risk genotypes of IGF2BP1 or IGF2BP2 substantially increased glioma susceptibility. This cumulative risk was especially notable among males, younger children (< 60 months), and patients diagnosed with early-stage (I + II) tumors. Additionally, eQTL and TCGA analyses revealed that the rs2270575 and rs7646419 alleles correlated significantly with altered mRNA expression levels of CALCOCO2 and AC099661.1 (ENSG00000286086), respectively, which further correlated with favorable molecular subtypes (IDH mutation status) and WHO tumor grades. CONCLUSION: Genetic polymorphisms within IGF2BP family genes significantly modulate pediatric glioma susceptibility and have cumulative, subtype-specific, and age-dependent effects; thus, these genes may serve as promising noninvasive biomarkers for early risk stratification of childhood glioma.

Adolescent↗

PubMed2026

Solid tumours in RASopathies: insights from a large monocentric cohort and systematic review of the literature.

BACKGROUND: Dysregulation of the RAS-mitogen-activated protein kinase signalling pathway underlies RASopathies, a family of neurodevelopmental disorders associated with variable cancer predisposition. However, the prevalence and spectrum of solid tumours and the contribution of specific variants to tumour susceptibility remain poorly defined. METHODS: We assessed solid tumour prevalence and spectrum in the largest single-centre cohort of individuals with RASopathies (n=138), excluding neurofibromatosis type 1 and integrated these findings with a systematic literature review to evaluate tumour distribution and genotype-phenotype correlations. RESULTS: In our cohort, at least one solid tumour was identified in 10.8% of individuals with Noonan syndrome (NS), 47.8% with Costello syndrome (CS) and 7.3% with cardiofaciocutaneous syndrome (CFCS). Malignant tumours occurred in 5.4%, 30.4% and 2.4%, respectively. CS showed the highest tumour burden, frequently with multiple primary tumours, predominantly of the bladder. In NS, low-grade central nervous system (CNS) tumours were most common, particularly among individuals carrying PTPN11 variants. Tumour onset occurred with a median age of 19, 14 and 13 years in NS, CS and CFCS, respectively. Literature data analysis identified candidate variants in HRAS, PTPN11 and SOS1 genes associated with increased risk for solid tumours, which differed from mutational hotspots reported in childhood leukaemia or sporadic cancers. CONCLUSION: Solid tumour risk in RASopathies is syndrome-dependent and genotype-dependent, with CS showing a high burden of bladder tumours and NS mainly associated with CNS tumours. These findings may support tailored surveillance strategies.

Human Genetics↗

PubMed2026

Third-generation whole-genome sequencing reveals the role of CNTNAP2 as a tumor suppressor gene in high-risk neuroblastomas.

BACKGROUND: Neuroblastoma is a common and aggressive pediatric sympathetic nervous system tumor. Genomic structural variants (SVs) contribute substantially to neuroblastoma, yet remain under-characterized in high-risk neuroblastomas. We aimed to elucidate neuroblastoma pathogenesis using third-generation whole-genome sequence high-risk cases to identify driver aberrations and explore potential therapeutic strategies. METHODS: We analyzed third-generation whole-genome sequencing data of 20 high-risk neuroblastoma samples and combined the findings with those obtained from the analysis of clinical samples, in vitro models, and public datasets. RESULTS: The contactin-associated protein-like 2 (CNTNAP2) gene was observed to be frequently aberrated because of structural variants in high-risk neuroblastoma samples. CNTNAP2 expression was significantly correlated with favorable histology and could be used to predict prognosis using clinical samples and neuroblastoma datasets. Overexpression and knockdown experiments and transcriptomic analysis revealed that CNTNAP2 was primarily involved in neuronal differentiation and axon guidance pathways; moreover, CNTNAP2 was required for neuroblastoma differentiation and affected cancer stemness. Immunoprecipitation and mass spectrometry revealed that CNTNAP2 interacted with cytoskeletal proteins like drebrin 1 (DBN1) and myosin-heavy chain 9 (MYH9). CNTNAP2 dynamically reorganises actin and microtubules for DBN1-mediated neuronal differentiation. CNTNAP2 also reduces CTNNB1 transcription and β-catenin pathway activation by inhibiting MYH9 nuclear translocation. CNTNAP2 overexpression in neuroblastoma cell lines resulted in cell cycle arrest, decreased cell proliferation and metastasis. CONCLUSIONS: The recurrent loss of CNTNAP2 in neuroblastoma contributes to an aggressive phenotype by impairing neuronal differentiation and increasing cancer stemness. These findings may serve as a foundation for developing therapeutic strategies to overcome barriers to differentiation.

Humans↗