e22637 Background: Most studies of pediatric cancer predisposition syndromes (CPS) are derived from Western populations, resulting in limited understanding of CPS spectra in low- and middle-income countries. We aimed to characterize the genetic landscape of CPS among children of Arab ancestry treated at King Hussein Cancer Center (KHCC), with a particular focus on the impact of consanguinity. Methods: We conducted a retrospective review of children (<18 years) referred to the KHCC Pediatric Cancer Predisposition Clinic between January 2020 and October 2025. Germline testing was performed using targeted next-generation sequencing panels (Invitae) covering cancer predisposition, immunodeficiency, and bone marrow failure syndromes. Patients were stratified based on reported parental consanguinity. Results: A total of 230 pediatric cancer patients underwent germline testing. Median age at cancer diagnosis was 5 years (range, 0.2–18), and 55% were male. The most common indications for CPS evaluation were a family history of cancer (59%), followed by tumor types suggestive of an underlying predisposition syndrome (46%). The overall consanguinity rate was 26%, increasing to 35% among patients with a positive family history. Overall, 76 patients were diagnosed with 24 distinct CPSs. Among children from consanguineous families, 27 of 30 (90%) had autosomal recessive (AR) CPSs, while 3 of 30 (10%) had autosomal dominant (AD) conditions. In the non-consanguineous group, 45 of 46 (98%) had AD CPSs, and one child (2%) had a mitochondrial disorder due to a heteroplasmic variant. The most frequent CPSs were constitutional mismatch repair deficiency (CMMRD, n=11), RB1-related predisposition (n=10), neurofibromatosis (n=8), and Li-Fraumeni syndrome (n=6). Variants of uncertain significance (VUS) considered likely contributory were identified in 17 patients. Genetic testing was negative in 54 of 230 patients (23%). Conclusions: Consanguinity profoundly shapes the spectrum of pediatric CPS in Arab populations, with a marked predominance of autosomal recessive syndromes. These findings underscore the need for population-specific genetic evaluation strategies. Future efforts should prioritize systematic reclassification of VUS through integrated tumor–germline analyses, trio-based testing, and functional studies. Broader implementation of whole-exome and whole-genome sequencing is essential for clinically high-risk patients with negative panel testing, particularly in highly consanguineous populations.

Cancer Predisposition Syndromes (CPS) are heritable genetic conditions associated with an increased risk of developing various cancers throughout life. While early identification and tumour surveillance can improve outcomes, CPS are often underdiagnosed in clinical practice. To evaluate clinicians’ perspectives and identify barriers to CPS identification and care across Europe, we conducted the SCOPE study: a three-part cross-sectional survey of paediatric haematology/oncology professionals, followed by a modified Delphi consensus process with members of the SIOP Europe Host Genome Working Group. A total of 185 paediatric oncologists from 22 countries participated in the survey. More than 40% of participants reported low or uncertain confidence across different CPS-related tasks, particularly in counselling families (64.3%) and interpreting germline genetic findings (57.3%). Access to clinical geneticists and dedicated CPS clinics were predictors of higher confidence for some domains, while individual experience and institutional patient volume had limited influence. Regular use of universal CPS screening tools was low (42.3%), with most clinicians relying on personal judgement rather than structured criteria. The most cited barriers were lack of screening guidelines (57%) and difficulties in interpreting results (35.1%). Regular training and workshops, availability of genetic counsellors or educators for patient support, and patient-friendly education material were most cited as areas of improvement. The Delphi process led to three recommendations: (1) improve clinician training and communication strategies, (2) integrate CPS screening into standard treatment plans, and (3) develop accessible, patient-centred educational materials. These recommendations highlight opportunities to enhance CPS care through structured support, interdisciplinary collaboration, and systematic screening approaches.

Segmental gain of chromosome 17q is the most common genetic aberration in high-risk neuroblastoma, but its role in disease progression is poorly understood. This study aims to address the contribution of 17q gain to neuroblastoma malignancy. We analyzed the genetic and transcriptional landscape of 417 neuroblastoma patients across various risk groups and clinical stages using multi-omic approaches. Single-cell RNA/DNA sequencing and SNP arrays were combined to characterize genomic aberrations, while evolutionary trajectories were mapped to explore the accumulation of genetic changes in patients with neuroblastoma. Additionally, DNA and RNA sequencing were used to assess mutational burden and gene expression patterns. Our findings suggest that chromosome 17 gain is an early genetic event acquired during neuroblastoma development, correlating with the accumulation of additional chromosomal aberrations and poor prognosis. Increased segmental gains of chromosome 17q were observed during clonal evolution, relapse disease and metastasis. We identified PPM1D, a p53-inducible Ser/Thr phosphatase located on chr17q22.3, as a key player activated by segmental 17q-gain, gene-fusion, or gain-of-function somatic and germline mutations, further promoting neuroblastoma development/progression. Gain of chromosome 17 is an early driver of genetic instability in neuroblastoma, with PPM1D emerging as a potential candidate gene implicated in high-risk disease progression.

Schwannomatosis (SWN) is a distinct cancer predisposition syndrome caused by germline pathogenic variants in the genes NF2, SMARCB1, or LZTR1. There is a significant clinical overlap between these syndromes with the hallmark of increased risk for cranial, spinal, and peripheral schwannomas. Neurofibromatosis type 2 was recently renamed as NF2-related SWN and is the most common SWN syndrome, with increased risk for bilateral vestibular schwannomas, intradermal schwannomas, meningiomas, and less commonly, ependymoma. SMARCB1-related SWN is a familial SWN syndrome associated with peripheral and spinal schwannomas and an increased risk for meningiomas and malignant peripheral nerve sheath tumors, even in the absence of radiation. These individuals do not develop bilateral vestibular schwannomas. Finally, patients with LZTR1-related SWN typically present with peripheral schwannomas, and unilateral vestibular schwannomas have been reported. The following perspective is intended to highlight the clinical presentation and international tumor surveillance recommendations across these SWN syndromes.

Background Inborn errors of immunity (IEI) and inherited bone marrow failure syndromes (IBMFS) are associated with an increased lifetime cancer risk. However, the role of most IEI/IBMFS in childhood cancer predisposition remains largely unexplored. This study investigated the potential contribution of germline variants in IEI/IBMFS-associated genes to pediatric hematological malignancy development. Methods We analyzed 151 children with leukemia or lymphoma for germline (likely) pathogenic variants in 541 IEI/IBMFS-associated genes. None had features indicative of IEI/IBMFS prior to their cancer diagnosis. Results Six patients (4 %) had monoallelic (likely) pathogenic variants in autosomal dominant genes (TNFRSF13B, MPL, AIRE, NLRP12). Thus far, these genes have no proven association with childhood cancer predisposition. The carrier frequency of monoallelic (likely) pathogenic variants in recessive genes was 33 %, considered to align with general population data. Twelve patients (8 %) carried variants in genes involved in DNA repair or chromosomal stability, half of which had been identified in previous work by our group or were known before the cancer diagnosis. Conclusion This study assessed for the first time in an unbiased and comprehensive manner the role of IEI/IBMFS in childhood hematological malignancy predisposition. Although the overall yield of this exploratory study was limited, our findings support the importance of research on childhood cancer predisposition at the intersection of hematological malignancies and IEI/IBMFS. We identified several variants in both dominant and recessive genes of which it would be interesting to investigate their causality. However, for now, sequencing of IEI/IBMFS-associated genes should be restricted to research context or in case of clinical suspicion.

Acute kidney injury (AKI) is a serious complication of pediatric cancer treatment that is suggested to increase the risk of chronic kidney disease (CKD). Children with a kidney tumor may be at particular risk. This study aimed to determine the incidence and risk factors of AKI and its association with CKD during pediatric kidney tumor treatment. We analyzed data from a prospective national cohort of patients ≤ 18 years old diagnosed with a kidney tumor between 2015 and 2021 in the Princess Máxima Center for Pediatric Oncology in the Netherlands. AKI was defined according to KDIGO criteria. CKD was assessed 1 year post-treatment based on proteinuria and/or decreased estimated glomerular filtration rate (eGFR). Of 147 patients, we observed AKI in 104 patients (71

MCM8 and MCM9 are newly proposed cancer predisposition genes, linked to polyposis and early-onset cancer, in addition to their previously established association with hypogonadism. Given the uncertain range of phenotypic manifestations and unclear cancer risk estimates, this study aimed to delineate the molecular and clinical characteristics of biallelic germline MCM8/MCM9 variant carriers. We found significant enrichment of biallelic MCM9 variants in individuals with colonic polyps (odds ratio [OR] 6.51, 95% confidence interval [CI] 1.24-34.11, p = 0.03), rectal polyps (OR 8.40, 95% CI 1.28-55.35, p = 0.03), and gastric cancer (OR 27.03, 95% CI 2.93-248.5; p = 0.004) in data from the 100000 Genomes Project, compared to controls. No similar enrichment was found for biallelic MCM8 variants or in the 200000 UK Biobank. Likewise, in our case series, which included 26 MCM8 and 28 MCM9 variant carriers, we documented polyposis, gastric cancer, and early-onset colorectal cancer (CRC) in MCM9 carriers but not in MCM8 carriers. Moreover, our case series indicates that beyond hypogonadism, biallelic MCM8 and MCM9 variants are associated with early-onset germ cell tumors (occurring before age 15). Tumors from MCM8/MCM9 variant carriers predominantly displayed clock-like mutational processes, without evidence of DNA repair deficiency-associated signatures. Collectively, our data indicate that biallelic MCM9 variants are associated with polyposis, gastric cancer, and early-onset CRC, while both biallelic MCM8 and MCM9 variants are linked to hypogonadism and the early development of germ cell tumors. These findings underscore the importance of including MCM8/MCM9 in diagnostic gene panels for certain clinical contexts and suggest that biallelic carriers may benefit from cancer surveillance.

Recessive Fanconi anemia (FA) phenotype is used in classification of BRCA1/FANCS, BRCA2/FANCD1 and PALB2/FANCN variants with respect to dominant hereditary breast-ovarian cancer syndrome. We assessed its utility by examining the spectrum of phenotypes observed in individuals biallelic for BRCA1, BRCA2 or PALB2 pathogenic variants, and exploring the relationship between cancer presentation and allele severity score based on variant molecular features. A data collection instrument comprising 158 Human Phenotype Ontology (HPO) terms was used to document clinical features for individuals with FA from published and/or prospectively collected (total n=172, 43 previously unpublished) phenotypic data. Unique FA-related variants (15 BRCA1, 123 BRCA2, 22 PALB2) were annotated for predicted molecular impact, location, observed splicing or functional impact, and potential in-frame splice rescue. Annotations were used to assign different permutations of allele severity scores, which were assessed for correlation with FA presentation features. The association of BRCA1 and BRCA2 allele severity score with magnitude of breast cancer risk in heterozygotes was evaluated using case-control analysis. Patient-detected features extended beyond the FA ORPHA:84 HPO list, including 84 terms related by hierarchy, and 94 novel terms. Genotype severity score was significantly associated with age at cancer diagnosis in BRCA2 FA individuals (p=1.8×10-8). A similar permutation approach revealed significant differences in magnitude of breast cancer risk according to BRCA1 and BRCA2 allele severity score in heterozygotes. Findings indicate potential to redefine the existing list of FA-related HPO terms, and to use an allele severity scoring approach to predict cancer risk in both FA patients and heterozygotes.

INTRODUCTION:SMARCA4 is a known susceptibility gene for malignant rhabdoid tumors (MRT) in children and small cell carcinoma of the ovary hypercalcemic type (SCCOHT) in young females and women. Recently, a novel association between germline SMARCA4 variants and predisposition to neuroblastoma was proposed. METHODS:We present a single-center study summarizing the clinical and genetic data of pediatric and adolescent cancer patients with a germline SMARCA4 variant diagnosed with and/or treated for an MRT, SCCOHT, or neuroblastoma. RESULTS:We identified nine patients with germline SMARCA4 variants, including one patient with an MRT, four patients with a SCCOHT, and four patients with a neuroblastoma. We observed two novel pathogenic SMARCA4 variants that were initially missed using diagnostic testing: a low-mosaic pathogenic SMARCA4 variant in the patient with an MRT, and a germline SMARCA4 partial gene deletion, encompassing the promoter region, in a patient with a SCCOHT. The patients with neuroblastoma in our cohort had a strikingly old age at diagnosis (range: 10-22 years old). In three of four patients with neuroblastoma, the germline SMARCA4 variant was a variant of unknown significance (VUS). In two of their neuroblastomas, we observed loss of heterozygosity at the SMARCA4 locus, and loss of BRG1 expression was found in one of these. CONCLUSIONS:This study highlights that awareness is needed for easy-to-miss germline variants in SMARCA4 and that knowledge about variant types, cancer spectrum, and cancer penetrance in individuals with a germline SMARCA4 variant is still evolving.

Pediatric acute lymphoblastic leukemia (ALL) is the most common childhood cancer, with significant advances in treatment leading to high cure rates. Recent studies have highlighted the importance of genetic predisposition in ALL. Identifying contributing heritable or de novo genetic factors is crucial for potential treatment modifications, early detection of second malignant neoplasms (SMNs) and genetic counseling for surveillance of patients and family members. Multiple syndromes, such as Down syndrome (DS) or Ataxia Telangiectasia (AT), are known to give rise to increased risk for developing ALL. Most of these syndromes can be recognized by the presence of specific clinical features. However, a notable proportion of patients harboring (likely) pathogenic germline variants in cancer predisposition genes (CPGs) can easily be missed due to the absence of these characteristics. Therefore, the diagnosis of cancer predisposition syndromes (CPS) requires multiple approaches that are based on phenotypic characteristics, germline genetic analysis and genomic characterization of the leukemia samples. Despite the recognized benefits, routine screening for germline variants has not yet been implemented in large study groups due to logistical and financial challenges. This review emphasizes the importance of integrating systematic genetic testing into standard care protocols for ALL patients and summarizes current practical considerations for CPS identification in children with ALL.

The management of children with syndromes associated with an increased risk of benign and malignant neoplasms is a complex challenge for health care professionals. The 2023 American Association for Cancer Research Childhood Cancer Predisposition Workshop provided updated consensus guidelines on cancer surveillance in these syndromes, aiming to improve early detection and intervention and reduce morbidity associated with such neoplasms. In this article, we review several of the rare conditions discussed in this workshop. Ollier disease and Maffucci syndrome are enchondromatoses (disorders featuring benign bone lesions) with up to 50% risk of malignancy, including chondrosarcoma. These patients require surveillance with baseline whole-body MRI and routine monitoring of potential malignant transformation of bony lesions. Hereditary multiple osteochondromas carry a lower risk of chondrosarcoma (<6%) but still require lifelong surveillance and baseline imaging. Related syndromes of benign bone lesions are also described. Hereditary leiomyomatosis and renal cell carcinoma syndrome, associated with fumarate hydratase pathogenic variants, is discussed in detail. Surveillance for renal cell carcinoma in pediatric age is recommended, as well as prompt intervention when a lesion is detected. Schinzel-Giedion syndrome and Rubinstein-Taybi syndrome are described for their associated malignancies and other complications, as well as expert consensus on the need for childhood cancer surveillance. Clinical recommendations, including imaging modalities and frequency of screenings, are proposed and are tailored to each syndrome's age-specific tumor risk profile. In all syndromes, patients and their families should be educated about the potential malignancy risk and advised to seek medical care for rapid growth of a mass, persistent pain, or other unexplained symptoms.

The recessive Fanconi anemia (FA) phenotype is used to classify BRCA1 (FANCS), BRCA2 (FANCD1), and PALB2 (FANCN) variants with respect to dominant hereditary breast-ovarian cancer syndrome. We assessed its utility by examining the phenotypic spectrum observed in individuals with bi-allelic BRCA1, BRCA2, or PALB2 pathogenic variants and exploring the relationship between cancer presentation and allele severity score based on variant molecular features. A data collection instrument comprising 158 Human Phenotype Ontology (HPO) terms was used to document clinical features for individuals with FA from published and/or prospectively collected sources (total n = 172, 43 previously unpublished). Distinct FA-related variants (15 BRCA1, 123 BRCA2, and 22 PALB2) were annotated for predicted molecular impact, location, observed splicing or functional impact, and potential in-frame splicing rescue and used to assign different permutations of allele severity scores, which were assessed for correlation with FA presentation features. The association of BRCA1 and BRCA2 allele severity score with the magnitude of breast cancer risk in heterozygotes was evaluated using case-control analysis. Clinical features extended beyond the HPO list, including 84 terms related by hierarchy and 94 additional terms. The BRCA2 genotype severity score was associated with age at cancer diagnosis in individuals with FA (p = 1.8 × 10-8). A similar permutation approach revealed significant differences in the magnitude of breast cancer risk according to the BRCA1 and BRCA2 allele severity score in heterozygotes. Our findings indicate the potential to redefine FA ORPHA:84 HPO terms and to use an allele severity scoring approach to predict cancer risk in individuals with bi-allelic or heterozygous BRCA1 or BRCA2 variants.

Constitutional mismatch repair deficiency (CMMRD), caused by bi-allelic germline variants in mismatch repair (MMR) genes, is associated with high cancer incidence early in life. A better understanding of mutational processes driving sequential CMMRD tumors can advance optimal treatment. Here, we describe a genomic characterization on a representative collection of CMMRD-associated tumors consisting of 41 tumors from 17 individuals. Mutational patterns in these tumors appear to be influenced by multiple factors, including the affected MMR gene and tumor type. Somatic polymerase proofreading mutations, commonly present in brain tumors, are also found in a T-cell lymphoblastic lymphoma displaying associated mutational patterns. We show prominent mutational patterns in two second primary hematological malignancies after temozolomide treatment. Furthermore, an indel signature, characterized by one-base pair cytosine insertions in cytosine homopolymers, is found in 54% of tumors. In conclusion, analysis of sequential CMMRD tumors reveals diverse mutational patterns influenced by the affected MMR gene, tumor type and treatment history.

This study explored the experiences and needs of adolescents, ranging from 12 to 18 years old, who have recently been diagnosed with cancer and participated in a nationwide germline genetic sequencing study within the context of pediatric oncology. The 21 adolescents in this qualitative interview study viewed genetic sequencing as an integral part of their cancer journey. They often characterized germline sequencing as “good-to-know” without specifying immediate utility. While the adolescents comprehended the significance of germline genetic sequencing, they were less focused on its potential long-term implications. Adolescents expressed a strong desire to be actively engaged in decisions related to genetics. They advocated for a participatory role in genetic decision-making from a young age onwards. They recommended that re-consent should be sought before re-analysis of their genetic data is performed and believe that patients should have the opportunity to provide (re-)consent once they reach adulthood. Moreover, the adolescents emphasized the importance of developing counseling materials that are not only concise but also visually attractive. In conclusion, this study underscores the positive perception that adolescents diagnosed with cancer hold regarding germline genetic sequencing. They articulate a strong interest in being actively involved in genetic decision-making. To address these articulated needs and preferences, we recommend the development of visually engaging counseling materials. These materials should effectively convey both the immediate and long-term implications of genetic sequencing, enabling adolescents with cancer to make informed decisions about genetic sequencing.

Background Germline data have become widely available in paediatric oncology since the introduction of paired tumour-germline sequencing. To guide best practice in cancer predisposition syndrome (CPS) diagnostics, we aimed to assess the diagnostic yield of extensive germline analysis compared with clinical selection-based genetic testing among all children with cancer. Methods In this prospective diagnostic study, all children (aged 0-19 years) with newly diagnosed neoplasms treated in the Netherlands national centre, the Princess M & aacute;xima Center for Pediatric Oncology (Utrecht, Netherlands), between June 1, 2020, and July 31, 2022, were offered two approaches to identify CPSs. In a phenotype-driven approach, paediatric oncologists used the McGill Interactive Pediatric OncoGenetic Guidelines tool to select children for referral to a clinical geneticist, and for genetic testing. In a phenotype-agnostic approach, CPS gene panel sequencing (143 genes) was offered to all children. In children declining the research CPS gene panel, 49 CPS genes were still analysed as part of routine diagnostics by the pathologist. Children with a causative CPS identified before neoplasm diagnosis were excluded. The primary objective was to compare the number and type of patients diagnosed with a CPS between the two approaches. Findings 1052 children were eligible for this study, of whom 733 (70%) completed both the phenotype-driven approach and received phenotype-agnostic CPS gene panel sequencing (143 genes n=600; 49 genes n=133). In 53 children, a CPS was identified: 14 (26%) were diagnosed by the phenotype-driven approach only, 22 (42%) by CPS gene sequencing only, and 17 (32%) by both approaches. In 27 (51%) of the 53 children, the identified CPS was considered causative for the child's neoplasm. Only one (4%) of the 27 causative CPSs was missed by the phenotype-driven approach and was identified solely by phenotype-agnostic CPS gene sequencing. In 26 (49%) children, a CPS with uncertain causality was identified, including 14 adult-onset CPSs. The CPSs with uncertain causality were mainly detected by the phenotype-agnostic approach (21 [81%] of 26). Interpretation Phenotype-driven genetic testing and phenotype-agnostic CPS gene panel sequencing were complementary. The phenotype-driven approach identified the most causative CPSs. CPS gene panel sequencing identified additional CPSs, many of those with uncertain causality, but some with clinical utility. We advise clinical evaluation for CPSs in all children with neoplasms. Phenotype-agnostic testing of all CPS genes is preferably conducted only in research settings and should be paired with counseling. Copyright (c) 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.

Purpose Germline DNA sequencing is increasingly used within pediatric oncology, yet parental experiences remain underexplored. Methods Parents of children undergoing cancer predisposition gene panel sequencing (143 genes) were surveyed before and after disclosure of results. Questionnaires assessed knowledge, expectations, worries, satisfaction, and regret. Next to descriptives, linear mixed models and generalized mixed models were utilized to explore factors associated with knowledge and worries. Results Out of 325 eligible families, 310 parents (176 mothers and 128 fathers of 188 families) completed all after-consent questionnaires whereas 260 parents (150 mothers and 110 fathers of 181 families) completed all after disclosure questionnaires. Most parents hoped their participation would benefit others, although individual hopes were also common. Sequencing-related worries were common, particularly concerning whether their child would get cancer again, cancer risks for family members and psychosocial implications of testing. Parental satisfaction after disclosure was high and regret scores were low. Lower education was associated with lower knowledge levels, whereas foreign-born parents were at increased risk of experiencing worries. Conclusion Germline sequencing of children with cancer is generally well received by their parents. However, careful genetic counseling is essential to ensure that parents are adequately informed and supported throughout the process.

Replication repair deficiency (RRD) is a pan-cancer mechanism characterized by abnormalities in the DNA mismatch repair (MMR) system due to pathogenic variants in the PMS2, MSH6, MSH2, or MLH1 genes, and/or in the polymerase-proofreading genes POLE and POLD1. RRD predisposition syndromes (constitutional MMR deficiency, Lynch, and polymerase proofreading-associated polyposis) share overlapping phenotypic and biological characteristics. Moreover, cancers stemming from germline defects of one mechanism can acquire somatic defects in another, leading to complete RRD. Here we describe the recent advances in the diagnostics, surveillance, and clinical management for children with RRD syndromes. For patients with constitutional MMR deficiency, new data combining clinical insights and cancer genomics have revealed genotype-phenotype associations and helped in the development of novel functional assays, diagnostic guidelines, and surveillance recommendations. Recognition of non-gastrointestinal/genitourinary malignancies, particularly aggressive brain tumors, in select children with Lynch and polymerase proofreading-associated polyposis syndromes harboring an RRD biology have led to new management considerations. Additionally, universal hypermutation and microsatellite instability have allowed immunotherapy to be a paradigm shift in the treatment of RRD cancers independent of their germline etiology. These advances have also stimulated a need for expert recommendations about genetic counseling for these patients and their families. Future collaborative work will focus on newer technologies such as quantitative measurement of circulating tumor DNA and functional genomics to tailor surveillance and clinical care, improving immune surveillance; develop prevention strategies; and deliver these novel discoveries to resource-limited settings to maximize benefits for patients globally.

Supplementary results, figures, and table notes