Genetic testing is increasingly recommended for adolescents and young adults (AYAs) with cancer; however, no AYA-specific models for cancer risk communication have been developed. We developed a chatbot-based patient- and family-centered cancer risk communication tool, the AYA-RISE (AYA-Risk Information and Screening Education) intervention for AYAs aged 12–24 years. The intervention was developed together with AYAs with cancer risk syndromes, their family members, and clinicians, using Invitae’s Gia® chatbot (study Phase 1). 17 AYAs participated in a group discussion and completed surveys for input regarding development. Content was developed for 9 different syndromes. AYA-RISE was then refined after iterative input (Phase 2) and evaluated for feasibility and preliminary outcomes in a pilot study (Phase 3). 100

Background/Objectives: Pediatric nasopharyngeal carcinoma (NPC) is a very rare childhood cancer strongly associated with Epstein–Barr virus (EBV) infection. We investigated the prognostic value of EBV DNA on staging and outcome in pediatric NPC from two large study centers, the Children’s Oncology Group (COG) in North America and the German Society of Pediatric Oncology and Hematology (GPOH) in Europe. Methods: Samples collected from NPC patients treated on the COG study ARAR0331 between 2006 and 2012 and the GPOH NPC protocol between 2003 and 2021 were retrospectively analyzed for the level of available plasma (P-EBV) or whole-blood EBV DNA (WB-EBV), both pre-treatment and post-induction chemotherapy. Patients were dichotomized into high and low groups based on the median pre-treatment EBV value. Results: Pre-treatment EBV DNA levels from 102 patients (50 and 23 P-EBV DNA from the COG and GPOH, respectively, and 29 WB-EBV from GPOH) and post-induction EBV DNA levels from 61 patients (31 and 12 P-EBV DNA from the COG and GPOH, respectively, and 18 WB-EBV DNA from GPOH) were evaluated. Patient characteristics, including age and disease stage, were not associated with high and low P-EBV values in any cohort. Disease stage correlated with high EBV levels in the WB-EBV GPOH cohort (p = 0.014). Pre-treatment P-EBV and WB-EBV levels showed no significant association with 5-year event-free survival (EFS: COG p = 0.65, GPOH P-EBV: p = 0.08, GPOH WB-EBV: p = 0.75) or 5-year overall survival (OS: COG p = 0.90, GPOH P-EBV p = 0.17, GPOH WB-EBV p = 0.19). Conclusions: Our study could not establish a significant correlation between outcome and pre-treatment EBV DNA in pediatric NPC patients from non-endemic areas.

At least 15% of children with cancer have a pathogenic germline variant in a cancer predisposition gene. Studies of germline cancer predisposition, however, have focused primarily on single nucleotide and copy number variants, leaving other classes such as transposable elements (TEs) largely unexplored. Although rare pathogenic TE insertions have been implicated in inherited cancer, their contribution to pediatric cancer predisposition remains unknown, partly because these repetitive sequences often require whole-genome sequencing for detection. We characterized the germline TE insertion landscape using non-tumor whole genome sequencing data from 2,334 pediatric cancer and 3,447 controls. Across 5,781 genomes, we identified 96,484 TE insertions, most of which were rare and located in intergenic or intronic regions. While global TE burden did not differ between cases and controls, rare TE insertions were significantly enriched in cancer genes in patients with solid tumors, particularly within 3' untranslated regions (p<0.02). Gene-phenotype concordance analysis identified 19 insertions in genes with established dominant cancer predisposition, representing ~0.8% of cases. Integration of RNA-seq data revealed transcriptional impact for a subset of insertions. Notably, a 3' UTR L1 insertion in the tumor suppressor PTEN disrupted alternative polyadenylation, whereas an SVA insertion in a STIM1 intron induced exonization, generating a novel transcript containing SVA sequence. These findings demonstrate that rare germline TE insertions in cancer predisposition genes can have functional consequences at the RNA level. Incorporating TE detection into genomic workflows may improve identification of cancer predisposition syndromes and expand understanding of noncoding contributions to pediatric cancer susceptibility.

PURPOSE Many children with very early-onset solid tumors remain without an identified germline risk factor after negative panel testing. Whole-genome sequencing (WGS) enables detection of large structural variants (SVs) and rare loss-of-function variants in highly constrained genes that are not routinely captured by standard clinical assays. The additional yield and spectrum of germline findings identified by WGS in this population remain incompletely defined. METHODS We conducted a retrospective cohort study of children with very early-onset solid or brain tumors evaluated at a tertiary cancer genetic risk clinic with clinically guided germline panel testing. Germline WGS was performed on blood-derived DNA. Analyses focused on pathogenic or likely pathogenic variants in established cancer predisposition genes (CPGs), large SVs (>1,000,000 bp), aneuploidies, and loss-of-function variants in highly constrained genes. RESULTS One hundred thirty-two patients were included, with median (IQR) age at diagnosis of 1.7 (0.8-3.2) years. Panel testing identified pathogenic CPG variants in 27 of 132 patients (20%). WGS recapitulated panel findings and identified nine additional putative pathogenic variants, increasing yield to 27%. Eight patients (6%) harbored large germline SVs or aneuploidies, including five events not previously recognized. Rare loss-of-function variants in highly constrained genes were identified in 46 patients (35%), many involving pathways relevant to cancer development. Overall, 66 of 132 patients (50%) carried at least one rare germline variant of potential pathogenic relevance. CONCLUSION In children with very early-onset solid tumors, germline WGS increased detection of potentially pathogenic variants, including novel structural and constrained-gene alterations. These findings support broader consideration of germline WGS in early-onset solid tumors to refine genetic risk assessment and enable discovery of novel susceptibility mechanisms.

Abstract Background: Rare pediatric cancers encompass a broad range of diagnoses, including both adult-onset carcinomas that rarely arise in children and very rare diagnoses unique to childhood. Although each individual diagnosis is exceedingly uncommon, rare tumors collectively account for ∼10% of all children with cancer. However, for many of these cancers, little is known about their genetic drivers. Methods: The Molecular Characterization Initiative (MCI), launched in 2022 by the NCI Childhood Cancer Data Initiative (CCDI), provides molecular profiling at no cost to the treating institution. Individuals 25 years old or younger newly diagnosed with a rare tumor, as defined by the Children’s Oncology Group (COG), are eligible for paired germline and tumor enhanced whole-exome sequencing and targeted RNA fusion analysis. Results are returned within 2-3 weeks from receipt of paired samples. Results: From 9/22/2022 to 03/31/2026, 872 individuals were enrolled from 160 institutions across 6 countries. The most common diagnosis subgroups were thyroid carcinoma (n=204), neuroendocrine tumors (n=92), sex cord-stromal tumors (n=75), and other rare tumors (n=182). Of the 683 patients with sequencing results, germline variants were reported in 153 patients (22.4%) and were generally consistent with established genotype-tumor associations. The most prevalent germline alterations affected DICER1 (n=37, 5.4% of total cohort), TP53 (n=16, 2.3%), RB1 (n=13,1.9%), and VHL (n=11, 1.6%). Notably, several individuals had segmental or chromosome-level copy number variants (CNVs) affecting these genes that would have been challenging to detect with smaller targeted sequencing panels. In addition, 52.3% (n=357) of tumors demonstrated somatic single-nucleotide variants (SNVs) or indels, and 54.3% (n=371) harbored somatic CNVs. Novel associations included KMT2D truncation and SMARCA4 missense variants, each seen in 4 children with nasopharyngeal carcinoma. Of the 583 patients with fusion results, oncogenic fusions were identified in 130 patients (22.8%), most commonly associated with thyroid cancer (affecting RET, NTRK3, and other kinases), desmoplastic small round cell tumor (EWSR1::WT1), or mucoepidermoid carcinoma (CRTC1::MAML2). Novel fusions included ADGRG12::NOTCH2 (adenoid cystic carcinoma), ERC1::BRAF (pancreatoblastoma), and RB1::DIAPH3 (retinoblastoma). Among the 229 patients with follow-up data, 21 (9.2%) were reported to receive a therapy matched to a molecular alteration identified by MCI. Conclusion: MCI has provided genomic profiling for children with a wide range of rare tumors across international COG centers. A reportable germline alteration of a cancer predisposition gene was identified in 22.4% of individuals with rare childhood cancers. These results highlight the importance of molecular profiling for the purposes of genetic counseling, tailoring therapy, and improving our understanding of the genetic drivers of rare pediatric tumors. Citation Format: Lauren Vasta, Jin Piao, Lea F. Surrey, John Hicks, Erin R. Rudzinski, Junne Kamihara, Jack F. Shern, Subhashini Jagu, Gregory Reaman, Malcolm Smith, Catherine Cottrell, Douglas S. Hawkins, Kris Ann P. Schultz, Theodore W. Laetsch, Kenneth S. Chen. The CCDI-COG Molecular Characterization Initiative (MCI) in rare pediatric cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Breaking Barriers in the Fight against Rare Cancers; 2026 Jul 18-20; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(14_Suppl):Abstract nr PR001.

Abstract While established predisposition genes account for syndromes like Cowden and Lynch syndrome, cancers frequently cluster in families without any identifiable pathogenic variant (PGV). We hypothesized that other germline factors beyond established PGVs might partially explain the large fraction of familial cancer cases with no known PGV. In this study, we systematically assessed potential genetic risk factors in 2,721 germline whole genomes from individuals with no recognized PGV, comparing 1,389 familial cancer cases across 18 cancer types to 1,332 controls with no family history of cancer in the NIH AllofUs Biobank. We performed genome-wide germline variant discovery using GATK-HC and GATK-SV to capture the full spectrum of rare and common SNVs, indels, and structural variants (SVs), notably including a total of 309,848 high-confidence SVs (9,639 SVs per genome). We first examined the rates of rare germline structural variants (SVs) predicted to cause loss-of-function of established predisposition genes, finding elevated rates of these likely pathogenic SVs in most cancer types compared to cancer-free controls, with neuroendocrine, colorectal, and ovarian cancer patients harboring notably high rates of these SVs (ORs: neuroendocrine 2.9; colorectal 3.1; ovarian 2.4). We also observed a small fraction of breast cancer patients carrying structural variants overlapping the BRCA1 promoter. We next tested for enrichment of rare missense variants of uncertain significance in established predisposition genes and found significant enrichment in endometrial, hematologic, prostate, and neuroendocrine cancer patients (p < 0.05). To search for potential new predisposition genes, we performed rare variant association tests for all 18,544 autosomal protein-coding genes, which nominated several candidate predisposition genes driven by rare damaging variants, such as BRAT1 in breast cancers (p=3.99e-5) and TSTD2 in thyroid cancers (p=3.26e-5). Finally, we assessed common-variant contributions and found that polygenic risk, long recognized in sporadic cancers, strongly contributed to familial cases in 11 of 15 cancer types with existing polygenic scores. Notably, polygenic risk scores were higher in patients from families with multiple occurrences of the same cancer type compared to patients whose own diagnosis was the only instance of that cancer in their family; conversely, in families with clusterings of a given cancer type, unaffected probands had polygenic risk scores for that cancer type on par with individuals who were both cancer-free and had no family history. Collectively, we estimate that 1-8.8% of unexplained familial cancers can be attributed to germline genetic factors detectable by genome sequencing but missed by routine gene panels, underscoring the potential clinical and diagnostic value of high-resolution germline testing for hereditary cancer patients and their families. Citation Format: Noah Fields, Ryan Collins, Seunghun Seunghun Han, Erin Shannon, Ryan Buehler, Deborah Wood Neklason, Jihye Park, Junne Kamihara, Judy Garber, Riaz Gillani, Saud H. AlDubayan, Eliezer Van Allen. Unraveling the missing heritability of unexplained familial cancers with germline genome sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6278.

Cancer frequently clusters in families due to shared environment and genetics. However, many familial cancer cases lack a clinically recognized pathogenic germline variant (PGV). We analyzed germline genomes and family history from 2,726 individuals without a PGV in the All of Us Research Program, including 1,496 cases across 18 cancer types with extensive family history and 1,230 family history-negative, cancer-free controls. We identified allelic series of rare structural variants inactivating MSH2 in individuals with phenotypes consistent with Lynch syndrome and BRCA1 in breast cancer. Cancer polygenic risk scores were enriched in cases and correlated with patterns of cancer diagnoses within families. Exome-wide rare variant analyses nominated six candidate predisposition genes, including TSTD2 and BRAT1 in thyroid and breast cancer, respectively. Overall, polygenic risk and rare variants impacting known genes explained a median of 5% of unexplained familial cancers, increasing to 11% when including newly nominated risk factors.

BACKGROUND:The InAdvance Study addresses the critical need for comprehensive data and biospecimen collection from individuals at elevated risk for cancer. Despite the existence of numerous biobanks for patients with cancer and individuals at average risk for cancer, a gap persists in resources targeting individuals with an elevated risk for cancer. METHODS:The InAdvance Study is longitudinally collecting biospecimens and health data from individuals with a range of cancer risk factors to facilitate collaborative research in cancer early detection and interception. Patient populations include those with precancerous or precursor lesions (e.g., oral precursor lesions and Barrett's esophagus), hereditary cancer risk, personal or family history of cancer, or a history of exposures associated with cancer risk. Additionally, we are enrolling patients receiving multicancer early detection (MCED) tests, family members of elevated risk participants, and controls. Key goals include optimized biospecimen collection through standardized procedures, participant enrollment and engagement through an online platform, and standardized scalable procedures. Data are compiled into a central repository, and researchers can request access through a streamlined data request process. RESULTS:Since April 2023, 1,415 participants have enrolled in the study. In total, 817 (58%) completed the baseline survey, and 816 (58%) gave a baseline blood sample. CONCLUSIONS:The InAdvance Study's comprehensive approach provides a framework for basic, population, and translational studies to elucidate the molecular and environmental factors that drive cancer development. IMPACT:Comprehensive data and biospecimen biorepositories are critical to informing strategies for early detection, risk stratification, early interception for risk mitigation, and improved outcomes for higher-risk populations.

Introduction Cancer is the most common cause of disease-related mortality in children, highlighting the urgent need for improved care in this population. It is estimated that >15% of children diagnosed with cancer harbour a germline pathogenic variant in a cancer predisposition gene which confers an increased risk to develop cancer. There are over 100 genes associated with cancer predisposition syndromes (CPSs) and greater availability and acceptability of genetic testing in the last decade has facilitated their recognition in childhood. However, individually, each of these CPSs is rare, impeding robust research and advancement of clinical care. Once a specific CPS is diagnosed, current recommendations for clinical care are based primarily on expert consensus with a ’one size fits all’ approach to management. Detailed knowledge of genotype-phenotype associations and the impact of genetic modifiers is lacking, and due to strong ascertainment bias of children already diagnosed with cancer predominantly being tested for a CPS, the true cancer risk is likely overestimated. Methods and analyses The Childhood Cancer Predisposition Study (CCPS) is a multi-centre registry and biorepository for children and adolescents aged 0–21 years with a clinical or molecularly confirmed CPS and their family members ( NCT04511806 ). The study objectives are to characterise the natural history of each CPS, correlate the natural history phenotype with CPS genotype, evaluate the efficacy of standard surveillance strategies and allow future investigation into the feasibility and effectiveness of novel surveillance strategies. The principal study question is whether adherence to recommended tumour surveillance guidelines is associated with earlier detection of tumours and/or improved survival. We will also address what barriers exist that prevent adherence to surveillance guidelines. Data collected from primary subjects includes detail about the CPS, genomic data, cancer history and family cancer history, as well as information about tumour surveillance. Required biospecimen collection includes germline DNA samples, with optional collection of serial blood and stool samples. Planned enrolment is 1050 primary subjects. Ethics and dissemination CCPS was reviewed and approved by a central IRB (WCG IRB 2020P002450) and the Research Ethics Board at The Hospital for Sick Children in Toronto (1000072286). Written informed consent is obtained from all participants. Data and specimens are available to qualified investigators by request to address specific research questions through a standardised research application process. In addition, de-identified data are available through the Pediatric Cancer Data Commons for exploration. Analysed data will be disseminated in peer-reviewed publications and at conferences including meetings inclusive of patient and family advocacy groups. Trial registration number NCT04511806 .

Abstract Purpose: ALRN-6924 is a stapled peptide that disrupts MDM2/MDMX-mediated inhibition of p53. We evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of ALRN-6924 in children with advanced malignancies. Patients and Methods: Patients with TP53 wild-type malignancies were enrolled in a monotherapy arm (solid/central nervous system tumors) or a combination arm with cytarabine (acute leukemia). Monotherapy dosing used the Targeted-Agent Continual Reassessment Method design for dose escalation. Pharmacodynamic assessment included serum macrophage inhibitory cytokine-1 (MIC-1) as a biomarker of p53 activation. Circulating tumor DNA (ctDNA) was analyzed for emergent TP53 mutations. Results: Twenty-two patients enrolled; 20 received treatment (17 monotherapy and 3 combination). The most common diagnosis was Ewing sarcoma (n = 5). One dose-limiting toxicity (DLT) occurred at monotherapy dose level 2 (2.7 mg/kg). Six patients were treated at dose level 3 (3.5 mg/kg) without DLT, and 1 patient was treated at dose level 4 (4.3 mg/kg) without DLT before study closure. No DLT occurred on the combination arm. Common treatment-related adverse events included anemia (90%) and nausea (70%). MIC-1 levels increased 30- to 50-fold by 24 hours after dose at dose levels 2 to 4, confirming on-target p53 activation. Among 19 response-evaluable patients, 1 partial remission occurred in a patient with relapsed acute lymphoblastic leukemia on the combination arm. Drug exposure was lower than in adults at equivalent doses. One patient with Ewing sarcoma had an emergent TP53 mutation detected in their baseline on-therapy ctDNA sample. Conclusions: ALRN-6924 was well tolerated in children, with on-target activity. Future efforts to evaluate this agent should focus on biomarker-selected populations, combination strategies, and the evaluation of higher dose levels.

PURPOSE:Individuals with Li-Fraumeni syndrome (LFS) are at risk of developing cancer in multiple organs and therefore require a multimodal screening program. We assessed the performance of annual whole-body noncontrast magnetic resonance imaging (WBMRI) in early cancer detection for individuals with LFS. METHODS:Individuals with a germline pathogenic or likely pathogenic variant in the TP53 gene (defined as LFS) and without cancer diagnosed or treated in the preceding 6 months were eligible to undergo annual noncontrast WBMRI. Clinical findings on WBMRI, follow-up studies, biopsies, and cancer incidence were prospectively assessed. RESULTS:One hundred sixty-two participants with LFS (127 adult, 35 pediatric) underwent 477 WBMRIs; 119 (73%) underwent three or more. The median age at enrollment was 37 years; 75% of participants were female. Classic or Chompret diagnostic criteria for LFS were met for 68.5% of participants. Follow-up studies for findings on WBMRI were pursued for 55.6% of participants. Biopsies were performed in 18% of participants; 39.5% of 38 biopsies confirmed a cancer diagnosis. The rate of follow-up interventions decreased with consecutive WBMRIs. During the study period, of 37 cancers diagnosed in 33 participants, 15 (40.5%) were diagnosed by WBMRI; 86% (13 of 15) were asymptomatic, localized cancers treated with curative intent. The 22 cancers not diagnosed on WBMRI included five sarcomas; one each of adrenocortical, lung, thyroid, and renal cell carcinomas; and 13 cancers that WBMRI would not be expected to detect. CONCLUSION:Annual WBMRI contributes substantially to the detection of asymptomatic localized cancers among individuals with LFS and is best used in conjunction with a multimodality approach endorsed by LFS guidelines. Our study highlights the need for further research to enhance early detection and interception of cancer in LFS.

Hereditary Pheochromocytoma/Paraganglioma Syndromes (HPPS) are a collection of conditions caused by variants in genes producing subunits of the succinate dehydrogenase (SDH) complex or related proteins. These conditions are characterized by substantial lifetime risks for developing pheochromocytomas, paragangliomas, and other tumors. Affected individuals who develop these tumors may experience severe, acute and chronic problems. Indeed, aggressive, malignant, and/or disseminated tumors may result in death. Tumor surveillance enables early intervention, which, in turn, should lead to improved clinical outcomes. However, the desire for intensive surveillance strategies must be balanced against medical and psychosocial risks. In 2017, consensus HPPS surveillance recommendations addressing germline predisposition to SDHA, SDHAF2, SDHB, SDHC, SDHD, MAX, TMEM127 (collectively, SDHx+) related tumors were published after the inaugural AACR Childhood Cancer Predisposition Workshop. Based on the limited available clinical data at that time, these recommendations advocated a uniform approach to tumor surveillance in HPPS. Since then, several other groups have proposed alternative consensus surveillance guidelines. Although these surveillance approaches share some common elements, including recommendations tailored to emerging differences in tumor phenotype based on underlying specific SDHx+ genes, these approaches also vary significantly amongst each other. As clinical data continue to accrue, it is critical that surveillance strategies continue to be refined to address emerging genotype-phenotype differences. In this review, we provide a brief up-to-date clinical overview of HPPS and describe recently proposed tumor surveillance regimens. We then detail our updated consensus pediatric-focused tumor surveillance recommendations from the 2023 AACR Childhood Cancer Predisposition Workshop.

BACKGROUND:Ovarian juvenile granulosa cell tumors (juvGCT) are rare sex cord-stromal tumors that occur primarily in children and adolescents. This study summarizes the clinical presentation and outcomes of patients with juvGCT. METHODS:Patients were enrolled in the International Ovarian and Testicular Stromal Tumor and/or International Pleuropulmonary Blastoma/DICER1 Registries. Available medical records were abstracted, and pathology was centrally reviewed. Surgical staging was classified using the 2014 International Federation of Gynecology and Obstetrics (FIGO) criteria. RESULTS:In total, 70 patients with juvGCT enrolled and were diagnosed between 2001 and 2024; most patients (81%, 57 of 70) presented with FIGO stage I disease. Adjuvant chemotherapy was given in 30% (21 of 70); all regimens were platinum-based. Three-year event-free survival among patients with stage IA tumors was 80.2% (95% confidence interval [CI], 62.4%-100.0%), IC1 was 87.4 (95% CI, 72.4%-100.0%), IC2-IC3 was 63.6% (95% CI, 40.7%-99.5%), and II-IV was 48% (95% CI, 24.6%-93.8%). Of the patients with recurrent juvGCT with known mitotic index (MI), all had MI greater than 19 mitoses per 10 high power fields (HPF) at diagnosis. CONCLUSION:Outcomes were worse for patients with FIGO stage ≥IC2 disease and for tumors with >19 mitoses per 10 HPF. Given the prognostic significance of MI, the authors strongly recommend the assessment of MI for all juvGCTs. More information about tumor biology is critical to identify which patients may benefit from adjuvant chemotherapy and to facilitate the development of novel therapies.

Von Hippel-Lindau disease (VHL) is a genetic condition characterized by a high lifetime risk for tumors and cysts throughout the body, including the central nervous system, visual-auditory systems, and intra-abdominal organs. This neoplasia leads to significant morbidity and potential mortality in affected individuals. Tumor surveillance enables early intervention and leads to improved clinical outcomes. Since the 2017 publication of VHL tumor surveillance recommendations from the inaugural American Association for Cancer Research Childhood Cancer Predisposition Workshop, several other groups have proposed alternative consensus surveillance recommendations. Although these screening paradigms share some common elements, they also deviate from each other in some substantial ways. Clinical data continue to accrue in VHL, allowing the condition to be better characterized. Furthermore, surgical techniques have improved over time, and the option of targeted medical therapy has emerged for individuals with VHL. It is critical that surveillance strategies continue to be refined. In this perspective, we provide an up-to-date clinical overview of VHL, describe recently proposed tumor screening regimens, and finally present our updated consensus tumor surveillance recommendations during childhood and adolescence from the 2023 American Association for Cancer Research Childhood Cancer Predisposition Workshop.

PURPOSE:Sertoli-Leydig cell tumors (SLCTs) are rare sex cord-stromal tumors, representing <0.5% of all ovarian tumors. We analyze the role of germline DICER1 status in outcomes of ovarian SLCT. METHODS:Patients with SLCT were enrolled in the International Pleuropulmonary Blastoma/DICER1 Registry and/or the International Ovarian and Testicular Stromal Tumor Registry. Medical records were systematically abstracted, and those with known germline DICER1 status were selected for analysis. RESULTS:Of 162 patients with SLCT, 60% had a germline DICER1 pathogenic or likely pathogenic (P/LP) variant. The adjusted 3-year recurrence-free survival (RFS) was 87.2% (95% CI, 79.4 to 95.8) for patients with a germline DICER1 P/LP variant compared with 78.1% (95% CI, 66.4 to 91.9) for those without a germline DICER1 P/LP variant (P = .043). The adjusted 3-year and 5-year overall survival (OS) was 93.9% (95% CI, 87.3 to 100.0) for those with a germline DICER1 P/LP variant compared with the 3-year OS of 91.3% (95% CI, 83.4 to 100.0) and the 5-year OS of 78.2% (95% CI, 63.8 to 95.9) for those without a germline DICER1 P/LP variant (P = .021). Among patients with a germline DICER1 P/LP variant, the risk of a subsequent, nonrecurrent event was 36.2% (95% CI, 21.4 to 48.1) within 10 years. Previous/concurrent and subsequent neoplasms were rare among those without a germline DICER1 P/LP variant. CONCLUSION:This cohort study of patients with SLCT demonstrated that those with germline DICER1 P/LP variants had superior RFS and OS even when adjusting for other prognostic factors. Beyond prognostic implications of a germline DICER1 P/LP variant, germline testing helps identify patients at risk of subsequent neoplasms, including metachronous SLCT.

Germline genetic testing is increasingly recommended at the time of a pediatric cancer diagnosis for children with solid tumors, but not routinely performed for patients with hematologic malignancies (HM). Studies regarding incidence of hereditary hematologic malignancies (HHM) are limited with variable rates reported in pediatric and adult cohorts (4-39%). In this retrospective study, we evaluated the prevalence of HHM in children and young adults with newly diagnosed or relapsed HM and the impact of these diagnoses on treatment decisions. Methods Patients with newly diagnosed or relapsed HM treated between 1/1/2020 and 12/31/2024 in the Pediatric Oncology Clinic at Dana-Farber Cancer Institute were eligible. We performed focused retrospective chart review on all patients in our study cohort with additional chart abstraction done for those patients identified with a HM who received genetic counseling (GC). All germline genetic testing was done using cell sources suitable for accurate detection of germline variants. Germline testing primarily consisted of multi-gene panels that screened >200 genes with known association to cancer predisposition and bone marrow failure. Results were obtained from a CLIA certified lab and variants were classified according to American College of Medical Genetics variant classification guidelines. Results 571 patients with a HM were included in our study cohort. 207/571 patients (36%) were referred for genetic counseling (GC). Of those seen for GC, 127 had a lymphoid neoplasm (acute lymphoblastic leukemia 48%, Hodgkin lymphoma 6%, non-Hodgkin lymphoma 4%, lymphoblastic lymphoma 3%) while 80 had a myeloid neoplasm (acute myeloid leukemia (AML), 32%, myelodysplastic syndrome 5%, myeloproliferative neoplasms 2%). The mean age of the GC-evaluated cohort at initial diagnosis of their HM was 9.1 years (0.2-28.4) with male predominance (62%). All 207 patients seen for GC were offered germline testing, and 141 patients (68%) consented. A pathogenic or likely pathogenic (P/LP) variant was identified in 67/141 (48%) patients. Specifically, 16 patients (16/141, 11%) of the tested cohort had a P/LP variant in a gene associated with a HHM and 11 patients (11/141, 8%) had a P/LP variant in a gene associated with solid tumor risks. One patient harbored two germline variants: one with HHM risk and the other with solid tumor risk. The remaining 41 patients (41/141, 29%) had a P/LP variant associated with carrier status of an autosomal recessive syndrome or risk for non-cancer phenotypes only. An additional 7 patients had a variant of uncertain significance (VUS) in a gene associated with HHM that was highly consistent with their phenotype and met at least one additional suggestive feature: functional evidence of pathogenicity, rarity in population databases, or familial segregation. In summary, 33 patients (33/141, 23%) had a P/LP variant or highly suspicious VUS in a cancer risk gene. Of that cohort, 54% (18/33) presented with myeloid disease while 45% (15/33) had a lymphoid malignancy. The P/LP variants associated with HHM included 3 patients with GATA2, two patients each with RUNX1, DDX41, POT1, and MPO, and one patient each with CBL, TP53, PAX5, CDKN2A and constitutional mismatch repair deficiency (PMS2 biallelic). For the 7 patients with highly suspicious VUS, the genes involved included ETV6, GATA2, LCP1, CEBPA, GATA1, TP53, and PIK3CD. AML treatment was upstaged to include hematopoietic stem cell transplantation in 2 patients due to their germline results. For all other patients, the germline results did not impact therapy but did lead to subsequent cancer surveillance and other practice changes, including cascade testing recommendations for family members, where applicable. ConclusionPrevalence of germline predisposition to pediatric HM remains unclear. Acknowledging the referral bias of this cohort, our findings show a significant rate (23%) of pediatric HM patients with a HHM, cancer predisposition syndrome, or VUS highly suggestive of such risk. Our data supports universal germline testing at time of HM diagnosis. In doing so, we will more accurately define the prevalence of HHM and determine if HHMs confer higher risk of relapse and adverse treatment effects in specific disease subsets.

Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition condition characterized by a high lifetime risk for a wide spectrum of malignancies associated with germline pathogenic/likely pathogenic variants in the TP53 tumor suppressor gene. Secondary malignant neoplasms are particularly common. Early cancer detection through surveillance enables early intervention and leads to improved clinical outcomes with reduced tumor-related mortality and treatment-related morbidity. Since the 2017 publication of LFS tumor surveillance guidelines from the inaugural American Association for Cancer Research Childhood Cancer Predisposition Workshop, understanding the genotype-phenotype relationships in LFS has evolved, and adaptations of the guidelines have been implemented in institutions worldwide. The "Toronto Protocol" remains the current standard for lifelong surveillance; however, as outlined in this perspective, modifications should be considered about the use of certain modalities to target organs in an age-dependent manner. The Working Group's recommendations have also been extended to include a more detailed outline for surveillance in the adult TP53 pathogenic/likely pathogenic variant carrier population, based on the recognition that early education of both practitioners and patients on what to expect after the transition from childhood/adolescence to young adulthood is important in preparing them for changes in surveillance strategies. In this perspective, we provide an up-to-date clinical overview of LFS and present our updated consensus tumor surveillance recommendations from the 2023 American Association for Cancer Research Childhood Cancer Predisposition Workshop.