Consensus classification of hereditary hematologic malignancies

IntroductionPrecision medicine has become central to pediatric oncology, with germline genomic sequencing commonly integrated into routine care. Families must interpret complex genomic findings during emotionally vulnerable periods, generating mixed reactions ranging from clarity and relief to anxiety and uncertainty. Palliative care clinicians, genetic counselors, psychologists, social workers, and oncology providers may each contribute to supporting families as they interpret and integrate these findings over the course of a child’s cancer care and beyond. Little is known about the trajectory of parental emotional and cognitive responses after receiving germline sequencing results, limiting clinicians’ ability to anticipate support needs across the cancer care continuum. This study quantitatively examines parental emotional and cognitive responses across time following disclosure of germline sequencing results in a pediatric oncology setting.MethodsParents (n = 218) self-reported sequencing-related distress, positive feelings, intrusive thoughts, certainty, and self-efficacy using validated measures at two longitudinal follow-up points after disclosure of their child’s germline test results. Outcomes were compared across germline test result types (pathogenic/likely pathogenic [P/LP], n = 31 [14%]; variants of uncertain significance [VUS], n = 86 [39%]; and negative, n = 101[46%]).ResultsParents of children receiving P/LP or P/LP+VUS results reported significantly higher distress yet greater positive feelings than parents receiving negative results. Notably, certainty and self-efficacy increased from Timepoint 1 (median 254 days following return of results) to Timepoint 2 (median 537 days). Intrusive thoughts did not significantly differ by genetic result type or change over time; however, the factors contributing to intrusive thoughts could not be determined from the current study.DiscussionThese findings provide insight into how families adapt to germline genomic information following a pediatric cancer diagnosis. As precision medicine becomes increasingly embedded in pediatric oncology, structured follow-up and communication that address families’ evolving informational and psychosocial needs are essential to ensure care that is scientifically precise, emotionally attuned, and centered on the family experience.

The contribution of 9p deletion to B cell acute lymphoblastic leukemia (B-ALL) has remained elusive since its discovery more than 40 years ago. Here we show that loss of CD72 is recurrent in B-ALL cases containing PAX5 deletions, and that Cd72 haploinsufficiency drives B-ALL development in Pax5+/- mice. Mechanistically, Cd72+/-;Pax5+/- precursor B cells exhibited an inflammatory transcriptional profile characterized by a decrease in Myd88 expression, a finding that aligns with our previous studies of B-ALL development in Pax5+/- mice following exposure to immune stressors. These combined genomic analyses and functional models provide compelling evidence that co-deletion of 2 contiguous genes, Pax5 and Cd72, drives B cell leukemogenesis.

Germline mutations in POT1 are linked to familial cancer predisposition, and somatic POT1 mutations occur recurrently in tumors. These mutations promote oncogenesis by enabling aberrant telomere elongation. For inherited POT1 mutations, a critical question is the extent to which elongated telomeres are transmitted to the next generation from the POT1 carrier parent and whether the inherited hyper-elongated telomeres elevate cancer risk. Using a nanopore sequencing approach that provides haplotype-specific telomere length measurements, we examined telomere inheritance in families harboring POT1 mutations. We found that individuals preferentially inherit their longest telomeres from the carrier parent, consistent with extensive telomere elongation in the carrier germline, whereas their comparatively short telomeres originate from the non-carrier parent. Analysis of carrier and non-carrier siblings showed that both sets of parental telomeres are longer in POT1 carriers, yet the shortest non-carrier-derived telomeres undergo disproportionately greater elongation than those inherited from the carrier parent. This identifies a mechanism of genetic anticipation in which the inheritance of long telomeres from one parent drives excessive extension of shorter telomeres. These findings demonstrate that telomere length inherited from both parents jointly defines the telomere-based tumor suppressor mechanism.

Fear of cancer recurrence (FCR) is a significant but understudied concern among parents of childhood cancer survivors. This study quantitatively characterized parental FCR and explored potential demographic and clinical correlates among parents of children treated for cancer. Parents (N = 192) completed the Fear of Cancer Recurrence Inventory-Parent Short Form (FCRI-Parent) and provided demographic information. Clinical variables were obtained from medical chart review. Associations between FCR and demographic or clinical variables were analyzed using t-tests, ANOVAs, and Pearson's correlations. Parents reported a mean FCR score of 18.64 (SD = 8.73), with 42.2% of parents endorsing FCR above a score of 22. Parental FCR significantly varied by parent race, education, and spirituality. Higher FCR was also significantly negatively correlated with child age, time since diagnosis, and time since treatment completion. Parents of children with central nervous system tumors or hematological malignancies endorsed significantly higher FCR compared to parents of children with solid tumors. Findings build on previously identified psychosocial needs for parents of children treated for cancer by quantitatively describing parental FCR and exploring subgroups that may be at increased risk for FCR. Tailored interventions, including strategies that support spiritual coping, may help mitigate FCR among at-risk parents.

Purpose:Pathogenic or likely pathogenic (P/LP) variants are increasingly identified in genes more commonly associated with adult-onset cancer predisposition, but their prevalence and relevance to a child's presenting cancer remain unclear. Methods:We retrospectively analyzed 1,280 consecutive pediatric patients with cancer who underwent clinical germline sequencing, using a virtual panel, from 2021 to 2024. Genes with P/LP variants were categorized as aoCPG or pediatric-onset cancer predisposition genes (poCPG) according to cancer risk before age 18 years and pediatric surveillance recommendations. Variant relevance was adjudicated using tumor diagnosis/histopathology, immunohistochemistry, and tumor molecular features and classified as primary, secondary, or indeterminate. Results:Among 1,280 patients, 197 (15.4%) harbored 211 P/LP variants across 54 genes. Sixty-six variants (31.3%) occurred in aoCPG, 87 (41.2%) in poCPG, and 58 (27.5%) were heterozygous variants in autosomal recessive genes. Among adult-onset variants, 7 (10.6%) were primary, 54 (81.8%) secondary, and 5 (7.6%) indeterminate. Among pediatric-onset variants, 77 (88.5%) were primary and 10 (11.5%) secondary. Six patients (3 adult-onset variants; 3 pediatric-onset variants) received targeted therapy informed by germline/somatic sequencing results. Conclusion:In pediatric oncology, most variants in aoCPG are secondary rather than tumor-related findings. Tumor-informed interpretation, beyond variant classification, may improve reporting, counseling, and therapeutic decision-making.

Recent studies reveal that a growing proportion of children with hematologic malignancies (HM) harbor germline pathogenic or likely pathogenic variants (hereafter "PV") in cancer predisposing genes (CPG). Identifying these children is critical as the information gained guides leukemia therapy, family testing, and selection of related donors for hematopoietic cell transplantation (HCT). Nevertheless, it remains unclear how often children with HM being considered for HCT undergo genetic evaluation, and whether germline data are used to guide clinical practice. To address this gap, we reviewed the records of 286 children who underwent >1 HCT for HM at our institution between Jan 1, 2017, and Dec. 31, 2023. We examined the timeline of genetic evaluation, prevalence of germline PV, and impact of PV on HCT outcomes. Overall, 227 (79%) children met with a genetic counselor prior to their first HCT, 192 underwent testing, and 142 had results returned before the HCT. Thirty-six patients (19%) harbored a germline CPG PV, among whom 12 (6%) had PV aligning with their HM diagnosis. One of five patients who received an HCT from a PV-positive relative developed donor-derived leukemia. We observed no significant differences in time to neutrophil engraftment, cumulative incidence of relapse, or overall survival between patients with and without PV, although the cohort was heterogeneous with respect to the underlying PV. Given the high prevalence of PV in children with HM, prompt referral to genetics is warranted to ensure timely counseling and germline testing to detect a hereditary predisposition and inform donor selection for HCT.

Abstract Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome characterized by excessive immune cell activation and hypersecretion of inflammatory cytokines, many of which signal via the Janus kinases (JAKs). Preclinical studies have demonstrated that the JAK1/2 inhibitor ruxolitinib ameliorates disease manifestations and prolongs survival in mouse models of HLH. Similarly, clinical studies have shown preliminary evidence of efficacy for treatment of HLH in children; however, prospective trials evaluating optimal ruxolitinib doses in HLH in pediatric are lacking. To address this gap, we developed HLHRUXO, a prospective clinical trial using a ruxolitinib-containing regimen for children with HLH. Patients received ruxolitinib 25 mg/m2 twice daily combined with dexamethasone, with or without etoposide, for 8 weeks, followed by continuation therapy at the discretion of the treating physician. Pharmacokinetic studies were performed on days 1 and 8. A total of 8 patients (average age, 7.6 years; 5 with primary HLH pHLH], and 3 with secondary HLH [sHLH]) completed the study; no patients experienced dose-limiting adverse events. All patients experienced a favorable response at 1 week, demonstrating clinical stabilization and improvement in serum ferritin levels. Furthermore, all 5 patients with newly diagnosed HLH (3 with pHLH, 2 with sHLH) achieved a complete response (CR) by 8 weeks, and all were alive at 1 year. One patient with relapsed/refractory sHLH achieved a CR at 8 weeks and was alive at 1 year, whereas 2 others with relapsed/refractory pHLH died. Our findings confirm the safety of this ruxolitinib-containing regimen for pediatric HLH, with the best results observed in patients with newly diagnosed disease. Further studies of ruxolitinib as frontline therapy for children with HLH are warranted. This trial was registered at www.clinicaltrials.gov as NCT04551131.

OBJECTIVE:Children with cancer increasingly undergo germline genetic testing to identify genetic predispositions and inform clinical care options. Parents of children with pathogenic/likely pathogenic (P/LP) germline results have reported more distress than parents of children with negative results. Little is known about modifiable risk and resilience factors for intervention, such as cognitive perceptions. This study examined the moderating effects of parents' cognitive perceptions on adjustment to their child's germline genetic test results. METHODS:Parents (N = 191) completed surveys reporting cognitive perceptions (i.e., intolerance of uncertainty, symptom attributions, and perceptions of child physical vulnerability) and psychological adjustment 1-3.99 years post-disclosure of their child's genetic test results. Moderation analyses examined whether parents' cognitive perceptions moderated the relation between children's cancer predisposition genetic testing results (P/LP, uncertain [VUS], or negative) and parental psychological adjustment. RESULTS:Moderation analyses revealed significant interactions between genetic test results and both intolerance of uncertainty and psychological attributions for children's symptoms. Specifically, parents of children with P/LP results endorsed significantly more distress and uncertainty compared to each VUS and negative results, only in cases of moderate to high intolerance of uncertainty and psychological attributions (distress outcomes). In contrast, somatic attributions for symptoms and perceived child vulnerability were directly associated with higher distress regardless of results. CONCLUSIONS:Cognitions such as intolerance of uncertainty and psychological symptom attribution may contribute to distress among parents of children with P/LP results. Therefore, cognitive interventions (e.g., Cognitive Behavioral Therapy, Acceptance and Commitment Therapy) may help parents manage distress regarding their child's genetic cancer risk.

BACKGROUND:Germline genetic susceptibility to pediatric acute lymphoblastic leukemia (pALL) remains incompletely characterized across the allelic spectrum, including ultrarare, high-penetrance cancer-predisposing variants (CPV). METHODS:We analyzed germline genetic data from 3,208 pALL survivors, 7,821 non-pALL survivors, and 377 noncancer controls from the St. Jude Lifetime Cohort Study and the Childhood Cancer Survivor Study. We evaluated enrichment of ultrarare CPVs in 60 curated cancer predisposition genes and conducted a genome-wide association study (GWAS) meta-analysis of common and low-frequency variants. RESULTS:Compared with noncancer controls, pALL survivors showed significant enrichment of ultrarare CPVs in BRCA1, PALB2, and PTPN11, in addition to established susceptibility genes CDKN2A and TP53. GWAS meta-analysis replicated 93% of previously reported pALL risk variants, with 7 loci achieving genome-wide significance (P < 5 × 10-8). Two novel variants were identified: rs112425636 within secreted and transmembrane protein 1 [SECTM1; odds ratio (OR) = 1.60; 95% confidence interval (CI), 1.39-1.84; P = 2.77 × 10-11] and rs1821340 at 8q24.21 (OR = 1.33; 95% CI, 1.22-1.44; P = 1.63 × 10-11). The rs112425636 risk allele was associated with reduced SECTM1 expression in B-cell pALL tumors. The median polygenic risk score was significantly higher in pALL survivors than in non-pALL survivors and noncancer controls (P = 6.64 × 10-147). Single-nucleotide polymorphism-based heritability was 0.19 (standard error = 0.054). CONCLUSIONS:This study comprehensively characterizes the genetic etiology of pALL by integrating ultrarare and common germline variations, expanding the spectrum of inherited risk factors. IMPACT:These findings advance the understanding of pALL genetic architecture and inform future risk stratification.

We report pediatric myeloid neoplasms with secondary somatic UBA1 mutations: one with somatic NRAS and UBA1_S56F subclone, another with germline RUNX1 disorder and somatic SH2B3 and UBA1_M41L clones. No UBA1 mutations were found among 834 pediatric AML cases.

Over 100 pediatric cancer predisposition syndromes (CPS) are now recognized, each conferring unique risks for cancer and, at times, nononcologic manifestations. Identification of children at increased genetic risk for cancer can optimize outcomes by informing clinical care, including the institution of cancer surveillance to identify tumors at their earliest and most treatable stages. Within surveillance regimens, imaging maintains a prominent role among testing methods. The large menu of available imaging tests provides ample options for detecting incipient tumors. The imaging examination performed depends on the underlying predisposition syndrome, expected age of tumor occurrence, and attributes of the modality. As surveillance for many CPS includes lifelong repeated imaging, surveillance protocols must consider cumulative toxicities, including anesthesia and radiation exposure, as well as potential economic burdens. This review explores imaging modalities used for pediatric cancer surveillance, critically assessing the association between modality-specific attributes and pediatric cancer surveillance practices. The article focuses on the most common and penetrant CPS in childhood and provides illustrative cases to show the radiologic concepts underpinning the current recommendations. Rapid advances in imaging techniques, further recognition of genotype-phenotype associations within CPS, and the emergence of nonimaging surveillance possibilities, including circulating DNA, make the space of surveillance for pediatric CPS an ever-changing field.

PURPOSE:To determine whether transitioning from a two-visit consent process led by an expert consenter to a decentralized model of consenting using an educational video and a clinical care provider translated into sustained decisional satisfaction and comparable levels of understanding about genomic sequencing for cancer predisposition. MATERIALS AND METHODS:A total of 150 parents of children with cancer agreed to participate in this study approximately 4 weeks (±2 weeks) after a consent conversation for genomic sequencing using a decentralized model to assess their genetic knowledge and decision satisfaction. Results were compared with a cohort of parents (n = 121) consented with an expert consenter using a two-visit process consisting of an informational session followed by knowledge reinforcement 5 weeks (±3 weeks) after diagnosis. RESULTS:Among parents in the decentralized consent process, 94% recalled providing consent. However, 53% could not recall who conducted the consent conversation. Less than half (44%) recalled reviewing a copy of the consent form, and only 17% viewed the educational video. Overall, parents endorsed consenting to sequencing as the right choice (mean 4.4/5-point Likert) without decisional regret (1.5 of 5). Parents who consented through the decentralized process did not significantly differ in genetic knowledge from the baseline preconsent genetic knowledge assessment for the comparison sample. Only 56% of parents who consented through the decentralized process answered at least 75% of the knowledge questions correctly (P < .001), compared with 82% of parents who consented through the expert consenter model. CONCLUSION:While the decentralized consenting processes translated into lower knowledge scores, parents maintained high levels of decisional satisfaction. Further research is warranted to maximize knowledge exchange and ensure values-aligned consent in decentralized models.

We report a case of hereditary bilateral retinoblastoma due to a de novo germline inversion on chromosome 13, resulting in disruption of the RB1 gene. The patient is a 22-month-old female who initially presented to the emergency room at 11 months of age with an erythematous left eye and leukocoria of the right eye. Computed tomography (CT) of the brain and orbits showed solid internal calcifications arising from the posterior globes concerning for bilateral retinoblastoma. Magnetic resonance imaging (MRI) of the brain and orbits confirmed bilateral retinoblastoma without associated pineal region or suprasellar mass. On initial examination under anesthesia, the right eye showed one tumor in the macula and two tumors in the inferior mid-periphery. Sub-retinal seeding extended to the inferior periphery. The left eye was enucleated and pathology showed leptomeningeal extension along the optic nerve extending to the surgical margin. The patient was treated on a non-protocol treatment plan with five cycles of vincristine, carboplatin, etoposide, cyclophosphamide, and weekly intraventricular topotecan via Ommaya reservoir, followed by autologous stem cell rescue. Tumor analysis showed loss of pRB protein expression by immunohistochemistry and methylation copy number profiling showed several segmental gains and losses, including focal loss of RB1 on 13q. A 123-gene cancer predisposition germline panel using genome and exome sequencing initially did not identify any RB1 single nucleotide variants or insertion/deletions. Subsequent constitutional chromosome analysis for RB1 showed a paracentric inversion between bands 13q14.2 and 13q31. Optical genome mapping (OGM) showed that the proximal breakpoint of the balanced inversion at 13q14.2 was within intron 17 of RB1, while the distal breakpoint at 13q31.3 did not interrupt any known genes of clinical significance. We review the various molecular techniques that aided in diagnosis of this patient and provide a summary of similar RB1-disrupting structural variants reported in the literature.

BACKGROUND:Cancer-predisposing germline variants are increasingly identified and disclosed during pediatric oncology clinical care. To understand whether and how parents communicate about identified cancer predisposition syndromes (CPS) with their adolescent and young adult (AYA) children, this study qualitatively characterized the content and approach (e.g., timing) of parent-AYA communication about AYAs' CPS. PROCEDURE:AYAs with a CPS identified during clinical cancer care and their parents independently completed semi-structured interviews regarding their CPS-related communication. Interviews were completed 1.0-3.99 years following genetic test result disclosure and coded using inductive content analysis. RESULTS:Twenty-one AYAs (age 13-20 years) and 24 parents (17 mothers, 6 fathers, 1 grandmother) completed interviews. Although most parents reported repeatedly communicating with their child, several AYAs did not recall these conversations and nearly half described a one-time conversation. Parents described communicating to disclose genetic results, educate regarding cancer risk, attend to AYAs' emotions, and provide anticipatory guidance for future risk management. Parents whose AYA had a CPS conferring risk for adult-onset cancers (e.g., colon cancer) expected to continue to remind their AYA about cancer surveillance well into adulthood. Parents and AYAs described their CPS-related communication as "light," prompted by the AYAs' medical appointments and questions, and impacted by parents' understanding of the CPS. CONCLUSIONS:Our findings highlight areas for targeted genetic education and support. Parents may benefit from screening to ascertain their CPS understanding, education regarding AYAs' CPS-related information and emotional support needs, and support for transitioning AYAs to independently manage CPS-related health needs. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT04848142.

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 .

BackgroundPrecision-based approaches are reshaping healthcare by tailoring assessments and therapies to a patient's individual needs. To ensure nursing remains integral to this evolving landscape, active collaboration with multidisciplinary teams is essential. Nurses must understand the clinical implications of genomic testing, be provided educational opportunities, and understand the patient and parent perspectives of precision-based care. Thus, the nurse is empowered to translate research into advancing patient-centered care.ObjectiveThis review presents our multidisciplinary team's approach to understanding the educational needs of nurses and physicians, as well as patient and parent perspectives of precision-based care, along with key nursing considerations.MethodThis is a process paper describing one institution's journey through in-depth inquiries identifying knowledge gaps related to genomic testing of tumor and germline tissues, consenting, pharmacogenetics, and gene therapy. We also explored expectations held by patients and their families surrounding testing and return of results.ResultsOur findings offer key insights, including the need for education of healthcare providers, equitable patient education and access to pharmacogenomic and cancer genomic testing, ethical complexities within the consenting process, and perspectives from parents and patients on clinical genomics and gene therapy for sickle cell disease.ConclusionThe findings from this institution's efforts may help guide or inform other institutions working to deliver precision-based oncology and hematology care. Nurses must be equipped with expertise to advocate effectively for patients and families. In doing so, they can guide them through the opportunities and challenges of precision-based care.