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A letter to the editor is presented concerning an article on germ-line mutations published in the May 14, 1992 issue.

Introduction: In Canada, care for individuals with hereditary cancer is fragmented across the provinces and territories, with carriers of pathogenic variants in cancer-susceptibility genes seeing multiple doctors and often advocating for their own management plans. The need for a national registry of carriers has been well established. While other cancer consortia exist, barriers in clinical and genomic data sharing limit the utility of the information gathered., Methods and Analysis: Within the province of Ontario, the Ontario Hereditary Cancer Research Network (OHCRN), funded by and located at the Ontario Institute for Cancer Research, is being developed to fill this gap. The registry will hold clinical, genomic and self-reported data from consented carriers and will make this data available to qualified researchers in anonymised and aggregated form. Individuals must agree to certain components to participate in OHCRN; there are also optional consents participants can agree to without impacting their involvement in OHCRN. We plan to open the registry for participant enrolment in mid-2025., Ethics and Dissemination: Ethics approval for registry creation was obtained from the Ontario Cancer Research Ethics Board, a centralised body that streamlines reviews for cancer research studies in Ontario. Registry data will be disseminated to participants and researchers as aggregate data through the OHCRN website and presented at scientific conferences, made available to Ontario Health (Cancer Care Ontario) to inform policy and evidence-based practice, as well as be available to the scientific community for further analysis and answering relevant questions., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Central nervous system germ cell tumors (CNS-GCT) are malignant neoplasms that arise predominantly during adolescence and young adulthood. These tumors are typically sensitive to treatment, but resulting long-term health deficits are common. Additional clinical challenges include surgical risks associated with tumor biopsy, and need to determine treatment response for adapting radiotherapy protocols. The aim of this study was to establish the detectability of circulating-tumor DNA (ctDNA) from cerebrospinal fluid (CSF) of children with CNS-GCT as a potential biomarker. We obtained CSF from patients with CNS-GCT by lumbar puncture or intra-operatively. Cell-free DNA (cfDNA) was extracted and subjected to low-pass whole genome sequencing (LP-WGS). Copy-number alterations (CNAs) were inferred and served as a marker of measurable residual disease (MRD). Comparisons with imaging findings and tumor marker levels were made. A total of 29 CSF samples from 21 patients (16 with germinoma, 5 with non-germinomatous GCT) were sequenced. Twenty samples from 19 patients were collected at diagnosis, and 9 samples from 7 patients were collected during or after therapy. Among the diagnostic samples, CNAs were detected in samples from 17/19 patients (89%), which included 8 with marker-negative tumors. Specific clinical scenarios suggested that serial cfDNA analysis may carry utility in tracking treatment responses as well as clarifying indeterminate imaging findings. Our results provide evidence for the high-sensitivity in detecting ctDNA from CSF of CNS-GCT patients using LP-WGS, with potential utility for non-invasive diagnosis and disease monitoring in upcoming CNS-GCT studies., Competing Interests: Declarations. Ethics approval and consent to participate: This study was approved by the Hospital for Sick Children Research Ethical Board (REB # 1000071241) and the Hong Kong Children’s Hospital Research Ethics Committee (HKCH-REC-2020-068). Written informed consent was obtained from all patients, their parents or guardians. Consent for publication: Written informed consent for the publication was obtained from all patients participants, their parents or guardians. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Whole-body MRI (WBMRI) is an integral part of screening infants, children, and adolescents for presymptomatic neoplasms in certain cancer predisposition syndromes, which include Li-Fraumeni and constitutional mismatch repair deficiency syndromes, among others. The list of syndromes in which WBMRI adds value, as part of a comprehensive surveillance protocol, continues to evolve in response to new evidence, growing experience, and more widespread adoption. In July 2023, the AACR reconvened an international, multidisciplinary panel to revise and update recommendations stemming from the 2016 AACR Special Workshop on Childhood Cancer Predisposition. That initial meeting resulted in a series of publications in Clinical Cancer Research in 2017, including "Pediatric Cancer Predisposition Imaging: Focus on Whole-Body MRI." This 2024 review of WBMRI in cancer predisposition syndrome updates the 2017 WBMRI publication, the revised recommendations derived from the 2023 AACR Childhood Cancer Predisposition Workshop based on available data, societal guidelines, and expert opinion. Different aspects of acquiring and interpreting WBMRI, including diagnostic accuracy, are discussed. The application of WBMRI in resource-poor environments, as well as integration of whole-body imaging techniques with emerging technologies, such as cell-free DNA ("liquid biopsies") and artificial intelligence/machine learning, is also considered., (©2024 American Association for Cancer Research.)

PTEN hamartoma tumor syndrome (PHTS), DICER1-related tumor predisposition (DICER1) and tuberous sclerosis complex (TSC) are rare conditions which each increase risk for distinct spectra of benign and malignant neoplasms throughout childhood and adulthood. Surveillance considerations for each of these conditions focus on patient and family education, early detection and multidisciplinary care. In this manuscript, we present updated surveillance recommendations and considerations for children and adolescents with PHTS, DICER1 and TSC and provide suggestions for further research in each of these conditions.

Rhabdoid tumor predisposition syndrome type-1 (RTPS1) is characterized by germline pathogenic variants in SMARCB1 and development of INI1-deficient rhabdoid tumors in early childhood. Due to its poor prognosis, the risk of subsequent tumor development and the impact of surveillance at later ages are poorly understood. We retrospectively reviewed individuals referred to the Cancer Genetics Program at The Hospital for Sick Children for SMARCB1 genetic testing and/or surveillance for RTPS1. In addition, to explore characteristics of late-onset tumors in RTPS1, a literature review was conducted. Of eighty-three individuals (55 probands and 28 family members), 12 probands and 4 family members were genetically confirmed with RTPS1. Four pediatric probands with RTPS1 underwent surveillance. An additional three individuals, including one patient with 22q11.2 distal deletion without history of tumor, one patient with negative genetic testing results but clinically diagnosed with RTPS1, and one sibling identified through cascade testing, underwent surveillance. Three patients with RTPS1 developed tumors between the ages of 9 and 17, including malignant rhabdoid tumors (N = 3), schwannomas (N = 4), and epithelioid malignant peripheral nerve sheath tumor (N = 1). Three of these lesions were asymptomatically detected by surveillance. A literature review revealed 17 individuals with RTPS1 who developed INI1-deficient tumors after age five. Individuals with RTPS1 remain at elevated risk for developing INI1-deficient tumors after the peak age of rhabdoid tumor in early childhood. Extension of surveillance beyond 5 years of age could lead to improved survival and reduced morbidity for these patients, and prospective evaluation of revised approaches will be important., Competing Interests: Competing interests The authors declare no competing interests. Ethics approval This study was approved by the Research Ethics Board (REB#1000053261) at the Hospital for Sick Children (SickKids; Toronto, Canada)., (© 2024. The Author(s), under exclusive licence to European Society of Human Genetics.)

Approximately 8.5%-16.2% of childhood cancers are associated with a pathogenic/likely pathogenic germline variant-a prevalence that is likely to rise with improvements in phenotype recognition, sequencing, and variant validation. One highly informative, classical hereditary cancer predisposition syndrome is Li-Fraumeni syndrome (LFS), associated with germline variants in the TP53 tumor suppressor gene, and a >90% cumulative lifetime cancer risk. In seeking to improve outcomes for young LFS patients, we must improve the specificity and sensitivity of existing cancer surveillance programs and explore how to complement early detection strategies with pharmacology-based risk-reduction interventions. Here, we describe novel precision screening technologies and clinical strategies for cancer risk reduction. In particular, we summarize the biomarkers for early diagnosis and risk stratification of LFS patients from birth, noninvasive and machine learning-based cancer screening, and drugs that have shown the potential to be repurposed for cancer prevention., (Copyright © 2024 Cold Spring Harbor Laboratory Press; all rights reserved.)

Background: Clinical and experimental studies indicate that the tumor protein p53 (TP53) gene loss of function due to missense mutations (MMs) may confer sensitivity to anti-angiogenics. This effect seems to be linked to cross-talk mechanisms among TP53, vascular endothelial growth factor (VEGF), and VEGF receptors. We investigated whether specific TP53 MMs are associated with clinical outcomes of patients with metastatic colorectal cancer (mCRC) treated with first-line chemotherapy plus Bevacizumab. The study focused on KRAS-mutated, liver-only mCRC cases as a homogeneous subgroup that may represent a relevant setting for exploring this association., Materials and Methods: MMs were identified on primary tumors. MMs were classified by mutant-specific residual transcriptional activity scores (TP53RTAS) as transcriptionally inactive (TP53inactive = TP53RTAS 0%) or active (TP53active = TP53RTAS ≥ 1%) and used for stratifying patients in progression-free survival (PFS), response rate, and overall survival (OS) analyses., Results: The study population consisted of 62 patients. MMs were found in 39 cases (62%) with 16 having TP53inactive and 23 TP53active MMs. Patients with TP53inactive MMs showed better PFS in comparison with the remaining groups (wild-type and TP53active). This effect was retained in the multivariate model. A similar clinical impact was observed in the OS analysis. There was a significant difference in the overall response rate and rate of post-treatment resection of liver metastases between the TP53inactive and the wild-type or TP53active MMs cases., Conclusions: Specific TP53 MMs may identify sub-groups of patients who benefit from Bevacizumab-based systemic therapy and these findings could lead to novel tailored treatment strategies in this setting., (© The Author(s) 2024. Published by Oxford University Press.)

Zebrafish ( Danio rerio ) are a good model for cancer research including studies on chemotherapy treatments. We treated wild-type and miR-34a deletion mutant zebrafish embryos at 24 h post-fertilization with 1 µM of the topoisomerase I inhibitor, camptothecin (CPT), for 4 h to catalogue gene expression changes induced by this DNA damage treatment and to understand if these changes are influenced by loss of miR-34a. The 4 sample groups of 3 independent biological samples consisting of 30 embryos each were analyzed by RNA-sequencing using the recently updated zebrafish transcriptome annotation based on GRCz11, which enabled a more complete and sensitive read mapping and gene assignment than standard annotations. Using this gene expression estimates dataset as the primary resource, we performed a differentially expressed gene (DEG) analysis based on treatment as loss of miR-34a had minimal effects on CPT-induced expression changes. The DEGs were analyzed for Gene Ontology and KEGG pathway terms. Enriched terms and pathways among up-regulated genes were mostly related to stress, cell death, cell cycle regulation, transcriptional regulation, cell signalling, developmental processes and synthesis of retinol and steroid hormones. By contrast, down-regulated genes were most strongly associated with genes involved in key developmental processes, adhesion molecules, as well as some transport and metabolic pathways, together suggesting a "developmental shutdown". We also identified interferon-regulated genes and p53 target genes activated or inhibited by DNA damage due to topoisomerase I inhibition, suggesting that they are important components of the response to this type of DNA damage in zebrafish embryos., (© 2024 The Author(s).)

Secondary findings (SFs) from genomic sequencing can have significant impacts on patient health, yet existing practices guiding their clinical investigation are inconsistent. We systematically reviewed existing SFs policies to identify variations and gaps in guidance. We cataloged and appraised international policies from academic databases (n = 5, inception-02/2022) and international human genetic societies (n = 64; inception-05/2022), across the continuum of SFs selection, analysis, and clinical management. We assessed quality using AGREE-II and interpreted results using qualitative description. Of the 63 SFs policies identified, most pertained to clinical management of SFs (98%; n = 62; primarily consent and disclosure), some guided SFs analysis (60%; n = 38), while fewer mentioned SFs selection (48%; n = 30). Overall, policies recommend (1) identifying clinically actionable, pathogenic variants with high positive predictive values for disease (selection), (2) bioinformatically filtering variants using evidence-informed gene lists (analysis), and (3) discussing with affected individuals the SFs identified, their penetrance, expressivity, medical implications, and management (clinical management). Best practices for SFs variant analysis, clinical validation, and follow-up (i.e., surveillance, treatment, etc.) were minimally described. Upon quality assessment, policies were highly rated for scope and clarity (median score, 69) but were limited by their rigor and applicability (median scores, 27 and 25). Our review represents a comprehensive international synthesis of policy guiding SFs across the continuum of selection, analysis, and clinical management. Our synthesis will help providers navigate critical decision points in SFs investigation, although significant work is needed to address gaps in SFs analysis, clinical validation, and follow-up processes and to support evidence-based practice., Competing Interests: Declaration of interests Y.B. is a co-author of one of the guidelines included in this review and a member of the Board of Directors of ASHG., (Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Although tumors of Li-Fraumeni syndrome (LFS) have a premalignant or dormant phase that could be exploited by early imaging detection, this has been underevaluated in the literature. We present a case series of patients with LFS followed by imaging over time to highlight patterns of growth of tumors and hotspots of missed tumors in this population. Clinical and imaging features were available for 29 tumors of 24 carriers of a germline TP53 pathogenic variant, developed between 1999 and 2023 were retrospectively reviewed in a single tertiary pediatric center. Imaging characteristics of tumors were evaluated with MRI, CT, and radiographs. Local invasion, time interval for developing primary cancer, and/or recurrent disease and metastasis, and factors that delayed the tumor diagnosis were assessed. In patients with multiple tumors the median time intervals for development of first, second, and third primary cancers were 45.9, 79.8, and 28.1 months, respectively. Hotspots of missed tumors included superficial soft tissues, areas close to bones, on the scalp, in tissues around the adrenal region and in small hypodense lesions on brain CT. In conclusion, the pattern of growth of tumors is variable and erratic in LFS patients with some tumors presenting with a dormant pattern., Competing Interests: A.S.D. is the Principal Investigator of the following grants unrelated to the current study: Novo Nordisk (Research Grant), Terry Fox Foundation (Research Grant), PSI Foundation (Research Grant), Society of Pediatric Radiology (Research Grant), Radiological Society of North America (Education Grant). The remaining authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Wearable digital health technologies and mobile apps (personal digital health technologies [DHTs]) hold great promise for transforming health research and care. However, engagement in personal DHT research is poor., Objective: The objective of this paper is to describe how participant engagement techniques and different study designs affect participant adherence, retention, and overall engagement in research involving personal DHTs., Methods: Quantitative and qualitative analysis of engagement factors are reported across 6 unique personal DHT research studies that adopted aspects of a participant-centric design. Study populations included (1) frontline health care workers; (2) a conception, pregnant, and postpartum population; (3) individuals with Crohn disease; (4) individuals with pancreatic cancer; (5) individuals with central nervous system tumors; and (6) families with a Li-Fraumeni syndrome affected member. All included studies involved the use of a study smartphone app that collected both daily and intermittent passive and active tasks, as well as using multiple wearable devices including smartwatches, smart rings, and smart scales. All studies included a variety of participant-centric engagement strategies centered on working with participants as co-designers and regular check-in phone calls to provide support over study participation. Overall retention, probability of staying in the study, and median adherence to study activities are reported., Results: The median proportion of participants retained in the study across the 6 studies was 77.2% (IQR 72.6%-88%). The probability of staying in the study stayed above 80% for all studies during the first month of study participation and stayed above 50% for the entire active study period across all studies. Median adherence to study activities varied by study population. Severely ill cancer populations and postpartum mothers showed the lowest adherence to personal DHT research tasks, largely the result of physical, mental, and situational barriers. Except for the cancer and postpartum populations, median adherences for the Oura smart ring, Garmin, and Apple smartwatches were over 80% and 90%, respectively. Median adherence to the scheduled check-in calls was high across all but one cohort (50%, IQR 20%-75%: low-engagement cohort). Median adherence to study-related activities in this low-engagement cohort was lower than in all other included studies., Conclusions: Participant-centric engagement strategies aid in participant retention and maintain good adherence in some populations. Primary barriers to engagement were participant burden (task fatigue and inconvenience), physical, mental, and situational barriers (unable to complete tasks), and low perceived benefit (lack of understanding of the value of personal DHTs). More population-specific tailoring of personal DHT designs is needed so that these new tools can be perceived as personally valuable to the end user., (©Sarah M Goodday, Emma Karlin, Alexa Brooks, Carol Chapman, Christiana Harry, Nelly Lugo, Shannon Peabody, Shazia Rangwala, Ella Swanson, Jonell Tempero, Robin Yang, Daniel R Karlin, Ron Rabinowicz, David Malkin, Simon Travis, Alissa Walsh, Robert P Hirten, Bruce E Sands, Chetan Bettegowda, Matthias Holdhoff, Jessica Wollett, Kelly Szajna, Kallan Dirmeyer, Anna Dodd, Shawn Hutchinson, Stephanie Ramotar, Robert C Grant, Adrien Boch, Mackenzie Wildman, Stephen H Friend. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 03.09.2024.)

Germline pathogenic TP53 variants predispose individuals to a high lifetime risk of developing multiple cancers and are the hallmark feature of Li-Fraumeni syndrome (LFS). Our group has previously shown that LFS patients harbor shorter plasma cell-free DNA fragmentation; independent of cancer status. To understand the functional underpinning of cfDNA fragmentation in LFS, we conducted a fragmentomic analysis of 199 cfDNA samples from 82 TP53 mutation carriers and 30 healthy TP53-wildtype controls. We find that LFS individuals exhibit an increased prevalence of A/T nucleotides at fragment ends, dysregulated nucleosome positioning at p53 binding sites, and loci-specific changes in chromatin accessibility at development-associated transcription factor binding sites and at cancer-associated open chromatin regions. Machine learning classification resulted in robust differentiation between TP53 mutant versus wildtype cfDNA samples (AUC-ROC = 0.710-1.000) and intra-patient longitudinal analysis of ctDNA fragmentation signal enabled early cancer detection. These results suggest that cfDNA fragmentation may be a useful diagnostic tool in LFS patients and provides an important baseline for cancer early detection., (© 2024. The Author(s).)

Background: Li-Fraumeni syndrome (LFS) is a penetrant cancer predisposition syndrome (CPS) associated with the development of many tumor types in young people including osteosarcoma and breast cancer (BC). The McGill Interactive Pediatric OncoGenetic Guidelines (MIPOGG) decision-support tool provides a standardized approach to identify patients at risk of CPSs., Methods: We conducted a cost-utility analysis, from the healthcare payer perspective, to compare MIPOGG-guided, physician-guided, and universal genetic testing strategies to detect LFS in female patients diagnosed at an age of less than 18 years with osteosarcoma. We developed a decision tree and discrete-event simulation model to simulate the clinical and cost outcomes of the three genetic referral strategies on a cohort of female children diagnosed with osteosarcoma, especially focused on BC as subsequent cancer. Outcomes included BC incidence, quality-adjusted life-years (QALYs), healthcare costs, and incremental cost-utility ratios (ICURs). We conducted probabilistic and scenario analyses to assess the uncertainty surrounding model parameters., Results: Compared to the physician-guided testing, the MIPOGG-guided strategy was marginally more expensive by $105 (-$516; $743), but slightly more effective by 0.003 (-0.04; 0.045) QALYs. Compared to MIPOGG, the universal testing strategy was $1333 ($732; $1953) more costly and associated with 0.011 (-0.043; 0.064) additional QALYs. The ICUR for the MIPOGG strategy was $33,947/QALY when compared to the physician strategy; the ICUR for universal testing strategy was $118,631/QALY when compared to the MIPOGG strategy., Discussion: This study provides evidence for clinical and policy decision-making on the cost-effectiveness of genetic referral strategies to identify LFS in the setting of osteosarcoma. MIPOGG-guided strategy was most likely to be cost-effective at a willingness-to-pay threshold value of $50,000/QALY., (© 2024 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

The p53 tumor suppressor, encoded by the TP53 gene, serves as a major barrier against malignant transformation. Patients with Li-Fraumeni syndrome (LFS) inherit a mutated TP53 allele from one parent and a wild-type TP53 allele from the other. Subsequently, the wild-type allele is lost and only the mutant TP53 allele remains. This process, which is termed loss of heterozygosity (LOH), results in only mutant p53 protein expression. We used primary dermal fibroblasts from LFS patients carrying the hotspot p53 gain-of-function pathogenic variant, R248Q to study the LOH process and characterize alterations in various pathways before and after LOH. We previously described the derivation of mutant p53 reactivating peptides, designated pCAPs (p53 Conformation Activating Peptides). In this study, we tested the effect of lead peptide pCAP-250 on LOH and on its associated cellular changes. We report that treatment of LFS fibroblasts with pCAP-250 prevents the accumulation of mutant p53 protein, inhibits LOH, and alleviates its cellular consequences. Furthermore, prolonged treatment with pCAP-250 significantly reduces DNA damage and restores long-term genomic stability. pCAPs may thus be contemplated as a potential preventive treatment to prevent or delay early onset cancer in carriers of mutant p53., (© 2024. The Author(s).)

Li-Fraumeni syndrome is caused by inherited TP53 tumor suppressor gene mutations. MicroRNA miR-34a is a p53 target and modifier gene. Interestingly, miR-34 triple-null mice exhibit normal p53 responses and no overt cancer development, but the lack of miR-34 promotes tumorigenesis in cancer-susceptible backgrounds. miR-34 genes are highly conserved and syntenic between zebrafish and humans. Zebrafish miR-34a and miR-34b/c have similar expression timing in development, but miR-34a is more abundant. DNA damage by camptothecin led to p53-dependent induction of miR-34 genes, while miR-34a mutants were adult-viable and had normal DNA damage-induced apoptosis. Nevertheless, miR-34a-/- compound mutants with a gain-of-function tp53R217H/ R217H or tp53-/- mutants were more cancer-prone than tp53 mutants alone, confirming the tumor-suppressive function of miR-34a. Through transcriptomic comparisons at 28 hours post-fertilization (hpf), we characterized DNA damage-induced transcription, and at 8, 28 and 72 hpf we determined potential miR-34a-regulated genes. At 72 hpf, loss of miR-34a enhanced erythrocyte levels and up-regulated myb-positive hematopoietic stem cells. Overexpression of miR-34a suppressed its reporter mRNA, but not p53 target induction, and sensitized injected embryos to camptothecin but not to γ-irradiation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Prykhozhij et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

With the increasing use of comprehensive germline genetic testing of children and adolescents with cancer, it has become evident that pathogenic variants (PV) in adult-onset cancer predisposition genes (aoCPG) underlying adult-onset cancer predisposition syndromes, such as Lynch syndrome or hereditary breast and ovarian cancer, are enriched and reported in 1% to 2% of children and adolescents with cancer. However, the causal relationship between PVs in aoCPGs and childhood cancer is still under investigation. The best-studied examples include heterozygous PVs in mismatch repair genes associated with Lynch syndrome in children with mismatch repair deficient high-grade glioma, heterozygous PVs in BARD1 in childhood neuroblastoma, and heterozygous PVs in BRCA2 in children with rhabdomyosarcoma. The low penetrance for pediatric cancers is considered to result from a combination of the low baseline risk of cancer in childhood and the report of only a modest relative risk of disease in childhood. Therefore, we do not advise that healthy children empirically be tested for PVs in an aoCPG before adulthood outside a research study. However, germline panel testing is increasingly being performed in children and adolescents with cancer, and exome and genome sequencing may be offered more commonly in this population in the future. The precise pediatric cancer risks and spectra associated with PVs in aoCPGs, underlying cellular mechanisms and somatic mutational signatures, as well as treatment response, second neoplasm risks, and psycho-oncological aspects require further research., (©2024 American Association for Cancer Research.)

Background: Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD., Methods: In this cohort study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries. Clinical data were extracted from the IRRDC database, medical records, and physician-completed case record forms. The primary objective was to describe the clinical features, cancer spectrum, and biology of the condition. Secondary objectives included estimations of cancer incidence and of the impact of the specific mismatch-repair gene and genotype on cancer onset and survival, including after cancer surveillance and immunotherapy interventions., Findings: We analysed data from 201 patients (103 males, 98 females) enrolled between June 5, 2007 and Sept 9, 2022. Median age at diagnosis of CMMRD or a related cancer was 8·9 years (IQR 5·9-12·6), and median follow-up from diagnosis was 7·2 years (3·6-14·8). Endogamy among minorities and closed communities contributed to high homozygosity within countries with low consanguinity. Frequent dermatological manifestations (117 [93%] of 126 patients with complete data) led to a clinical overlap with neurofibromatosis type 1 (35 [28%] of 126). 339 cancers were reported in 194 (97%) of 201 patients. The cumulative cancer incidence by age 18 years was 90% (95% CI 80-99). Median time between cancer diagnoses for patients with more than one cancer was 1·9 years (IQR 0·8-3·9). Neoplasms developed in 15 organs and included early-onset adult cancers. CNS tumours were the most frequent (173 [51%] cancers), followed by gastrointestinal (75 [22%]), haematological (61 [18%]), and other cancer types (30 [9%]). Patients with CNS tumours had the poorest overall survival rates (39% [95% CI 30-52] at 10 years from diagnosis; log-rank p<0·0001 across four cancer types), followed by those with haematological cancers (67% [55-82]), gastrointestinal cancers (89% [81-97]), and other solid tumours (96% [88-100]). All cancers showed high mutation and microsatellite indel burdens, and pathognomonic mutational signatures. MLH1 or MSH2 variants caused earlier cancer onset than PMS2 or MSH6 variants, and inferior survival (overall survival at age 15 years 63% [95% CI 55-73] for PMS2, 49% [35-68] for MSH6, 19% [6-66] for MLH1, and 0% for MSH2; p<0·0001). Frameshift or truncating variants within the same gene caused earlier cancers and inferior outcomes compared with missense variants (p<0·0001). The greater deleterious effects of MLH1 and MSH2 variants as compared with PMS2 and MSH6 variants persisted despite overall improvements in survival after surveillance or immune checkpoint inhibitor interventions., Interpretation: The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD., Funding: The Canadian Institutes for Health Research, Stand Up to Cancer, Children's Oncology Group National Cancer Institute Community Oncology Research Program, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Harry and Agnieszka Hall, Meagan's Walk, BRAINchild Canada, The LivWise Foundation, St Baldrick Foundation, Hold'em for Life, and Garron Family Cancer Center., Competing Interests: Declaration of interests ALa reports payment from Alexion, support from Servier and stock from Gilead, outside of the submitted work. AV is co-lead role of the Consortium for Childhood Cancer Predisposition, outside of the submitted work. BH reports payment and stock from Invitae, outside of the submitted work. BC reports participation as data safety and monitoring board member in ReRad Study, participation in the chapter advisory board for Make a Wish Canada Nova Scotia, and participation in the medical advisory committee for Make a Wish Canada, outside of the submitted work. CCP reports grants from St Baldrick's Foundation, outside of the submitted work. DSZ reports consulting fees for Bayer, AstraZeneca, Accendatech, Novartis, Day One, FivePhusion, Alexion, Amgen, and Norgine, outside of the submitted work. DTB reports grants from MSD and Novocure, consulting fees from Nanocarry Therapeutics and Servier, and payment from Servier, outside of the submitted work. EO reports payment and support from Alexion for educational event, outside of the submitted work. EB reports grants from Roche and board participation for Novartis, Alexion and Gilead, outside of the submitted work. FC reports grants from Hall Hunter Foundation (UK), outside of the submitted work. HBF reports payments from Illumina and Sanofi Genzyme, support from Illumina, participation as scientific advisory committee for Sanofi Genzyme, International Gaucher Alliance and Igentify, stock from Igentify, and receipt of materials from Illumina, outside of the submitted work. IW reports grants from Chimerix and payment from COG Partners, outside of the submitted work. IS reports grants from Fondation Saint-Luc and FNRS-CDR, outside of the submitted work. JK reports other financial interests at Servier and PRA Health Sciences, outside of the submitted work. JRG-S reports participation on the board of the Philippine Society of Pediatric Oncology and Philippine Board of Pediatric Oncology, and stock in Macrogenics, Moderna, Mirati Therapeutics, CRISPR Therapeutics, Repligen, Quidelortho, and Shockwave Medical, outside of the submitted work. KJB reports consulting fees from US WorldMeds, Springworks Therapeutics, Alexion, and YmAbs, and payment from Alexion, outside of the submitted work. MS reports grants and support from the Swedish Childhood Cancer Fund, participation as a data safety and monitoring board member for clinical trial NCT05230758, and participation in the Swedish Pediatric CNS tumour group, outside of the submitted work. MAC reports financial support from SUNY Upstate Department of Pediatrics and board participation for Paige's Butterfly Run, outside of the submitted work. MO reports payment from Aptitude Health and participation on a data safety monitoring board or advisory board for Ultragenyx and Abeona, outside of the submitted works. MZ reports payment and support from and board participation for AstraZeneca. NW reports grants from CANSEARCH Foundation, Childhood Cancer Research Switzerland, and the Foundation for Children and Adolescents with Cancer; payment, support, and advisory board participation for Swedish Orphan Biovitrum; and board participation for Childhood Cancer Switzerland, outside of the submitted work. NH reports grants from the National Institutes of Health (NIH) and board participation for Incyte and Pfizer, outside of the submitted work. PCN reports grants from the Canadian Institutes for Health Research (CIHR) Foundation, US Department of Defense, and Garron Family Cancer Centre, outside of the submitted work. RP reports participation in the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer, outside of the submitted work. RT reports consulting fees from Fennec Pharmaceuticals and Day One Biopharmaceuticals and payment from Fennec Pharmaceuticals, outside of the submitted work. SS reports payments from Sanofi Pharmaceuticals and Mylan Pharmaceutical, and board participation for Sanofi Pharmaceuticals, outside of the submitted work. SB reports consulting fees from Hoffmann-La Roche, YmAbs, MAP Biopharma and SERB SAS, and payment from Zschimmer & Schwarz Mohsdorf, outside of the submitted work. UI reports board participation in Pakistan Society of Pediatric Oncology, outside of the submitted work., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Trauma is prevalent amongst early psychosis patients and associated with adverse outcomes. Past trials of trauma-focused therapy have focused on chronic patients with psychosis/schizophrenia and comorbid Post-Traumatic Stress Disorder (PTSD). We aimed to determine the feasibility of a large-scale randomized controlled trial (RCT) of an Eye Movement Desensitization and Reprocessing for psychosis (EMDRp) intervention for early psychosis service users., Methods: A single-blind RCT comparing 16 sessions of EMDRp + TAU v. TAU only was conducted. Participants completed baseline, 6-month and 12-month post-randomization assessments. EMDRp and trial assessments were delivered both in-person and remotely due to COVID-19 restrictions. Feasibility outcomes were recruitment and retention, therapy attendance/engagement, adherence to EMDRp treatment protocol, and the 'promise of efficacy' of EMDRp on relevant clinical outcomes., Results: Sixty participants (100% of the recruitment target) received TAU or EMDR + TAU. 83% completed at least one follow-up assessment, with 74% at 6-month and 70% at 12-month. 74% of EMDRp + TAU participants received at least eight therapy sessions and 97% rated therapy sessions demonstrated good treatment fidelity. At 6-month, there were signals of promise of efficacy of EMDRp + TAU v. TAU for total psychotic symptoms (PANSS), subjective recovery from psychosis, PTSD symptoms, depression, anxiety, and general health status. Signals of efficacy at 12-month were less pronounced but remained robust for PTSD symptoms and general health status., Conclusions: The trial feasibility criteria were fully met, and EMDRp was associated with promising signals of efficacy on a range of valuable clinical outcomes. A larger-scale, multi-center trial of EMDRp is feasible and warranted.

Objective: Mitotane is an important cornerstone in the treatment of pediatric adrenal cortical tumors (pACC), but experience with the drug in the pediatric age group is still limited and current practice is not guided by robust evidence. Therefore, we have compiled international consensus statements from pACC experts on mitotane indications, therapy, and management of adverse effects., Methods: A Delphi method with 3 rounds of questionnaires within the pACC expert consortium of the international network groups European Network for the Study of Adrenal Tumors pediatric working group (ENSAT-PACT) and International Consortium of pediatric adrenocortical tumors (ICPACT) was used to create 21 final consensus statements., Results: We divided the statements into 4 groups: environment, indications, therapy, and adverse effects. We reached a clear consensus for mitotane treatment for advanced pACC with stages III and IV and with incomplete resection/tumor spillage. For stage II patients, mitotane is not generally indicated. The timing of initiating mitotane therapy depends on the clinical condition of the patient and the setting of the planned therapy. We recommend a starting dose of 50 mg/kg/d (1500 mg/m²/d) which can be increased up to 4000 mg/m2/d. Blood levels should range between 14 and 20 mg/L. Duration of mitotane treatment depends on the clinical risk profile and tolerability. Mitotane treatment causes adrenal insufficiency in virtually all patients requiring glucocorticoid replacement shortly after beginning. As the spectrum of adverse effects of mitotane is wide-ranging and can be life-threatening, frequent clinical and neurological examinations (every 2-4 weeks), along with evaluation and assessment of laboratory values, are required., Conclusions: The Delphi method enabled us to propose an expert consensus statement, which may guide clinicians, further adapted by local norms and the individual patient setting. In order to generate evidence, well-constructed studies should be the focus of future efforts., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Importance: Determining the impact of germline cancer-predisposition variants (CPVs) on outcomes could inform novel approaches to testing and treating children with rhabdomyosarcoma., Objective: To assess whether CPVs are associated with outcome among children with rhabdomyosarcoma., Design, Setting, and Participants: In this cohort study, data were obtained for individuals, aged 0.01-23.23 years, newly diagnosed with rhabdomyosarcoma who were treated across 171 Children's Oncology Group sites from March 15, 1999, to December 8, 2017. Data analysis was performed from June 16, 2021, to May 15, 2023., Exposure: The presence of a CPV in 24 rhabdomyosarcoma-associated cancer-predisposition genes (CPGs) or an expanded set of 63 autosomal-dominant CPGs., Main Outcomes and Measures: Overall survival (OS) and event-free survival (EFS) were the main outcomes, using the Kaplan-Meier estimator to assess survival probabilities and the Cox proportional hazards regression model to adjust for clinical covariates. Analyses were stratified by tumor histology and the fusion status of PAX3 or PAX7 to the FOXO1 gene., Results: In this study of 580 individuals with rhabdomyosarcoma, the median patient age was 5.9 years (range, 0.01-23.23 years), and the male-to-female ratio was 1.5 to 1 (351 [60.5%] male). For patients with CPVs in rhabdomyosarcoma-associated CPGs, EFS was 48.4% compared with 57.8% for patients without a CPV (P = .10), and OS was 53.7% compared with 65.3% for patients without a CPV (P = .06). After adjustment, patients with CPVs had significantly worse OS (adjusted hazard ratio [AHR], 2.49 [95% CI, 1.39-4.45]; P = .002), and the outcomes were not better among patients with embryonal histology (EFS: AHR, 2.25 [95% CI, 1.25-4.06]; P = .007]; OS: AHR, 2.83 [95% CI, 1.47-5.43]; P = .002]). These associations were not due to the development of a second malignant neoplasm, and importantly, patients with fusion-negative rhabdomyosarcoma who harbored a CPV had similarly inferior outcomes as patients with fusion-positive rhabdomyosarcoma without CPVs (EFS: AHR, 1.35 [95% CI, 0.71-2.59]; P = .37; OS: AHR, 1.71 [95% CI, 0.84-3.47]; P = .14). There were no significant differences in outcome by CPV status of the 63 CPG set., Conclusions and Relevance: This cohort study identified a group of patients with embryonal rhabdomyosarcoma who had a particularly poor outcome. Other important clinical findings included that individuals with TP53 had poor outcomes independent of second malignant neoplasms and that patients with fusion-negative rhabdomyosarcoma who harbored a CPV had outcomes comparable to patients with fusion-positive rhabdomyosarcoma. These findings suggest that germline CPV testing may aid in clinical prognosis and should be considered in prospective risk-based clinical trials.

Immune checkpoint inhibition (ICI) is effective for replication-repair-deficient, high-grade gliomas (RRD-HGG). The clinical/biological impact of immune-directed approaches after failing ICI monotherapy is unknown. We performed an international study on 75 patients treated with anti-PD-1; 20 are progression free (median follow-up, 3.7 years). After second progression/recurrence (n = 55), continuing ICI-based salvage prolonged survival to 11.6 months (n = 38; P < 0.001), particularly for those with extreme mutation burden (P = 0.03). Delayed, sustained responses were observed, associated with changes in mutational spectra and the immune microenvironment. Response to reirradiation was explained by an absence of deleterious postradiation indel signatures (ID8). CTLA4 expression increased over time, and subsequent CTLA4 inhibition resulted in response/stable disease in 75%. RAS-MAPK-pathway inhibition led to the reinvigoration of peripheral immune and radiologic responses. Local (flare) and systemic immune adverse events were frequent (biallelic mismatch-repair deficiency > Lynch syndrome). We provide a mechanistic rationale for the sustained benefit in RRD-HGG from immune-directed/synergistic salvage therapies. Future approaches need to be tailored to patient and tumor biology., Significance: Hypermutant RRD-HGG are susceptible to checkpoint inhibitors beyond initial progression, leading to improved survival when reirradiation and synergistic immune/targeted agents are added. This is driven by their unique biological and immune properties, which evolve over time. Future research should focus on combinatorial regimens that increase patient survival while limiting immune toxicity. This article is featured in Selected Articles from This Issue, p. 201., (©2023 American Association for Cancer Research.)

People with Li-Fraumeni syndrome (LFS) harbor a germline pathogenic variant in the TP53 tumor suppressor gene, face a near 100% lifetime risk of cancer, and routinely undergo intensive surveillance protocols. Liquid biopsy has become an attractive tool for a range of clinical applications, including early cancer detection. Here, we provide a proof-of-principle for a multimodal liquid biopsy assay that integrates a targeted gene panel, shallow whole-genome, and cell-free methylated DNA immunoprecipitation sequencing for the early detection of cancer in a longitudinal cohort of 89 LFS patients. Multimodal analysis increased our detection rate in patients with an active cancer diagnosis over uni-modal analysis and was able to detect cancer-associated signal(s) in carriers prior to diagnosis with conventional screening (positive predictive value = 67.6%, negative predictive value = 96.5%). Although adoption of liquid biopsy into current surveillance will require further clinical validation, this study provides a framework for individuals with LFS., Significance: By utilizing an integrated cell-free DNA approach, liquid biopsy shows earlier detection of cancer in patients with LFS compared with current clinical surveillance methods such as imaging. Liquid biopsy provides improved accessibility and sensitivity, complementing current clinical surveillance methods to provide better care for these patients. See related commentary by Latham et al., p. 23. This article is featured in Selected Articles from This Issue, p. 5., (©2023 The Authors; Published by the American Association for Cancer Research.)

Background: The prognosis for Li-Fraumeni syndrome (LFS) patients with medulloblastoma (MB) is poor. Comprehensive clinical data for this patient group is lacking, challenging the development of novel therapeutic strategies. Here, we present clinical and molecular data on a retrospective cohort of pediatric LFS MB patients., Methods: In this multinational, multicenter retrospective cohort study, LFS patients under 21 years with MB and class 5 or class 4 constitutional TP53 variants were included. TP53 mutation status, methylation subgroup, treatment, progression free- (PFS) and overall survival (OS), recurrence patterns, and incidence of subsequent neoplasms were evaluated., Results: The study evaluated 47 LFS individuals diagnosed with MB, mainly classified as DNA methylation subgroup "SHH&#95;3" (86%). The majority (74%) of constitutional TP53 variants represented missense variants. The 2- and 5-year (y-) PFS were 36% and 20%, and 2- and 5y-OS were 53% and 23%, respectively. Patients who received postoperative radiotherapy (RT) (2y-PFS: 44%, 2y-OS: 60%) or chemotherapy before RT (2y-PFS: 32%, 2y-OS: 48%) had significantly better clinical outcome then patients who were not treated with RT (2y-PFS: 0%, 2y-OS: 25%). Patients treated according to protocols including high-intensity chemotherapy and patients who received only maintenance-type chemotherapy showed similar outcomes (2y-PFS: 42% and 35%, 2y-OS: 68% and 53%, respectively)., Conclusions: LFS MB patients have a dismal prognosis. In the presented cohort use of RT significantly increased survival rates, whereas chemotherapy intensity did not influence their clinical outcome. Prospective collection of clinical data and development of novel treatments are required to improve the outcome of LFS MB patients., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Cancer predisposition syndromes (CPSs) are responsible for at least 10% of cancer diagnoses in children and adolescents, most of which are not clinically recognised prior to cancer diagnosis. A variety of clinical screening guidelines are used in healthcare settings to help clinicians detect patients who have a higher likelihood of having a CPS. The McGill Interactive Pediatric OncoGenetic Guidelines (MIPOGG) is an electronic health decision support tool that uses algorithms to help clinicians determine if a child/adolescent diagnosed with cancer should be referred to genetics for a CPS evaluation., Methods: This study assessed MIPOGG's performance in identifying Li-Fraumeni, DICER1, Constitutional mismatch repair deficiency and Gorlin (nevoid basal cell carcinoma) syndromes in a retrospective series of 84 children diagnosed with cancer and one of these four CPSs in Canadian hospitals over an 18-year period., Results: MIPOGG detected 82 of 83 (98.8%) evaluable patients with any one of these four genetic conditions and demonstrated an appropriate rationale for suggesting CPS evaluation. When compared with syndrome-specific clinical screening criteria, MIPOGG's ability to correctly identify children with any of the four CPSs was equivalent to, or outperformed, existing clinical criteria respective to each CPS., Conclusion: This study adds evidence that MIPOGG is an appropriate tool for CPS screening in clinical practice. MIPOGG's strength is that it starts with a specific cancer diagnosis and incorporates criteria relevant for associated CPSs, making MIPOGG a more universally accessible diagnostic adjunct that does not require in-depth knowledge of each CPS., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Aims: Prior studies have identified predictors of inadequate preparation with limited success. We aimed to build a model that could predict the likelihood of inadequate preparation by also including factors related to the patient's reaction to drinking the laxative preparation., Methods: Demographic, clinical, and preparation-related data were prospectively collected on patients undergoing colonoscopy. An inadequate preparation was defined as a Boston Bowel Preparation Scale < 6. Statistical analyses were performed to identify predictors of inadequate preparation and create a predictive model., Results: 324 patients were included (age 67 +/- 14 years, 52% male). 77 (23.7%) had inadequate preparations. Diabetes ( p < 0.001), cerebrovascular accident (CVA) ( p < 0.001), incomplete prep consumption ( p = 0.007), high school level education and above ( p < 0.001), use of Bisacodyl ( p = 0.005), >10 bowel movements ( p = 0.02), and use of Sodium Picosulfate or low-volume polyethylene glycol (PEG) solution (2L) compared to PEG 3L ( p < 0.001) were significant variables. In a multivariate analysis, prior CVA increased the risk for inadequate preparation (OR = 4.8, CI 1.6-14.5), whereas high school level education and above (OR = 0.4, CI 0.2-0.8), consumption of Bisacodyl (OR = 0.4, CI 0.2-0.8), >10 bowel movements (OR = 0.5, CI 0.3-0.9), and use of Sodium Picosulfate (OR = 0.5, CI 0.3-0.9) decreased the risk for inadequate prep. Using these, a predictive model for patients likely to have an inadequate colon preparation was created with an area under the curve of 0.74 (35% sensitivity, 90% specificity at a cutoff point of 39%)., Conclusion: Given the low sensitivity, this predictive model does not appear ready for clinical use. However, due to its high specificity, it may be helpful in high-risk, sicker populations by preventing inadequately prepped procedures.

Background: Paediatric precision oncology aims to match therapeutic agents to driver gene targets. We investigated whether parents and patients regret participation in precision medicine trials, particularly when their hopes are unfulfilled., Methods: Parents and adolescent patients completed questionnaires at trial enrolment (T0) and after receiving results (T1). Parents opted-in to an interview at T1. Bereaved parents completed a questionnaire 6-months post-bereavement (T1B). We analysed quantitative data with R and qualitative data thematically with NVivo, before integrating all data for interpretation., Results: 182 parents and 23 patients completed T0; 108/182 parents and 8/23 patients completed T1; 27/98 bereaved parents completed T1B; and 45/108 parents were interviewed. At enrolment, participants held concurrent hopes that precision medicine would benefit future children and their child. Participants expressed concern regarding wait-times for receipt of results. Most participants found the trial beneficial and not burdensome, including bereaved parents. Participants reported high trial satisfaction (median scores: parents: 93/100; patients: 80/100). Participants expressed few regrets (parent median scores: parents: 10/100; bereaved parents: 15/100; patient regret: 2/8 expressed minimal regret)., Conclusions: Even when trial outcomes did not match their hopes, parents and patients rarely regretted participating in a childhood cancer precision medicine trial. These data are critical for integrating participants' views into future precision medicine delivery., (© 2023. The Author(s).)

At least 5% of cancer diagnoses are attributed to a causal pathogenic or likely pathogenic germline genetic variant (hereditary cancer syndrome-HCS). These individuals are burdened with lifelong surveillance monitoring organs for a wide spectrum of cancers. This is associated with substantial uncertainty and anxiety in the time between screening tests and while the individuals are awaiting results. Cell-free DNA (cfDNA) sequencing has recently shown potential as a non-invasive strategy for monitoring cancer. There is an opportunity for high-yield cancer early detection in HCS. To assess clinical validity of cfDNA in individuals with HCS, representatives from eight genetics centers from across Canada founded the CHARM (cfDNA in Hereditary and High-Risk Malignancies) Consortium in 2017. In this perspective, we discuss operationalization of this consortium and early data emerging from the most common and well-characterized HCSs: hereditary breast and ovarian cancer, Lynch syndrome, Li-Fraumeni syndrome, and Neurofibromatosis type 1. We identify opportunities for the incorporation of cfDNA sequencing into surveillance protocols; these opportunities are backed by examples of earlier cancer detection efficacy in HCSs from the CHARM Consortium. We seek to establish a paradigm shift in early cancer surveillance in individuals with HCSs, away from highly centralized, regimented medical screening visits and toward more accessible, frequent, and proactive care for these high-risk individuals., Competing Interests: Declaration of interests William D. Foulkes has research funding from AstraZeneca. Sophie Sun has a consulting and advisory relationship with Novartis, Bristol-Myers Squibb, Pfizer, Purdue, Takeda, and AstraZeneca. Kasmintan A. Schrader has a consulting and advisory relationship with and has received honoraria from AstraZeneca Canada and Pfizer and research funding from AstraZeneca Canada. Dean Regier has a consulting/advisory relationship with Roche Canada and AstraZeneca. Trevor J. Pugh has a consulting and advisory relationship with Chrysalis Biomedical Advisors and the Canadian Pension Plan Investment Board, is on the scientific advisory board for Illumina, has received honoraria from AstraZeneca, Merck, PACT Pharma, and SAGA Diagnostics, and has research funding from Roche (Genentech), the National Institutes of Health, and the US Department of Defense. Yvonne Bombard has ownership interests and intellectual property rights as an inventor and patent holder with Genetics Adviser. The other authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Cancer immunotherapies including immune checkpoint inhibitors and Chimeric Antigen Receptor (CAR) T-cell therapy have shown variable response rates in paediatric patients highlighting the need to establish robust biomarkers for patient selection. While the tumour microenvironment in adults has been widely studied to delineate determinants of immune response, the immune composition of paediatric solid tumours remains relatively uncharacterized calling for investigations to identify potential immune biomarkers., Methods: To inform immunotherapy approaches in paediatric cancers with embryonal origin, we performed an immunogenomic analysis of RNA-seq data from 925 treatment-naïve paediatric nervous system tumours (pedNST) spanning 12 cancer types from three publicly available data sets., Results: Within pedNST, we uncovered four broad immune clusters: Paediatric Inflamed (10%), Myeloid Predominant (30%), Immune Neutral (43%) and Immune Desert (17%). We validated these clusters using immunohistochemistry, methylation immune inference and segmentation analysis of tissue images. We report shared biology of these immune clusters within and across cancer types, and characterization of specific immune cell frequencies as well as T- and B-cell repertoires. We found no associations between immune infiltration levels and tumour mutational burden, although molecular cancer entities were enriched within specific immune clusters., Conclusions: Given the heterogeneity of immune infiltration within pedNST, our findings suggest personalized immunogenomic profiling is needed to guide selection of immunotherapeutic strategies., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Studies to date have yielded inconclusive results as to whether maternal medical history during pregnancy, and a child's early-life medical history contribute to the development of childhood brain tumours (CBTs). This study examined associations between maternal and childhood medical history and the risk of CBTs., Methods: The Childhood Brain Tumour Epidemiology Study of Ontario (CBREO) examined children 0-15 years of age with newly diagnosed CBTs from 1997 to 2003. Multivariable logistic regression analysis determined associations for prenatal medications and childhood medical history, adjusted for child's demographics, and maternal education. Analyses were stratified by histology. A latency period analysis was conducted using 12- and 24-month lead times., Results: Maternal intake of immunosuppressants during the prenatal period was significantly associated with glial tumours (OR 2.73, 95% CI 1.17-6.39). Childhood intake of anti-epileptics was significantly associated with CBTs overall, after accounting for 12-month (OR 8.51, 95% CI 3.35-21.63) and 24-month (OR 6.04, 95% CI 2.06-17.70) lead time before diagnosis. No associations for other medications were found., Conclusions: This study underscores the need to examine potential carcinogenic effects of the medication classes highlighted and of the indication of medication use. Despite possible reverse causality, increased CBT surveillance for children with epilepsy might be warranted., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Precision medicine programs aim to utilize novel technologies to identify personalized treatments for children with cancer. Delivering these programs requires interdisciplinary efforts, yet the many groups involved are understudied. This study explored the experiences of a broad range of professionals delivering Australia's first precision medicine trial for children with poor-prognosis cancer: the PRecISion Medicine for Children with Cancer (PRISM) national clinical trial of the Zero Childhood Cancer Program. We conducted semi-structured interviews with 85 PRISM professionals from eight professional groups, including oncologists, surgeons, clinical research associates, scientists, genetic professionals, pathologists, animal care technicians, and nurses. We analyzed interviews thematically. Professionals shared that precision medicine can add complexity to their role and result in less certain outcomes for families. Although many participants described experiencing a greater emotional impact from their work, most expressed very positive views about the impact of precision medicine on their profession and its future potential. Most reported navigating precision medicine without formal training. Each group described unique challenges involved in adapting to precision medicine in their profession. Addressing training gaps and meeting the specific needs of many professional groups involved in precision medicine will be essential to ensure the successful implementation of standard care.

Rhabdomyosarcoma (RMS) is a well-described cancer in Li-Fraumeni syndrome, resulting from germline TP53 pathogenic variants (PVs). RMS exhibiting anaplasia (anRMS) are associated with a high rate of germline TP53 PVs. This study provides updated estimates of the prevalence of TP53 germline PVs in RMS (3%) and anRMS (11%) from a large cohort (n = 239) enrolled in five Children's Oncology Group (COG) clinical trials. Although the prevalence of germline TP53 PVs in patients with anRMS in this series is much lower than previously reported, this prevalence remains elevated. Germline evaluation for TP53 PVs should be strongly considered in patients with anRMS., (© 2023 Wiley Periodicals LLC.)

Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer-predisposition disorder. Approximately 70% of individuals who fit the clinical definition of LFS harbor a pathogenic germline variant in the TP53 tumor suppressor gene. However, the remaining 30% of patients lack a TP53 variant and even among variant TP53 carriers , approximately 20% remain cancer-free. Understanding the variable cancer penetrance and phenotypic variability in LFS is critical to developing rational approaches to accurate, early tumor detection and risk-reduction strategies. We leveraged family-based whole-genome sequencing and DNA methylation to evaluate the germline genomes of a large, multi-institutional cohort of patients with LFS ( n = 396) with variant ( n = 374) or wildtype TP53 ( n = 22). We identified alternative cancer-associated genetic aberrations in 8/14 wildtype TP53 carriers who developed cancer. Among variant TP53 carriers, 19/49 who developed cancer harbored a pathogenic variant in another cancer gene. Modifier variants in the WNT signaling pathway were associated with decreased cancer incidence. Furthermore, we leveraged the noncoding genome and methylome to identify inherited epimutations in genes including ASXL1 , ETV6 , and LEF1 that confer increased cancer risk. Using these epimutations, we built a machine learning model that can predict cancer risk in patients with LFS with an area under the receiver operator characteristic curve (AUROC) of 0.725 (0.633-0.810)., Significance: Our study clarifies the genomic basis for the phenotypic variability in LFS and highlights the immense benefits of expanding genetic and epigenetic testing of patients with LFS beyond TP53 . More broadly, it necessitates the dissociation of hereditary cancer syndromes as single gene disorders and emphasizes the importance of understanding these diseases in a holistic manner as opposed to through the lens of a single gene., (© 2023 The Authors; Published by the American Association for Cancer Research.)

Cancer is the leading cause of disease-related death in children, adolescents, and young adults beyond the newborn period in North America. Improving survival rates for patients with hard-to-cure cancer remains a challenge. One approach that has gained particular traction is 'precision oncology', whereby next-generation sequencing is used to identify genomic or transcriptomic changes that can help clarify the diagnosis, refine prognosis, define an underlying genetic cause, or identify a unique treatment target for a patient's cancer. In this primer, we provide a brief overview of the evolution of precision paediatric oncology, its current application to clinical oncology practice, and its future potential as a foundational approach to paediatric oncology care in Canada and around the world. We also address the many challenges and limitations inherent to the implementation of precision oncology as the standard of care, including ethical and economic considerations., Competing Interests: DAM: paid consultancy to ymAbs Therapeutics, Clarity Pharmaceuticals, EUSA Pharma, received honoraria or travel support from Ology Medical Education, HMP Global, Marathon Healthcare, WebMD Global and Abbvie, and participates on an advisory board for Oncoheroes and Clarity Pharmaceuticals. He also reports his institution received a grant from BMS. DM: paid consultancy to Bayer Canada. Other authors: none., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Canadian Paediatric Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The causes of pediatric cancers' distinctiveness compared to adult-onset tumors of the same type are not completely clear and not fully explained by their genomes. In this study, we used an optimized multilevel RNA clustering approach to derive molecular definitions for most childhood cancers. Applying this method to 13,313 transcriptomes, we constructed a pediatric cancer atlas to explore age-associated changes. Tumor entities were sometimes unexpectedly grouped due to common lineages, drivers or stemness profiles. Some established entities were divided into subgroups that predicted outcome better than current diagnostic approaches. These definitions account for inter-tumoral and intra-tumoral heterogeneity and have the potential of enabling reproducible, quantifiable diagnostics. As a whole, childhood tumors had more transcriptional diversity than adult tumors, maintaining greater expression flexibility. To apply these insights, we designed an ensemble convolutional neural network classifier. We show that this tool was able to match or clarify the diagnosis for 85% of childhood tumors in a prospective cohort. If further validated, this framework could be extended to derive molecular definitions for all cancer types., (© 2023. The Author(s).)

Approximately 20 TP53 retrogenes exist in the African and Asian elephant genomes (Loxodonta Africana, Elephas Maximus) in addition to a conserved TP53 gene that encodes a full-length protein. Elephant TP53-RETROGENE 9 (TP53-R9) encodes a p53 protein (p53-R9) that is truncated in the middle of the canonical DNA binding domain. This C-terminally truncated p53 retrogene protein lacks the nuclear localization signals and oligomerization domain of its full-length counterpart. When expressed in human osteosarcoma cells (U2OS), p53-R9 binds to Tid1, the chaperone protein responsible for mitochondrial translocation of human p53 in response to cellular stress. Tid1 expression is required for p53-R9-induced apoptosis. At the mitochondria, p53-R9 binds to the pro-apoptotic BCL-2 family member Bax, which leads to caspase activation, cytochrome c release, and cell death. Our data show, for the first time, that expression of this truncated elephant p53 retrogene protein induces apoptosis in human cancer cells. Understanding the molecular mechanism by which the additional elephant TP53 retrogenes function may provide evolutionary insight that can be utilized for the development of therapeutics to treat human cancers., (© 2023. The Author(s).)

Purpose of Review: Childhood cancer is rare, but it remains the leading cause of disease-related mortality among children 1-14 years of age. As exposure to environmental factors is lower in children, inherited genetic factors become an important player in the cause of childhood cancer. This review highlights the current knowledge and approach for cancer predisposition syndromes in children., Recent Findings: Current literature suggests that 10-18% of paediatric cancer patients have an underlying genetic susceptibility to their disease. With better knowledge and technology, more genes and syndromes are being discovered, allowing tailored treatment and surveillance for the probands and their families.Studies have demonstrated that focused surveillance can detect early malignancies and increase overall survival in several cancer predisposition syndromes. Various approaches have been proposed to refine early tumour detection strategies while minimizing the burden on patients and families. Newer therapeutic strategies are being investigated to treat, or even prevent, tumours in children with cancer predisposition., Summary: This review summarizes the current knowledge about different cancer predisposition syndromes, focusing on the diagnosis, genetic counselling, surveillance and future directions., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Diagnosis of Mismatch Repair Deficiency (MMRD) is crucial for tumor management and early detection in patients with the cancer predisposition syndrome constitutional mismatch repair deficiency (CMMRD). Current diagnostic tools are cumbersome and inconsistent both in childhood cancers and in determining germline MMRD., Patients and Methods: We developed and analyzed a functional Low-pass Genomic Instability Characterization (LOGIC) assay to detect MMRD. The diagnostic performance of LOGIC was compared with that of current established assays including tumor mutational burden, immunohistochemistry, and the microsatellite instability panel. LOGIC was then applied to various normal tissues of patients with CMMRD with comprehensive clinical data including age of cancer presentation., Results: Overall, LOGIC was 100% sensitive and specific in detecting MMRD in childhood cancers (N = 376). It was more sensitive than the microsatellite instability panel (14%, P = 4.3 × 10 -12 ), immunohistochemistry (86%, P = 4.6 × 10 -3 ), or tumor mutational burden (80%, P = 9.1 × 10 -4 ). LOGIC was able to distinguish CMMRD from other cancer predisposition syndromes using blood and saliva DNA ( P < .0001, n = 277). In normal cells, MMRDness scores differed between tissues (GI > blood > brain), increased over time in the same individual, and revealed genotype-phenotype associations within the mismatch repair genes. Importantly, increased MMRDness score was associated with younger age of first cancer presentation in individuals with CMMRD ( P = 2.2 × 10 -5 )., Conclusion: LOGIC was a robust tool for the diagnosis of MMRD in multiple cancer types and in normal tissues. LOGIC may inform therapeutic cancer decisions, provide rapid diagnosis of germline MMRD, and support tailored surveillance for individuals with CMMRD.