The landscape of primary mismatch repair deficient gliomas in children, adolescents, and young adults: a multi-cohort study.

Background: Gliomas are a major cause of cancer-related death among children, adolescents, and young adults (age 0-40 years). Primary mismatch repair deficiency (MMRD) is a pan-cancer mechanism with unique biology and therapeutic opportunities. We aimed to determine the extent and impact of primary MMRD in gliomas among children, adolescents, and young adults.

tp53 R217H and R242H mutant zebrafish exhibit dysfunctional p53 hallmarks and recapitulate Li-Fraumeni syndrome phenotypes.

Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome associated with a highly penetrant cancer spectrum characterized by germline TP53 mutations. We characterized the first LFS zebrafish hotspot mutants, tp53 R217H and R242H (human R248H and R273H), and found these mutants exhibit partial-to-no activation of p53 target genes, have defective cell-cycle checkpoints, and display partial-to-full resistance to apoptosis, although the R217H mutation has hypomorphic characteristics. Spontaneous tumor development histologically resembling human sarcomas was observed as early as 6 months.

Update on cancer screening in children with syndromes of bone lesions, hereditary leiomyoma and renal cell carcinoma syndrome, and other rare syndromes.

The management of children with syndromes associated with an increased risk of benign and malignant neoplasms is a complex challenge for healthcare professionals. The 2023 AACR Childhood Cancer Predisposition Workshop provided updated consensus guidelines on cancer surveillance in these syndromes, aiming to improve early detection, intervention, and reduce morbidity associated with such neoplasms. In this paper, we review several of the rare conditions discussed in this workshop.

A dataset of transcriptomic effects of camptothecin treatment on early zebrafish embryos.

Zebrafish () are a good model for cancer research including studies on chemotherapy treatments. We treated wild-type and 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.

Update on Pediatric Surveillance Recommendations for PTEN Hamartoma Tumor Syndrome, DICER1-Related Tumor Predisposition, and Tuberous Sclerosis Complex.

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.

Clinical impact of TP53 functional mutations in patients with metastatic colorectal cancer treated with bevacizumab and chemotherapy.

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.

Update on Whole-Body MRI Surveillance for Pediatric Cancer Predisposition Syndromes.

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.

Value of Engagement in Digital Health Technology Research: Evidence Across 6 Unique Cohort Studies.

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.

Cell-free DNA from germline TP53 mutation carriers reflect cancer-like fragmentation patterns.

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.

Patterns of Growth of Tumors in Li-Fraumeni Syndrome by Imaging: A Case Series.

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.

Late-onset tumors in rhabdoid tumor predisposition syndrome type-1 (RTPS1) and implications for surveillance.

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.

miR-34a is a tumor suppressor in zebrafish and its expression levels impact metabolism, hematopoiesis and DNA damage.

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.

Cost-effectiveness of the McGill interactive pediatric oncogenetic guidelines in identifying Li-Fraumeni syndrome in female patients with osteosarcoma.

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.

Mutant p53 reactivation restricts the protumorigenic consequences of wild type p53 loss of heterozygosity in Li-Fraumeni syndrome patient-derived fibroblasts.

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.

New Paradigms in the Clinical Management of Li-Fraumeni Syndrome.

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.

International consensus on mitotane treatment in pediatric patients with adrenal cortical tumors: indications, therapy, and management of adverse effects.

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.

Germline Genetic Testing and Survival Outcomes Among Children With Rhabdomyosarcoma: A Report From the Children's Oncology Group.

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.