Pediatric Central Nervous System Cancer Research Articles

In This Issue

In This Issue

Pediatric Central Nervous System Cancers, Version 2.2023, NCCN Clinical Practice Guidelines in Oncology.

Central nervous system (CNS) cancers account for approximately one quarter of all pediatric tumors and are the leading cause of cancer-related death in children. More than 4,000 brain and CNS tumors are diagnosed each year in children and teens, and the incidence rate has remained stagnant in recent years. The most common malignant pediatric CNS tumors are gliomas, embryonal tumors consisting of predominately medulloblastomas, and germ cell tumors. The inaugural version of the NCCN Guidelines for Pediatric Central Nervous System Cancers focuses on the diagnosis and management of patients with pediatric diffuse high-grade gliomas. The information contained in the NCCN Guidelines is designed to help clinicians navigate the complex management of pediatric patients with diffuse high-grade gliomas. The prognosis for these highly aggressive tumors is generally poor, with 5-year survival rates of <20% despite the use of combined modality therapies of surgery, radiation therapy and systemic therapy. Recent advances in molecular profiling has expanded the use of targeted therapies in patients whose tumors harbor certain alterations. However, enrollment in a clinical trial is the preferred treatment for eligible patients.

Pediatric Central Nervous System Cancers in the Democratic People's Republic of Korea.

Purpose:Central nervous system (CNS) cancers rank as the most frequent solid tumors and the leading cause of cancer-related deaths in children and adolescents. There is less information available about pediatric brain and CNS tumors in low-income and middle-income countries, suggesting a lack of surgical accessibility or limited capacity to treat these conditions. In this study, we chose to study the epidemiology of CNS cancers in the Democratic People's Republic of Korea (DPRK).Methods:We extracted the prevalence, incidence, deaths, and disability-adjusted life years (DALYs) associated with CNS cancers in individuals under the age of 20 from the 2017 Global Burden of Disease study from the Institute for Health Metrics and Evaluation. DALYs, which signify the number of healthy life years lost due to ill health, disability, or early death. Economic impact was calculated from DALYs.Conclusions:Given the large burden of brain and CNS cancers among all pediatric cancers in the DPRK, scaling up and strengthening surgical services for children is an essential component to improving care of pediatric CNS cancers in the DPRK. Childhood cancers are time sensitive, and early diagnosis and treatment are vital in ensuring improved survival for the vulnerable pediatric cancer patient population. As surgical treatment can often prolong lives and even prevent premature deaths from these cancers, further analysis of current surgical capacity can inform the path to meeting these critical pediatric surgical needs.

SMARCB1 deletion in atypical teratoid rhabdoid tumors results in human endogenous retrovirus K (HML-2) expression

Atypical Teratoid Rhabdoid Tumor (AT/RT) is a rare pediatric central nervous system cancer often characterized by deletion or mutation of SMARCB1, a tumor suppressor gene. In this study, we found that SMARCB1 regulates Human Endogenous Retrovirus K (HERV-K, subtype HML-2) expression. HML-2 is a repetitive element scattered throughout the human genome, encoding several intact viral proteins that have been associated with stem cell maintenance and tumorigenesis. We found HML-2 env expression in both the intracellular and extracellular compartments in all AT/RT cell lines (n = 4) and in 95% of AT/RT patient tissues (n = 37) evaluated. SMARCB1 knock-down in neural stem cells (NSCs) led to an upregulation of HML-2 transcription. We found that SMARCB1 binds adjacent to the HML-2 promoter, repressing its transcription via chromatin immunoprecipitation; restoration of SMARCB1 expression in AT/RT cell lines significantly downregulated HML-2 expression. Further, targeted downregulation of HML-2 transcription via CRISPR-dCas9 coupled with suppressor proteins led to cellular dispersion, decreased proliferation, and cell death in vitro. HML-2 knock-down with shRNA, siRNA, and CRISPR-dCas9 significantly decreased Ras expression as measured by qRT-PCR, suggesting that HML-2 modulates MAPK/ERK signaling in AT/RT cells. Overexpression of NRAS was sufficient to restore cellular proliferation, and MYC, a transcription factor downstream of NRAS, was bound to the HERV-K LTR significantly more in the absence of SMARCB1 expression in AT/RT cells. We show a mechanism by which these undifferentiated tumors remain pluripotent, and we demonstrate that their formation is aided by aberrant HML-2 activation, which is dependent on SMARCB1 and its interaction with MYC.

Profiling 523 cancer associated genes in circulating tumor DNA of children with CNS tumors.

3023 Background: Pediatric central nervous system (CNS) cancers often pose unique challenges including tumor ‘invisibility’, where surgical resection is restricted due to the sensitive tumor location and tissue biopsy is not always feasible. Detecting cancer associated mutations and copy number variations (CNV) at diagnosis is increasingly important, as the WHO classification of pediatric CNS cancers has incorporated molecular signatures with tumor grade. To achieve CNS tumor molecular ‘visibility’, we previously established a liquid biopsy platform for detecting single nucleotide variants in circulating tumor DNA (ctDNA). However, our method was limited by the restricted number of genes that can be monitored and the inability to detect genomic events including CNVs. To address this, we developed a deep sequencing liquid biopsy approach to profile alterations across selected genes. Our platform provides an opportunity for multi-gene monitoring, to assess tumor subclonal evolution and response to treatment in the absence of repeat tissue biopsies. Methods: We tested the performance of our platform using paired tissue, CSF, and plasma/serum from 10 children with diffuse midline glioma (DMG). ctDNA was analyzed using the TruSight Oncology 500 (TSO500) ctDNA targeted panel covering 523 genes. Matched tumor, CSF, and blood were assessed for concordance and sequencing results were compared to digital droplet PCR (ddPCR) detection of H3K27M mutation. Results: The median exons with ³500X coverage was 96% for 7 CSF samples with optimal input (³60ng), 0.01% for 3 CSF samples with &lt; 5ng input, and 74.5% for plasma/serum samples. ctDNA was more readily detectable in CSF, yet concordance between paired tumor, CSF and plasma/serum was observed. DMG associated mutations in genes including H3F3A, HIST1H3B, TP53, and ACVR1 were detected in ctDNA. Of 9 H3K27M mutations identified in tumor, 8 were present in CSF and 3 in plasma/serum, for a positive percent agreement of 89% and 33%, respectively, with the tumor results. Among CSF samples, H3.3K27M was detected in 6/6 cases, and H3.1K27M in 2/3 cases, with variant allele frequencies comparable to ddPCR results. CNVs including PDGFRA/B and MDM4 amplifications were present in CSF and confirmed by analysis of paired tumor. Additional events, including PIK3CA p.E545Q, PPM1D truncation, and KRAS amplification, were detected in CSF but absent from paired tumor, indicating tissue heterogeneity. Strategies to optimize ctDNA detection, including optimization of ctDNA isolation and adjustment of library QC metrics, were identified. Conclusions: This proof-of-concept study demonstrates the feasibility of our high depth, targeted sequencing approach for detecting clinically relevant mutations in ctDNA from children with CNS tumors. This approach may aid in diagnosis of CNS tumor molecular subtype, and monitoring of tumor evolution and response to therapy in serially collected ctDNA.

Trends in pediatric central nervous system cancers in Turkey

Aim: Paediatric central nervous system (CNS) cancers have a high incidence and mortality relative to other paediatric malignancies. The objective was to provide a brief, nonspecialist review of the incidence and outlook of paediatric CNS cancers in Turkey. Materials and Methods: It is based on Turkish National Cancer Statistics and data from the International Incidence of Childhood Cancer (IICC) collaborative project. The pediatric CNS cancers data of Turskish children were analyzed and compared with the World statistics data. Results: CNS cancers are the second most prevalent cancers in boys and girls in Turkey. About 21.7% of the cancers in boys and 25.5% in girls in Turkey from 2010 to 2015 were CNS tumours, which is consistent with the rates in other world regions. The Turkish National Cancer Centre reported that the ASRs/100 000 person years of pediatric CNS cancers were varying from 5 to 8.5 in boys and from 4.4 to 7.9 in girls between the years of 2010 and 2015. The group with the highest incidence of CNS cancers in childhood is observed as 0-4 years. Conclusion: Cancer registries in Turkey and international agencies such as the IICC provide reliable incidence data, but surveillance data specific to paediatric CNS tumours may not always be easy to obtain.Dedicated paediatric cancer registries worldwide and broad surveillance worldwide will increase our understanding of epidemiology these tumours.

Recurrent SPECC1L-NTRK fusions in pediatric sarcoma and brain tumors.

The identification of rearrangements driving expression of neurotrophic receptor tyrosine kinase (NTRK) family kinases in tumors has become critically important because of the availability of effective, specific inhibitor drugs. Whole-genome sequencing (WGS) combined with RNA sequencing (RNA-seq) can identify novel and recurrent expressed fusions. Here we describe three SPECC1L–NTRK fusions identified in two pediatric central nervous system cancers and an extracranial solid tumor using WGS and RNA-seq. These fusions arose either through a simple balanced rearrangement or in the context of a complex chromoplexy event. We cloned the SPECC1L–NTRK2 fusion directly from a patient sample and showed that enforced expression of this fusion is sufficient to promote cytokine-independent survival and proliferation. Cells transformed by SPECC1L–NTRK2 expression are sensitive to a TRK inhibitor drug. We report here that SPECC1L–NTRK fusions can arise in a range of pediatric cancers. Although WGS and RNA-seq are not required to detect NTRK fusions, these techniques may be of benefit when NTRK fusions are not suspected on clinical grounds or not identified by other methods.

Locoregionally Delivered CAR T Cells Are Effective in CNS Cancer Models

In pediatric central nervous system cancer models, locoregional CAR T-cell delivery was effective.

Population-Based Analysis of Demographic and Socioeconomic Disparities in Pediatric CNS Cancer Survival in the United States

Previous studies have demonstrated effects of racial and socioeconomic factors on survival of adults with cancer. While less studied in the pediatric population, data exist demonstrating disparities of care and survival in pediatric oncology patients based on socioeconomic and racial/ethnic factors. Brain cancers recently overtook leukemia as the number one cause of childhood cancer fatalities, but demographic and socioeconomic disparities in these tumors have not been adequately studied. We obtained data from the SEER Program of the National Cancer Institute (NCI). We selected patients under 19 years of age with central nervous system (CNS) cancers diagnosed between 2000 and 2015. We included patient demographics, tumor characteristics, treatment, and socioeconomic characteristics as covariates in the analysis. We measured overall survival and extent of disease at diagnosis. We saw that Black and Hispanic patients overall had a higher risk of death than non-Hispanic White patients on multivariable analysis. On stratified analysis, Black and Hispanic patients with both metastatic and localized disease at diagnosis had a higher risk of death compared to White, non-Hispanic patients, although the difference in Black patients was not significant after adjusting for mediating factors. However, our findings on extent of disease at diagnosis demonstrated that neither Black race nor Hispanic ethnicity increased the chance of metastatic disease at presentation when controlling for mediating variables. In summary, racial and ethnic disparities in childhood CNS tumor survival appear to have their roots at least partially in post-diagnosis factors, potentially due to the lack of access to high quality care, leading to poorer overall outcomes.

Trends in Pediatric Central Nervous System Tumor Incidence in the United States, 1998-2013.

Brain and other central nervous system (CNS) cancers are the leading cause of U.S. pediatric cancer mortality. Incidence trends can provide etiologic insight. We report trends in incidence rates of pediatric malignant CNS cancers and pilocytic astrocytoma (nonmalignant but historically registered) in the United States. Age-standardized incidence rates and annual percent changes (APC) in rates during 1998 to 2013 were calculated for children aged 0 to 19, stratified by subtype, age, sex, and for gliomas, histology and location. We estimated the absolute change in number of cases diagnosed U.S.-wide during 2013 compared with the expected number of cases had 1998 rates remained stable. Rates of all pediatric malignant CNS cancer combined (n = 18,612) did not change [APC: 0.16; 95% confidence interval (CI): -0.21-0.53]. There were statistically significant changes in several subtypes; however, glioma incidence (n = 10,664) increased by 0.77% per year (95% CI: 0.29-1.26), embryonal cancer rates (n = 5,423) decreased by 0.88% per year (95% CI: -1.33 to -0.43), and pilocytic astrocytoma rates (n = 6,858) increased by 0.89% per year (95% CI: 0.21-1.58). Of the 1,171 malignant tumors and 450 pilocytic astrocytomas diagnosed in U.S. children in 2013, we estimated 120 excess gliomas, 94 excess pilocytic astrocytomas, and 72 fewer embryonal CNS tumors than would be expected had 1998 rates remained stable. The gradual changes in incidence we observed for specific types of pediatric CNS cancers are likely due to a combination of changes in classification and diagnosis and true changes in CNS cancer. Continued surveillance of pediatric CNS tumors should remain a priority, given their significant contribution to pediatric cancer-related deaths.

TMOD-14. A PATIENT-DERIVED CANCER CELL LINE ATLAS OF PRIMARY AND METASTATIC CENTRAL NERVOUS SYSTEM TUMORS

BACKGROUND Tumors involving the central nervous system (CNS) include over 200 primary and metastatic subtypes with major clinical impact. Research on CNS neoplasms has been hampered by the lack of appropriate models for many subtypes. We established a robust workflow and systematic culturing approach to create cancer cell line models from all adult and pediatric CNS cancer patients and here report the results of these ongoing efforts.

Management of diffuse intrinsic pontine glioma in children: current and future strategies for improving prognosis.

Diffuse intrinsic pontine glioma (DIPG) is one of the deadliest pediatric central nervous system cancers in spite of treatment with radiation therapy, the current standard of care. The outcome of affected children remains dismal despite multiple clinical trials that investigated radiation therapy combined with chemotherapy. Recently, multiple genome-wide studies unveiled the distinct molecular characteristics of DIPGs and preclinical models of DIPG were developed to mimic the human disease. Both of these accomplishments have generated tremendous progress in the research of new therapies for children with DIPG. Here we review some of these promising new strategies.

Adults with Childhood Onset Disabilities: A Focused Review of Three Conditions

Adults with childhood onset conditions now have improved survival rates, and are experiencing health, medical, and performance issues related to their original conditions or treatments. The published science regarding the medical and performance issues of adults with cerebral palsy, spina bifida, and pediatric central nervous system cancer is increasing in quality, rigor, and clinical usefulness. This article is a systematized, focused review, with an appraisal of the literature, of these three conditions. Most of the published research is observational, from which recommendations can be made; however, there are few studies that demonstrate effective interventions. Although each of the three conditions has associated specific health and medical issues, they also have common problems and concerns related to health care, activity, performance, participation, and quality of life.