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16 pages, 2139 KiB

Open AccessArticle

A microRNA Prognostic Signature in Patients with Diffuse Intrinsic Pontine Gliomas through Non-Invasive Liquid Biopsy

by Maria F. Iannó, Veronica Biassoni, Elisabetta Schiavello, Andrea Carenzo, Luna Boschetti, Lorenza Gandola, Barbara Diletto, Edoardo Marchesi, Claudia Vegetti, Alessandra Molla, Christof M. Kramm, Dannis G. van Vuurden, Patrizia Gasparini, Francesca Gianno, Felice Giangaspero, Piergiorgio Modena, Brigitte Bison, Andrea Anichini, Sabina Vennarini, Emanuele Pignoli, Maura Massimino and Loris De Cecco Show full author list Hide full author list

Cancers 2022, 14(17), 4307; https://doi.org/10.3390/cancers14174307 - 2 Sep 2022

Cited by 5 | Viewed by 2681

Abstract

Diffuse midline gliomas (DMGs) originate in the thalamus, brainstem, cerebellum and spine. This entity includes tumors that infiltrate the pons, called diffuse intrinsic pontine gliomas (DIPGs), with a rapid onset and devastating neurological symptoms. Since surgical removal in DIPGs is not feasible, the [...] Read more.

Diffuse midline gliomas (DMGs) originate in the thalamus, brainstem, cerebellum and spine. This entity includes tumors that infiltrate the pons, called diffuse intrinsic pontine gliomas (DIPGs), with a rapid onset and devastating neurological symptoms. Since surgical removal in DIPGs is not feasible, the purpose of this study was to profile circulating miRNA expression in DIPG patients in an effort to identify a non-invasive prognostic signature with clinical impact. Using a high-throughput platform, miRNA expression was profiled in serum samples collected at the time of MRI diagnosis and prior to radiation and/or systemic therapy from 47 patients enrolled in clinical studies, combining nimotuzumab and vinorelbine with concomitant radiation. With progression-free survival as the primary endpoint, a semi-supervised learning approach was used to identify a signature that was also tested taking overall survival as the clinical endpoint. A signature comprising 13 circulating miRNAs was identified in the training set (n = 23) as being able to stratify patients by risk of disease progression (log-rank p = 0.00014; HR = 7.99, 95% CI 2.38–26.87). When challenged in a separate validation set (n = 24), it confirmed its ability to predict progression (log-rank p = 0.00026; HR = 5.51, 95% CI 2.03–14.9). The value of our signature was also confirmed when overall survival was considered (log-rank p = 0.0021, HR = 4.12, 95% CI 1.57–10.8). We have identified and validated a prognostic marker based on the expression of 13 circulating miRNAs that can shed light on a patient’s risk of progression. This is the first demonstration of the usefulness of nucleic acids circulating in the blood as powerful, easy-to-assay molecular markers of disease status in DIPG. This study provides Class II evidence that a signature based on 13 circulating miRNAs is associated with the risk of disease progression. Full article

(This article belongs to the Special Issue Pediatric Brain Tumors)

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11 pages, 1479 KiB

Open AccessCommunication

YAP1 Is a Potential Predictive Molecular Biomarker for Response to SMO Inhibitor in Medulloblastoma Cells

by Gustavo Alencastro Veiga Cruzeiro, Taciani de Almeida Magalhães, Graziella Ribeiro de Sousa, Ricardo Bonfim Silva, Carlos Alberto Oliveira de Biagi Junior, Pablo Ferreira das Chagas, Rosane Gomes de Paula Queiroz, Carlos Alberto Scrideli, Luiz Gonzaga Tone and Elvis Terci Valera

Cancers 2021, 13(24), 6249; https://doi.org/10.3390/cancers13246249 - 13 Dec 2021

Cited by 2 | Viewed by 2519

Abstract

Advances in genomics have led to the identification of twelve relevant molecular subtypes within medulloblastoma (MB). The alpha subtype of Sonic hedgehog-driven MB is resistant to therapy (including smoothened inhibitors) due to activation of genes from the non-canonical SHH pathway, such as MYCN [...] Read more.

Advances in genomics have led to the identification of twelve relevant molecular subtypes within medulloblastoma (MB). The alpha subtype of Sonic hedgehog-driven MB is resistant to therapy (including smoothened inhibitors) due to activation of genes from the non-canonical SHH pathway, such as MYCN, YAP1, or TP53. Using retrospective cohort microarray data, we found that YAP1 is overexpressed in SHH alpha MB and patients profiled as resistant to SMO inhibitors compared to good responders. Here, we performed YAP1 depletion via CRISPR/Cas9 in two in vitro models of SHH-like MB cells and found that this protein is involved in responsiveness to the SMO inhibitor regarding proliferation, apoptosis, and colony formation. Further, considering the synergic combination of YAP1 depletion with SMO inhibition, we assessed single-cell RNA-seq data from five patients and found that SMO and YAP1 are enriched within cells of SHH MB. Importantly, our data suggest that YAP1 is not only a reliable biomarker for cellular response to SMOi but may indicate prospective testing of combination therapy using YAP1 and SMO inhibitors in preclinical models of SHH MB. Full article

(This article belongs to the Special Issue Pediatric Brain Tumors)

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18 pages, 822 KiB

Open AccessArticle

Processing Speed and Time since Diagnosis Predict Adaptive Functioning Measured with WeeFIM in Pediatric Brain Tumor Survivors

by Maria Chiara Oprandi, Viola Oldrati, Morena delle Fave, Daniele Panzeri, Lorenza Gandola, Maura Massimino, Alessandra Bardoni and Geraldina Poggi

Cancers 2021, 13(19), 4776; https://doi.org/10.3390/cancers13194776 - 24 Sep 2021

Cited by 4 | Viewed by 2150

Abstract

(1) Background: Brain tumor (BT) survivors show difficulties in the acquisition of developmental milestones, related to academic achievement, vocational employment, social relationships, and autonomy. The skills underlying adaptive functioning (AF) are usually damaged in BT survivors due to the presence of the brain [...] Read more.

(1) Background: Brain tumor (BT) survivors show difficulties in the acquisition of developmental milestones, related to academic achievement, vocational employment, social relationships, and autonomy. The skills underlying adaptive functioning (AF) are usually damaged in BT survivors due to the presence of the brain tumor, treatment-related factors, and other neurological sequelae. In this study, we aimed to explore the contribution of different cognitive factors in children with BT to AF, considering diagnosis-related variables. (2) Methods: Standardized cognitive assessment was undertaken and clinical information was collected from a retrospective cohort of 78 children with a BT, aged between 6 and 18 year old at the time of the assessment. Regression models were computed to investigate the influence of the selected variables on daily functional skills as measured by the Functional Independence Measure for Children (WeeFIM). (3) Results: The analyses showed that the main explanatory variables are processing speed and time since diagnosis. Other clinical variables, such as age at diagnosis and hydrocephalus, differentially influence functional skills according to distinct domains (i.e., self-care, mobility, and cognition). (4) Conclusions: The main explanatory variables of AF that emerged in our models point to a potential target of improving AF management in pediatric BT survivors. Full article

(This article belongs to the Special Issue Pediatric Brain Tumors)

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25 pages, 2856 KiB

Open AccessArticle

Identification and Functional Characterization of Novel MYC-Regulated Long Noncoding RNAs in Group 3 Medulloblastoma

by Jessica Rea, Annamaria Carissimo, Daniela Trisciuoglio, Barbara Illi, Daniel Picard, Marc Remke, Pietro Laneve and Elisa Caffarelli

Cancers 2021, 13(15), 3853; https://doi.org/10.3390/cancers13153853 - 30 Jul 2021

Cited by 4 | Viewed by 2624

Abstract

The impact of protein-coding genes on cancer onset and progression is a well-established paradigm in molecular oncology. Nevertheless, unveiling the contribution of the noncoding genes—including long noncoding RNAs (lncRNAs)—to tumorigenesis represents a great challenge for personalized medicine, since they (i) constitute the majority [...] Read more.

The impact of protein-coding genes on cancer onset and progression is a well-established paradigm in molecular oncology. Nevertheless, unveiling the contribution of the noncoding genes—including long noncoding RNAs (lncRNAs)—to tumorigenesis represents a great challenge for personalized medicine, since they (i) constitute the majority of the human genome, (ii) are essential and flexible regulators of gene expression and (iii) present all types of genomic alterations described for protein-coding genes. LncRNAs have been increasingly associated with cancer, their highly tissue- and cancer type-specific expression making them attractive candidates as both biomarkers and therapeutic targets. Medulloblastoma is one of the most common malignant pediatric brain tumors. Group 3 is the most aggressive subgroup, showing the highest rate of metastasis at diagnosis. Transcriptomics and reverse genetics approaches were combined to identify lncRNAs implicated in Group 3 Medulloblastoma biology. Here we present the first collection of lncRNAs dependent on the activity of the MYC oncogene, the major driver gene of Group 3 Medulloblastoma. We assessed the expression profile of selected lncRNAs in Group 3 primary tumors and functionally characterized these species. Overall, our data demonstrate the direct involvement of three lncRNAs in Medulloblastoma cancer cell phenotypes. Full article

(This article belongs to the Special Issue Pediatric Brain Tumors)

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16 pages, 4875 KiB

Open AccessArticle

A DNA Repair and Cell Cycle Gene Expression Signature in Pediatric High-Grade Gliomas: Prognostic and Therapeutic Value

by Natacha Entz-Werlé, Laetitia Poidevin, Petr V. Nazarov, Olivier Poch, Benoit Lhermitte, Marie Pierre Chenard, Hélène Burckel, Eric Guérin, Quentin Fuchs, David Castel, Georges Noel, Laurence Choulier, Monique Dontenwill and Eric Van Dyck

Cancers 2021, 13(9), 2252; https://doi.org/10.3390/cancers13092252 - 7 May 2021

Cited by 3 | Viewed by 2461

Abstract

Background: Pediatric high-grade gliomas (pHGGs) are the leading cause of mortality in pediatric neuro-oncology, displaying frequent resistance to standard therapies. Profiling DNA repair and cell cycle gene expression has recently been proposed as a strategy to classify adult glioblastomas. To improve our understanding [...] Read more.

Background: Pediatric high-grade gliomas (pHGGs) are the leading cause of mortality in pediatric neuro-oncology, displaying frequent resistance to standard therapies. Profiling DNA repair and cell cycle gene expression has recently been proposed as a strategy to classify adult glioblastomas. To improve our understanding of the DNA damage response pathways that operate in pHGGs and the vulnerabilities that these pathways might expose, we sought to identify and characterize a specific DNA repair and cell-cycle gene expression signature of pHGGs. Methods: Transcriptomic analyses were performed to identify a DNA repair and cell-cycle gene expression signature able to discriminate pHGGs (n = 6) from low-grade gliomas (n = 10). This signature was compared to related signatures already established. We used the pHGG signature to explore already transcriptomic datasets of DIPGs and sus-tentorial pHGGs. Finally, we examined the expression of key proteins of the pHGG signature in 21 pHGG diagnostic samples and nine paired relapses. Functional inhibition of one DNA repair factor was carried out in four patients who derived H3.3 K27M mutant cell lines. Results: We identified a 28-gene expression signature of DNA repair and cell cycle that clustered pHGGs cohorts, in particular sus-tentorial locations, in two groups. Differential protein expression levels of PARP1 and XRCC1 were associated to TP53 mutations and TOP2A amplification and linked significantly to the more radioresistant pHGGs displaying the worst outcome. Using patient-derived cell lines, we showed that the PARP-1/XRCC1 expression balance might be correlated with resistance to PARP1 inhibition. Conclusion: We provide evidence that PARP1 overexpression, associated to XRCC1 expression, TP53 mutations, and TOP2A amplification, is a new theranostic and potential therapeutic target. Full article

(This article belongs to the Special Issue Pediatric Brain Tumors)

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13 pages, 2577 KiB

Open AccessArticle

BLBP Is Both a Marker for Poor Prognosis and a Potential Therapeutic Target in Paediatric Ependymoma

by Durgagauri H. Sabnis, Jo-Fen Liu, Lucy Simmonds, Sophie Blackburn, Richard G. Grundy, Ian D. Kerr and Beth Coyle

Cancers 2021, 13(9), 2100; https://doi.org/10.3390/cancers13092100 - 27 Apr 2021

Cited by 6 | Viewed by 2859

Abstract

Paediatric ependymomas are aggressive, treatment-resistant tumours with a tendency towards relapse, consistent with a sub-population of therapy-resistant cancer stem cells. These cells are believed to derive from brain lipid binding protein (BLBP)-expressing radial glia, hence we proposed that BLBP may be a marker [...] Read more.

Paediatric ependymomas are aggressive, treatment-resistant tumours with a tendency towards relapse, consistent with a sub-population of therapy-resistant cancer stem cells. These cells are believed to derive from brain lipid binding protein (BLBP)-expressing radial glia, hence we proposed that BLBP may be a marker for ependymoma therapy resistance. BLBP protein expression correlated with reduced overall survival (OS) in patients from two trials (CNS9204, a chemotherapy-led infant trial—5 y OS 45% vs. 80%, p = 0.011—and CNS9904, a radiotherapy-led trial—OS 38% vs. 85%, p = 0.002). All ependymoma cell lines examined by qRT-PCR expressed BLBP, with expression elevated in stem cell-enriched neurospheres. Modulation of BLBP function in 2D and 3D assays, using either peroxisome proliferator activated receptor (PPAR) antagonists or BLBP’s fatty acid substrate docosahexaneoic acid (DHA), potentiated chemotherapy response and reduced cell migration and invasion in ependymoma cell lines. BLBP is therefore an independent predictor of poor survival in paediatric ependymoma, and treatment with PPAR antagonists or DHA may represent effective novel therapies, preventing chemotherapy resistance and invasion in paediatric ependymoma patients. Full article

(This article belongs to the Special Issue Pediatric Brain Tumors)

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15 pages, 1247 KiB

Open AccessArticle

High-Grade Gliomas in Children—A Multi-Institutional Polish Study

by Aleksandra Napieralska, Aleksandra Krzywon, Agnieszka Mizia-Malarz, Joanna Sosna-Zielińska, Ewa Pawłowska, Małgorzata A. Krawczyk, Katarzyna Konat-Bąska, Aneta Kaczorowska, Anna Dąbrowska and Maciej Harat

Cancers 2021, 13(9), 2062; https://doi.org/10.3390/cancers13092062 - 24 Apr 2021

Cited by 8 | Viewed by 2218

Abstract

Due to the rarity of high-grade gliomas (HGG) in children, data on this topic are scarce. The study aimed to investigate the long-term results of treatment of children with HGG and to identify factors related to better survival. We performed a retrospective analysis [...] Read more.

Due to the rarity of high-grade gliomas (HGG) in children, data on this topic are scarce. The study aimed to investigate the long-term results of treatment of children with HGG and to identify factors related to better survival. We performed a retrospective analysis of patients treated for HGG who had the main tumor located outside the brainstem. The evaluation of factors that correlated with better survival was performed with the Cox proportional-hazard model. Survival was estimated with the Kaplan–Meier method. The study group consisted of 82 consecutive patients. All of them underwent surgery as primary treatment. Chemotherapy was applied in 93% of children with one third treated with temozolomide. After or during the systemic treatment, 79% of them received radiotherapy with a median dose of 54 Gy. Median follow-up was 122 months, and during that time, 59 patients died. One-, 2-, 5-, and 10-year overall survival was 78%, 48%, 30% and 17%, respectively. Patients with radical (R0) resection and temozolomide-based chemotherapy had better overall survival. Progression-free survival was better in patients after R0 resection and radical radiotherapy. The best outcome in HGG patients was observed in patients after R0 resection with immediate postoperative temozolomide-based chemotherapy and radical radiotherapy. Full article

(This article belongs to the Special Issue Pediatric Brain Tumors)

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16 pages, 3880 KiB

Open AccessArticle

The Implementation of DNA Methylation Profiling into a Multistep Diagnostic Process in Pediatric Neuropathology: A 2-Year Real-World Experience by the French Neuropathology Network

by Melanie Pages, Emmanuelle Uro-Coste, Carole Colin, David Meyronet, Guillaume Gauchotte, Claude-Alain Maurage, Audrey Rousseau, Catherine Godfraind, Karima Mokhtari, Karen Silva, Dominique Figarella-Branger, Pascale Varlet and on behalf of the RENOCLIP-LOC Network

Cancers 2021, 13(6), 1377; https://doi.org/10.3390/cancers13061377 - 18 Mar 2021

Cited by 12 | Viewed by 2615

Abstract

DNA methylation profiling has recently emerged as a powerful tool to help establish diagnosis in neuro-oncology. Here we present our national diagnostic strategy as the French neuropathology network (RENOCLIP-LOC) and our current approach of integrating DNA methylation profiling into our multistep diagnostic process [...] Read more.

DNA methylation profiling has recently emerged as a powerful tool to help establish diagnosis in neuro-oncology. Here we present our national diagnostic strategy as the French neuropathology network (RENOCLIP-LOC) and our current approach of integrating DNA methylation profiling into our multistep diagnostic process for challenging pediatric CNS tumors. The tumors with diagnostic uncertainty were prospectively selected for DNA methylation after two rounds of review by neuropathology experts. We first integrated the classifier score into the histopathological findings. Subsequent analyses using t-SNE (t-Distributed Stochastic Neighbor Embedding) representation were performed. An additional step consisted of analyzing copy-number variation data (CNV). Finally, we combined all data to establish diagnoses and evaluated the impact of DNA methylation profiling on diagnostic and grading changes that would affect patient management. Over two years, 62 pediatric tumors were profiled. (1) Integrating the classifier score to the histopathological findings impacted the diagnosis in 33 cases (53%). (2) t-SNE analysis provided arguments for diagnosis in 26/35 cases with calibrated scores <0.84 (74.3%). (3) CNV investigations also evidenced alterations used for diagnosis and prognostication. (4) A diagnosis was finally established for 44 tumors (71%). Our results support the use of DNA methylation for challenging pediatric tumors. We demonstrated how additional methylation-based analyses complement the classifier score to support conventional histopathological diagnosis. Full article

(This article belongs to the Special Issue Pediatric Brain Tumors)

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19 pages, 6979 KiB

Open AccessArticle

CENPE Inhibition Leads to Mitotic Catastrophe and DNA Damage in Medulloblastoma Cells

by Giorgia Iegiani, Marta Gai, Ferdinando Di Cunto and Gianmarco Pallavicini

Cancers 2021, 13(5), 1028; https://doi.org/10.3390/cancers13051028 - 1 Mar 2021

Cited by 15 | Viewed by 3616

Abstract

Medulloblastoma (MB) is the most frequent brain tumor in children. The standard treatment consists in surgery, followed by radiotherapy and chemotherapy. These therapies are only partially effective since many patients still die and those who survive suffer from neurological and endocrine disorders. Therefore, [...] Read more.

Medulloblastoma (MB) is the most frequent brain tumor in children. The standard treatment consists in surgery, followed by radiotherapy and chemotherapy. These therapies are only partially effective since many patients still die and those who survive suffer from neurological and endocrine disorders. Therefore, more effective therapies are needed. Primary microcephaly (MCPH) is a rare disorder caused by mutations in 25 different genes. Centromere-associated protein E (CENPE) heterozygous mutations cause the MCPH13 syndrome. As for other MCPH genes, CENPE is required for normal proliferation and survival of neural progenitors. Since there is evidence that MB shares many molecular features with neural progenitors, we hypothesized that CENPE could be an effective target for MB treatment. In ONS-76 and DAOY cells, CENPE knockdown induced mitotic defects and apoptosis. Moreover, CENPE depletion induced endogenous DNA damage accumulation, activating TP53 or TP73 as well as cell death signaling pathways. To consolidate CENPE as a target for MB treatment, we tested GSK923295, an allosteric inhibitor already in clinical trial for other cancer types. GSK923295, induced effects similar to CENPE depletion with higher penetrance, at low nM levels, suggesting that CENPE’s inhibition could be a therapeutic strategy for MB treatment. Full article

(This article belongs to the Special Issue Pediatric Brain Tumors)

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17 pages, 7612 KiB

Open AccessArticle

Melanotic Neuroectodermal Tumor of Infancy (MNTI) and Pineal Anlage Tumor (PAT) Harbor A Medulloblastoma Signature by DNA Methylation Profiling

by Oscar Lopez-Nunez, Rita Alaggio, Ivy John, Andrea Ciolfi, Lucia Pedace, Angela Mastronuzzi, Francesca Gianno, Felice Giangaspero, Sabrina Rossi, Vittoria Donofrio, Giuseppe Cinalli, Lea F. Surrey, Marco Tartaglia, Franco Locatelli and Evelina Miele

Cancers 2021, 13(4), 706; https://doi.org/10.3390/cancers13040706 - 9 Feb 2021

Cited by 13 | Viewed by 3703

Abstract

MNTI is a rare tumor of indeterminate histogenesis and molecular signature. We performed methylation and copy number variation (CNV) profiles in patients with MNTI (n = 7) and PAT (n = 1) compared to the methylation brain tumor classifier v11b4 (BT-C) [...] Read more.

MNTI is a rare tumor of indeterminate histogenesis and molecular signature. We performed methylation and copy number variation (CNV) profiles in patients with MNTI (n = 7) and PAT (n = 1) compared to the methylation brain tumor classifier v11b4 (BT-C) and the medulloblastoma (MB) classifier group 3/4 v1.0 (MB3/4-C). The patients’ mean age was 8 months (range: 4–48). The BT-C classified five MNTIs and one PAT (relapse) as class family MB-G3/G4, subclass group 3 (score: >0.9). The remaining two MNTIs and PAT (primary) were classified as class family plexus tumor, subclass pediatric (scores: >0.45). The MB3/4-C classified all MNTIs as high-risk MB-G3, Subtype II (score: >0.45). The primary PAT was classified as subtype III (score: 0.99) and its relapse as subtype II/III. MNTI and PAT clustered close to MB-G3. CNV analysis showed multiple rearrangements in one PAT and two MNTIs. The median follow-up was 54 months (four MNTIs in remission, one PAT died). In conclusion, we demonstrated that MNTI shares a homogenous methylation profile with MB-G3, and possibly with PAT. The role of a multipotent progenitor cell (i.e., early cranial neural crest cell) in their histogenesis and the influence of the anatomical site, tumor microenvironment, and other cytogenetic events in their divergent biologic behavior deserve further investigation. Full article

(This article belongs to the Special Issue Pediatric Brain Tumors)

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17 pages, 614 KiB

Open AccessArticle

Can National Tests from the Last Year of Compulsory School Be Used to Obtain More Detailed Information about Academic Performance in Children Treated for Brain Tumours? A Nationwide, Population-Based Study from Sweden

by Malin Lönnerblad, Eva Berglund, Ingrid van’t Hooft and Klas Blomgren

Cancers 2021, 13(1), 135; https://doi.org/10.3390/cancers13010135 - 4 Jan 2021

Cited by 5 | Viewed by 2422

Abstract

Children treated for brain tumours often have late-appearing complications that may affect their school performance. Uneven skill profiles may help reveal late complications that can be compensated for but otherwise remain undetected. We investigated Swedish national school tests of oral, reading and writing [...] Read more.

Children treated for brain tumours often have late-appearing complications that may affect their school performance. Uneven skill profiles may help reveal late complications that can be compensated for but otherwise remain undetected. We investigated Swedish national school tests of oral, reading and writing skills in the first foreign language (English), the mother tongue (Swedish) and mathematics. Data were obtained from The Swedish Childhood Cancer Registry and Statistics Sweden. The results from 475 children diagnosed with a brain tumour before their 15th birthday and 2197 matched controls showed that children treated for brain tumours evinced more difficulties with national tests than controls in almost all subtests, especially in the subject English, and that they may perform better on oral than written tasks. There were larger differences between female cases and controls than between male cases and controls; age at diagnosis played a significant role for some subtests, whereas tumour grade did not. Missing information from national tests proved to be a strong predictor of poor academic performance. Our results show that regular educational follow-ups, as a complement to neuropsychological follow-ups, are important for all children treated for brain tumours, regardless of sex, age at diagnosis or tumour grade. Full article

(This article belongs to the Special Issue Pediatric Brain Tumors)

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14 pages, 2198 KiB

Open AccessArticle

Secreting Germ Cell Tumors of the Central Nervous System: A Long-Term Follow-up Experience

by Veronica Biassoni, Elisabetta Schiavello, Lorenza Gandola, Emilia Pecori, Geraldina Poggi, Filippo Spreafico, Monica Terenziani, Cristina Meazza, Marta Podda, Andrea Ferrari, Roberto Luksch, Michela Casanova, Nadia Puma, Stefano Chiaravalli, Luca Bergamaschi, Graziella Cefalo, Fabio Simonetti, Giovanna Gattuso, Ettore Cesare Seregni, Federica Pallotti, Francesca Gianno, Barbara Diletto, Francesco Barretta and Maura Massimino Show full author list Hide full author list

Cancers 2020, 12(9), 2688; https://doi.org/10.3390/cancers12092688 - 21 Sep 2020

Cited by 4 | Viewed by 2636

Abstract

Introduction: Due to the rarity of nongerminomatous germ cell tumors (NGGCT) with non-standard treatment as yet, we report retrospectively our 30 year experience with chemotherapy followed by craniospinal irradiation (CSI), plus a boost of whole ventricular irradiation (WVI)/tumor bed (TB), tailored to pre-radiation [...] Read more.

Introduction: Due to the rarity of nongerminomatous germ cell tumors (NGGCT) with non-standard treatment as yet, we report retrospectively our 30 year experience with chemotherapy followed by craniospinal irradiation (CSI), plus a boost of whole ventricular irradiation (WVI)/tumor bed (TB), tailored to pre-radiation chemotherapy response. Methods: Between 1988 and 2016, 28 patients received four cycles of PEB (cisplatin/etoposide/bleomycin), then CSI, and two further PEB cycles. Between 1988 and1994, CSI was 25.5 Gy for patients in complete remission (CR), 30 Gy if in partial remission (PR) or metastatic, with a boost to TB up to 45–54 Gy. In the period of 1995–2010, the boost included WVI and any extra-ventricular tumor sites up to 45 Gy. After 2010, CSI was reduced to 25.5 Gy for all non-metastatic patients, and a boost was given only to TB up to 40.5/45.5 Gy, depending on patients’ CR/PR status. After 2003, patients with alfafetoprotein (αFP) > 1000 ng/mL received intensified treatment, also including autologous stem cell transplantation. Results: Among 28 patients (23 males; median age 12 years, 6 metastatic), 25 responded to PEB, and three progressed (PD) after one to four cycles; 26 received radiotherapy obtaining 13 CR, 7 PR and 5 stable disease (SD), 1 PD; 6 (21%) died (5 for disease, 1 for pneumonia while in CR). Five-year overall survival (OS) and progression-free survival (PFS) were both 81%; 10 year OS and PFS 81% and 76%, respectively (median follow-up 11 years). Conclusions: Survival for children with NGGCT, independently from disease extent, was encouraging. Further studies should elucidate which patients could benefit from reduced volume and dose irradiation. Full article

(This article belongs to the Special Issue Pediatric Brain Tumors)

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16 pages, 2661 KiB

Open AccessArticle

Pre- and Post-Zygotic TP53 De Novo Mutations in SHH-Medulloblastoma

by Jacopo Azzollini, Elisabetta Schiavello, Francesca Romana Buttarelli, Carlo Alfredo Clerici, Laura Tizzoni, Giovanna De Vecchi, Fabio Capra, Federica Pisati, Veronica Biassoni, Letterio Runza, Giorgio Carrabba, Felice Giangaspero, Maura Massimino, Valeria Pensotti and Siranoush Manoukian

Cancers 2020, 12(9), 2503; https://doi.org/10.3390/cancers12092503 - 3 Sep 2020

Cited by 1 | Viewed by 2759

Abstract

Li-Fraumeni syndrome (LFS) is an autosomal dominant disorder caused by mutations in the TP53 gene, predisposing to a wide spectrum of early-onset cancers, including brain tumors. In medulloblastoma patients, the role of TP53 has been extensively investigated, though the prevalence of de novo [...] Read more.

Li-Fraumeni syndrome (LFS) is an autosomal dominant disorder caused by mutations in the TP53 gene, predisposing to a wide spectrum of early-onset cancers, including brain tumors. In medulloblastoma patients, the role of TP53 has been extensively investigated, though the prevalence of de novo mutations has not been addressed. We characterized TP53 mutations in a monocentric cohort of consecutive Sonic Hedgehog (SHH)-activated medulloblastoma patients. Germline testing was offered based on tumor p53 immunostaining positivity. Among 24 patients, three (12.5%) showed tumor p53 overexpression, of whom two consented to undergo germline testing and resulted as carriers of TP53 mutations. In the first case, family history was uneventful and the mutation was not found in either of the parents. The second patient, with a family history suggestive of LFS, unexpectedly resulted as a carrier of the mosaic mutation c.742=/C>T p.(Arg248=/Trp). The allele frequency was 26% in normal tissues and 42–77% in tumor specimens. Loss of heterozygosity (LOH) in the tumor was also confirmed. Notably, the mosaic case has been in complete remission for more than one year, while the first patient, as most TP53-mutated medulloblastoma cases from other cohorts, showed a severe and rapidly progressive disease. Our study reported the first TP53 mosaic mutation in medulloblastoma patients and confirmed the importance of germline testing in p53 overexpressed SHH-medulloblastoma, regardless of family history. Full article

(This article belongs to the Special Issue Pediatric Brain Tumors)

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17 pages, 3953 KiB

Open AccessArticle

CN133, a Novel Brain-Penetrating Histone Deacetylase Inhibitor, Hampers Tumor Growth in Patient-Derived Pediatric Posterior Fossa Ependymoma Models

by Roberta Antonelli, Carlos Jiménez, Misha Riley, Tiziana Servidei, Riccardo Riccardi, Aroa Soriano, Josep Roma, Elena Martínez-Saez, Maurizio Martini, Antonio Ruggiero, Lucas Moreno, Josep Sánchez de Toledo, Soledad Gallego, Jordi Bové, Jacob M. Hooker and Miguel F. Segura

Cancers 2020, 12(7), 1922; https://doi.org/10.3390/cancers12071922 - 16 Jul 2020

Cited by 8 | Viewed by 3171

Abstract

Pediatric ependymoma (EPN) is a highly aggressive tumor of the central nervous system that remains incurable in 40% of cases. In children, the majority of cases develop in the posterior fossa and can be classified into two distinct molecular entities: EPN posterior fossa [...] Read more.

Pediatric ependymoma (EPN) is a highly aggressive tumor of the central nervous system that remains incurable in 40% of cases. In children, the majority of cases develop in the posterior fossa and can be classified into two distinct molecular entities: EPN posterior fossa A (PF-EPN-A) and EPN posterior fossa B (PF-EPN-B). Patients with PF-EPN-A have poor outcome and are in demand of new therapies. In general, PF-EPN-A tumors show a balanced chromosome copy number profile and have no recurrent somatic nucleotide variants. However, these tumors present abundant epigenetic deregulations, thereby suggesting that epigenetic therapies could provide new opportunities for PF-EPN-A patients. In vitro epigenetic drug screening of 11 compounds showed that histone deacetylase inhibitors (HDACi) had the highest anti-proliferative activity in two PF-EPN-A patient-derived cell lines. Further screening of 5 new brain-penetrating HDACi showed that CN133 induced apoptosis in vitro, reduced tumor growth in vivo and significantly extended the survival of mice with orthotopically-implanted EPN tumors by modulation of the unfolded protein response, PI3K/Akt/mTOR signaling, and apoptotic pathways among others. In summary, our results provide solid preclinical evidence for the use of CN133 as a new therapeutic agent against PF-EPN-A tumors. Full article

(This article belongs to the Special Issue Pediatric Brain Tumors)

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Review

Jump to: Research

17 pages, 1213 KiB

Open AccessReview

Advanced Pediatric Diffuse Pontine Glioma Murine Models Pave the Way towards Precision Medicine

by Zirong Chen, Peng Peng, Xiaolin Zhang, Barbara Mania-Farnell, Guifa Xi and Feng Wan

Cancers 2021, 13(5), 1114; https://doi.org/10.3390/cancers13051114 - 5 Mar 2021

Cited by 10 | Viewed by 3769

Abstract

Diffuse intrinsic pontine gliomas (DIPGs) account for ~15% of pediatric brain tumors, which invariably present with poor survival regardless of treatment mode. Several seminal studies have revealed that 80% of DIPGs harbor H3K27M mutation coded by HIST1H3B, HIST1H3C and H3F3A genes. The [...] Read more.

Diffuse intrinsic pontine gliomas (DIPGs) account for ~15% of pediatric brain tumors, which invariably present with poor survival regardless of treatment mode. Several seminal studies have revealed that 80% of DIPGs harbor H3K27M mutation coded by HIST1H3B, HIST1H3C and H3F3A genes. The H3K27M mutation has broad effects on gene expression and is considered a tumor driver. Determination of the effects of H3K27M on posttranslational histone modifications and gene regulations in DIPG is critical for identifying effective therapeutic targets. Advanced animal models play critical roles in translating these cutting-edge findings into clinical trial development. Here, we review current molecular research progress associated with DIPG. We also summarize DIPG animal models, highlighting novel genomic engineered mouse models (GEMMs) and innovative humanized DIPG mouse models. These models will pave the way towards personalized precision medicine for the treatment of DIPGs. Full article

(This article belongs to the Special Issue Pediatric Brain Tumors)

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Open AccessReview

Pediatric Glioma: An Update of Diagnosis, Biology, and Treatment

by Yusuke Funakoshi, Nobuhiro Hata, Daisuke Kuga, Ryusuke Hatae, Yuhei Sangatsuda, Yutaka Fujioka, Kosuke Takigawa and Masahiro Mizoguchi

Cancers 2021, 13(4), 758; https://doi.org/10.3390/cancers13040758 - 12 Feb 2021

Cited by 25 | Viewed by 5619

Abstract

Recent research has promoted elucidation of the diverse biological processes that occur in pediatric central nervous system (CNS) tumors. Molecular genetic analysis is essential not only for proper classification, but also for monitoring biological behavior and clinical management of tumors. Ever since the [...] Read more.

Recent research has promoted elucidation of the diverse biological processes that occur in pediatric central nervous system (CNS) tumors. Molecular genetic analysis is essential not only for proper classification, but also for monitoring biological behavior and clinical management of tumors. Ever since the 2016 World Health Organization classification of CNS tumors, molecular profiling has become an indispensable step in the diagnosis, prediction of prognosis, and treatment of pediatric as well as adult CNS tumors. These molecular data are changing diagnosis, leading to new guidelines, and offering novel molecular targeted therapies. The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) makes practical recommendations using recent advances in CNS tumor classification, particularly in molecular discernment of these neoplasms as morphology-based classification of tumors is being replaced by molecular-based classification. In this article, we summarize recent knowledge to provide an overview of pediatric gliomas, which are major pediatric CNS tumors, and describe recent developments in strategies employed for their diagnosis and treatment. Full article

(This article belongs to the Special Issue Pediatric Brain Tumors)

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18 pages, 1395 KiB

Open AccessReview

Paediatric Gliomas: BRAF and Histone H3 as Biomarkers, Therapy and Perspective of Liquid Biopsies

by Jean Yin Tan, Ipalawattage Vindya Stephnie Wijesinghe, Muhamad Noor Alfarizal Kamarudin and Ishwar Parhar

Cancers 2021, 13(4), 607; https://doi.org/10.3390/cancers13040607 - 4 Feb 2021

Cited by 15 | Viewed by 4472

Abstract

Paediatric gliomas categorised as low- or high-grade vary markedly from their adult counterparts, and denoted as the second most prevalent childhood cancers after leukaemia. As compared to adult gliomas, the studies of diagnostic and prognostic biomarkers, as well as the development of therapy [...] Read more.

Paediatric gliomas categorised as low- or high-grade vary markedly from their adult counterparts, and denoted as the second most prevalent childhood cancers after leukaemia. As compared to adult gliomas, the studies of diagnostic and prognostic biomarkers, as well as the development of therapy in paediatric gliomas, are still in their infancy. A body of evidence demonstrates that B-Raf Proto-Oncogene or V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF) and histone H3 mutations are valuable biomarkers for paediatric low-grade gliomas (pLGGs) and high-grade gliomas (pHGGs). Various diagnostic methods involving fluorescence in situ hybridisation, whole-genomic sequencing, PCR, next-generation sequencing and NanoString are currently used for detecting BRAF and histone H3 mutations. Additionally, liquid biopsies are gaining popularity as an alternative to tumour materials in detecting these biomarkers, but still, they cannot fully replace solid biopsies due to several limitations. Although histone H3 mutations are reliable prognosis biomarkers in pHGGs, children with these mutations have a dismal prognosis. Conversely, the role of BRAF alterations as prognostic biomarkers in pLGGs is still in doubt due to contradictory findings. The BRAF V600E mutation is seen in the majority of pLGGs (as seen in pleomorphic xanthoastrocytoma and gangliomas). By contrast, the H3K27M mutation is found in the majority of paediatric diffuse intrinsic pontine glioma and other midline gliomas in pHGGs. pLGG patients with a BRAF V600E mutation often have a lower progression-free survival rate in comparison to wild-type pLGGs when treated with conventional therapies. BRAF inhibitors (Dabrafenib and Vemurafenib), however, show higher overall survival and tumour response in BRAF V600E mutated pLGGs than conventional therapies in some studies. To date, targeted therapy and precision medicine are promising avenues for paediatric gliomas with BRAF V600E and diffuse intrinsic pontine glioma with the H3K27M mutations. Given these shortcomings in the current treatments of paediatric gliomas, there is a dire need for novel therapies that yield a better therapeutic response. The present review discusses the diagnostic tools and the perspective of liquid biopsies in the detection of BRAF V600E and H3K27M mutations. An in-depth understanding of these biomarkers and the therapeutics associated with the respective challenges will bridge the gap between paediatric glioma patients and the development of effective therapies. Full article

(This article belongs to the Special Issue Pediatric Brain Tumors)

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