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Cancers
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Rare Childhood Malignancy
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Rare Childhood Malignancy

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 27016

Special Issue Editor

Ass. Prof. Elizabeth M. Algar

E-Mail Website
Guest Editor
1. Hudson Institute of Medical Research, Clayton, 3168, Australia
2. Department of Translational Medicine, Monash University, Clayton, 3168, Australia
Interests: cancer syndromes; Wilms tumor; malignant rhabdoid tumor; molecular pathology of brain tumors, including genetics and epigenetics

Special Issue Information

Dear Colleagues,

Childhood cancer is a relatively rare disease; however, it is still a major cause of disease-related death in infants and children in countries of high economic status. Although five-year survival rates for many childhood cancers currently exceed 80%, there are several tumor groups for which survival rates remain persistently low. Tumor morphology, molecular subtype, age at diagnosis, disease stage, and tumor location are important factors influencing treatment outcomes.

The main diagnostic groups in pediatric cancer include leukemia, lymphoma, central nervous system (CNS) tumors, neuroblastoma, retinoblastoma, renal tumors, hepatic tumors, bone tumors, soft tissue sarcomas, germ cell tumors, and epithelial tumors. Within these diagnostic groups exist subgroups with five-year survival rates of less than 80%. These cancers are comparatively rare in the pediatric population, occurring at frequencies of less than 5%, and include: acute myeloid leukemia (~4.1%), malignant rhabdoid tumor, including atypical teratoid rhabdoid tumor (<1%), neuroblastoma (~5%), desmoplastic small round cell tumor (<1%), hepatoblastoma (~1%), anaplastic Wilms tumor (<1%), osteosarcoma (~1.8%) rhabdomyosarcoma (~2.5%), the CNS tumors, ependymoma (~1.8%), medulloblastoma (~3%), and glioma (~2.2%).

The focus of this Special Issue is on highlighting biological and (pre)clinical studies on these less common pediatric cancers with comparatively poor outcomes, encompassing but not limited to studies advancing knowledge on tumor origin, tumor molecular genetics and epigenetics, biologically-based or targeted therapies, and tumor models, including organoids.

Dr. Elizabeth M. Algar
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • rare pediatric cancers

Published Papers (9 papers)

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Editorial

Jump to: Research, Review

2 pages, 166 KiB  
Editorial
Rare Childhood Malignancy
by Elizabeth M Algar
Cancers 2021, 13(7), 1504; https://doi.org/10.3390/cancers13071504 - 25 Mar 2021
Viewed by 952
Abstract
This small collection of six original research papers and two review articles in the Special Issue “Rare Childhood Malignancy” highlights the diversity and importance of empirical research into childhood malignancy, a theme that underpins the significant advances that have been made in treating [...] Read more.
This small collection of six original research papers and two review articles in the Special Issue “Rare Childhood Malignancy” highlights the diversity and importance of empirical research into childhood malignancy, a theme that underpins the significant advances that have been made in treating the diseases that constitute cancers in children [...] Full article
(This article belongs to the Special Issue Rare Childhood Malignancy)

Research

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21 pages, 3978 KiB  
Article
Transcriptomic Analyses of MYCN-Regulated Genes in Anaplastic Wilms’ Tumour Cell Lines Reveals Oncogenic Pathways and Potential Therapeutic Vulnerabilities
by Marianna Szemes, Zsombor Melegh, Jacob Bellamy, Ji Hyun Park, Biyao Chen, Alexander Greenhough, Daniel Catchpoole and Karim Malik
Cancers 2021, 13(4), 656; https://doi.org/10.3390/cancers13040656 - 06 Feb 2021
Cited by 6 | Viewed by 3178
Abstract
The MYCN proto-oncogene is deregulated in many cancers, most notably in neuroblastoma, where MYCN gene amplification identifies a clinical subset with very poor prognosis. Gene expression and DNA analyses have also demonstrated overexpression of MYCN mRNA, as well as focal amplifications, copy number [...] Read more.
The MYCN proto-oncogene is deregulated in many cancers, most notably in neuroblastoma, where MYCN gene amplification identifies a clinical subset with very poor prognosis. Gene expression and DNA analyses have also demonstrated overexpression of MYCN mRNA, as well as focal amplifications, copy number gains and presumptive change of function mutations of MYCN in Wilms’ tumours with poorer outcomes, including tumours with diffuse anaplasia. Surprisingly, however, the expression and functions of the MYCN protein in Wilms’ tumours still remain obscure. In this study, we assessed MYCN protein expression in primary Wilms’ tumours using immunohistochemistry of tissue microarrays. We found MYCN protein to be expressed in tumour blastemal cells, and absent in stromal and epithelial components. For functional studies, we used two anaplastic Wilms’ tumour cell-lines, WiT49 and 17.94, to study the biological and transcriptomic effects of MYCN depletion. We found that MYCN knockdown consistently led to growth suppression but not cell death. RNA sequencing identified 561 MYCN-regulated genes shared by WiT49 and 17.94 cell-lines. As expected, numerous cellular processes were downstream of MYCN. MYCN positively regulated the miRNA regulator and known Wilms’ tumour oncogene LIN28B, the genes encoding methylosome proteins PRMT1, PRMT5 and WDR77, and the mitochondrial translocase genes TOMM20 and TIMM50. MYCN repressed genes including the developmental signalling receptor ROBO1 and the stromal marker COL1A1. Importantly, we found that MYCN also repressed the presumptive Wilms’ tumour suppressor gene REST, with MYCN knockdown resulting in increased REST protein and concomitant repression of RE1-Silencing Transcription factor (REST) target genes. Together, our study identifies regulatory axes that interact with MYCN, providing novel pathways for potential targeted therapeutics for poor-prognosis Wilms’ tumour. Full article
(This article belongs to the Special Issue Rare Childhood Malignancy)
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17 pages, 4722 KiB  
Article
Abemaciclib, A Selective CDK4/6 Inhibitor, Restricts the Growth of Pediatric Ependymomas
by Muh-Lii Liang, Chun-Han Chen, Yun-Ru Liu, Man-Hsu Huang, Yu-Chen Lin, Tai-Tong Wong, Sey-En Lin, Shing-Shiung Chu, Yi-Huei Ding and Tsung-Han Hsieh
Cancers 2020, 12(12), 3597; https://doi.org/10.3390/cancers12123597 - 01 Dec 2020
Cited by 8 | Viewed by 2556
Abstract
Pediatric ependymomas are a type of malignant brain tumor that occurs in children. The overall 10-year survival rate has been reported as being 45–75%. Maximal safe surgical resection combined with adjuvant chemoradiation therapy is associated with the highest overall and progression-free survival rates. [...] Read more.
Pediatric ependymomas are a type of malignant brain tumor that occurs in children. The overall 10-year survival rate has been reported as being 45–75%. Maximal safe surgical resection combined with adjuvant chemoradiation therapy is associated with the highest overall and progression-free survival rates. Despite aggressive treatment, one-third of ependymomas exhibit recurrence within 2 years of initial treatment. Therefore, this study aimed to find new agents to overcome chemoresistance and defer radiotherapy treatment since, in addition, radiation exposure may cause long-term side effects in the developing brains of young children. By using integrated bioinformatics and through experimental validation, we found that at least one of the genes CCND1 and CDK4 is overexpressed in ependymomas. The use of abemaciclib, a highly selective CDK4/6 inhibitor, effectively inhibited cell proliferation and reduced the expression of cell-cycle-related and DNA-repair-related gene expression via the suppression of RB phosphorylation, which was determined through RNA-seq and Western blot analyses. Furthermore, abemaciclib effectively induced cell death in vitro. The efficiency of abemaciclib was validated in vivo using subcutaneously implanted ependymoma tissues from patient-derived xenografts (PDXs) in mouse models. Treatment with abemaciclib showed encouraging results in preclinical pediatric ependymoma models and represents a potential therapeutic strategy for treating challenging tumors in children. Full article
(This article belongs to the Special Issue Rare Childhood Malignancy)
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12 pages, 2183 KiB  
Article
Spinal Deformities after Childhood Tumors
by Anna K. Hell, Ingrid Kühnle, Heiko M. Lorenz, Lena Braunschweig, Katja A. Lüders, Hans Christoph Bock, Christof M. Kramm, Hans Christoph Ludwig and Konstantinos Tsaknakis
Cancers 2020, 12(12), 3555; https://doi.org/10.3390/cancers12123555 - 28 Nov 2020
Cited by 6 | Viewed by 1788
Abstract
Childhood tumors of the central nervous system (CNS) and other entities affecting the spine are rare. Treatment options vary from surgical biopsy to partial, subtotal, and total resection, to radiation, to chemotherapy. The aim of this study is to investigate spinal deformity and [...] Read more.
Childhood tumors of the central nervous system (CNS) and other entities affecting the spine are rare. Treatment options vary from surgical biopsy to partial, subtotal, and total resection, to radiation, to chemotherapy. The aim of this study is to investigate spinal deformity and subsequent surgical interventions in this patient cohort. A retrospective review at our institution identified children with CNS tumors, spinal tumors, and juxta-spinal tumors, as well as spinal deformities. Tumor entity, treatment, mobilization, and radiographic images were analyzed relative to the spinal deformity, using curve angles in two planes. Conservative or surgical interventions such as orthotic braces, growth-friendly spinal implants, and spinal fusions were evaluated and analyzed with respect to treatment results. Tumor entities in the 76 patients of this study included CNS tumors (n = 41), neurofibromatosis with spinal or paraspinal tumors (n = 14), bone tumors (n = 12), embryonal tumors (n = 7), and others (n = 2). The initial treatment consisted of surgical biopsy (n = 5), partial, subtotal, or total surgical resection (n = 59), or none (n = 12), followed by chemotherapy, radiotherapy, or both (n = 40). Out of 65 evaluated patients, 25 revealed a moderate or severe scoliotic deformity of 71° (range 21–116°), pathological thoracic kyphosis of 66° (range 50–130°), and lordosis of 61° (range 41–97°). Surgical treatment was performed on 21 patients with implantation of growth-friendly spinal implants (n = 9) as well as twelve dorsal spinal fusions (two with prior halo distraction). Surgical interventions significantly improved spinal deformities without additional neurological impairment. With the increasing number of children surviving rare tumors, attention should be focused on long-term problems such as spinal deformities and consequent disabilities. A significant number of children with CNS tumors, spinal tumors or juxta-spinal tumors required surgical intervention. Early information about spinal deformities and a close follow-up are mandatory for this patient group. Full article
(This article belongs to the Special Issue Rare Childhood Malignancy)
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24 pages, 7193 KiB  
Article
A Novel Orthotopic Patient-Derived Xenograft Model of Radiation-Induced Glioma Following Medulloblastoma
by Jacqueline P. Whitehouse, Meegan Howlett, Hilary Hii, Chelsea Mayoh, Marie Wong, Paulette Barahona, Pamela Ajuyah, Christine L. White, Molly K. Buntine, Jason M. Dyke, Sharon Lee, Santosh Valvi, Jason Stanley, Clara Andradas, Brooke Carline, Mani Kuchibhotla, Paul G. Ekert, Mark J. Cowley, Nicholas G. Gottardo and Raelene Endersby
Cancers 2020, 12(10), 2937; https://doi.org/10.3390/cancers12102937 - 12 Oct 2020
Cited by 6 | Viewed by 3784
Abstract
Radiation-induced glioma (RIG) is a highly aggressive brain cancer arising as a consequence of radiation therapy. We report a case of RIG that arose in the brain stem following treatment for paediatric medulloblastoma, and the development and characterisation of a matched orthotopic patient-derived [...] Read more.
Radiation-induced glioma (RIG) is a highly aggressive brain cancer arising as a consequence of radiation therapy. We report a case of RIG that arose in the brain stem following treatment for paediatric medulloblastoma, and the development and characterisation of a matched orthotopic patient-derived xenograft (PDX) model (TK-RIG915). Patient and PDX tumours were analysed using DNA methylation profiling, whole genome sequencing (WGS) and RNA sequencing. While initially thought to be a diffuse intrinsic pontine glioma (DIPG) based on disease location, results from methylation profiling and WGS were not consistent with this diagnosis. Furthermore, clustering analyses based on RNA expression suggested the tumours were distinct from primary DIPG. Additional gene expression analysis demonstrated concordance with a published RIG expression profile. Multiple genetic alterations that enhance PI3K/AKT and Ras/Raf/MEK/ERK signalling were discovered in TK-RIG915 including an activating mutation in PIK3CA, upregulation of PDGFRA and AKT2, inactivating mutations in NF1, and a gain-of-function mutation in PTPN11. Additionally, deletion of CDKN2A/B, increased IDH1 expression, and decreased ARID1A expression were observed. Detection of phosphorylated S6, 4EBP1 and ERK via immunohistochemistry confirmed PI3K pathway and ERK activation. Here, we report one of the first PDX models for RIG, which recapitulates the patient disease and is molecularly distinct from primary brain stem glioma. Genetic interrogation of this model has enabled the identification of potential therapeutic vulnerabilities in this currently incurable disease. Full article
(This article belongs to the Special Issue Rare Childhood Malignancy)
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17 pages, 7198 KiB  
Article
Characterization of mTOR Activity and Metabolic Profile in Pediatric Rhabdomyosarcoma
by Luca Felkai, Ildikó Krencz, Dorottya Judit Kiss, Noémi Nagy, Gábor Petővári, Titanilla Dankó, Tamás Micsík, András Khoor, Tamás Tornóczky, Zoltán Sápi, Anna Sebestyén and Monika Csóka
Cancers 2020, 12(7), 1947; https://doi.org/10.3390/cancers12071947 - 17 Jul 2020
Cited by 10 | Viewed by 2537
Abstract
mTOR activation has been observed in rhabdomyosarcoma (RMS); however, mTOR complex (mTORC) 1 inhibition has had limited success thus far. mTOR activation alters the metabolic pathways, which is linked to survival and metastasis. These pathways have not been thoroughly analyzed in RMSs. We [...] Read more.
mTOR activation has been observed in rhabdomyosarcoma (RMS); however, mTOR complex (mTORC) 1 inhibition has had limited success thus far. mTOR activation alters the metabolic pathways, which is linked to survival and metastasis. These pathways have not been thoroughly analyzed in RMSs. We performed immunohistochemistry on 65 samples to analyze the expression of mTOR complexes (pmTOR, pS6, Rictor), and several metabolic enzymes (phosphofructokinase, lactate dehydrogenase-A, β-F1-ATPase, glucose-6-phosphate dehydrogenase, glutaminase). RICTOR amplification, as a potential mechanism of Rictor overexpression, was analyzed by FISH and digital droplet PCR. In total, 64% of the studied primary samples showed mTOR activity with an mTORC2 dominance (82%). Chemotherapy did not cause any relevant change in mTOR activity. Elevated mTOR activity was associated with a worse prognosis in relapsed cases. RICTOR amplification was not confirmed in any of the cases. Our findings suggest the importance of the Warburg effect and the pentose-phosphate pathway beside a glutamine demand in RMS cells. The expression pattern of the studied mTOR markers can explain the inefficacy of mTORC1 inhibitor therapy. Therefore, we suggest performing a detailed investigation of the mTOR profile before administering mTORC1 inhibitor therapy. Furthermore, our findings highlight that targeting the metabolic plasticity could be an alternative therapeutic approach. Full article
(This article belongs to the Special Issue Rare Childhood Malignancy)
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18 pages, 4754 KiB  
Article
The Proteasome Inhibitor Ixazomib Inhibits the Formation and Growth of Pulmonary and Abdominal Osteosarcoma Metastases in Mice
by Michael A. Harris, Mark A. Miles, Tanmay M. Shekhar, Carmelo Cerra, Smitha R. Georgy, Stewart D. Ryan, Claire M. Cannon and Christine J. Hawkins
Cancers 2020, 12(5), 1207; https://doi.org/10.3390/cancers12051207 - 11 May 2020
Cited by 13 | Viewed by 3090
Abstract
Osteosarcoma is the most common form of primary bone cancer. Over 20% of osteosarcoma patients present with pulmonary metastases at diagnosis, and nearly 70% of these patients fail to respond to treatment. Previous work revealed that human and canine osteosarcoma cell lines are [...] Read more.
Osteosarcoma is the most common form of primary bone cancer. Over 20% of osteosarcoma patients present with pulmonary metastases at diagnosis, and nearly 70% of these patients fail to respond to treatment. Previous work revealed that human and canine osteosarcoma cell lines are extremely sensitive to the therapeutic proteasome inhibitor bortezomib in vitro. However, bortezomib has proven disappointingly ineffective against solid tumors including sarcomas in animal experiments and clinical trials. Poor tumor penetration has been speculated to account for the inconsistency between in vitro and in vivo responses of solid tumors to bortezomib. Here we show that the second-generation proteasome inhibitor ixazomib, which reportedly has enhanced solid tumor penetration compared to bortezomib, is toxic to human and canine osteosarcoma cells in vitro. We used experimental osteosarcoma metastasis models to compare the efficacies of ixazomib and bortezomib against primary tumors and metastases derived from luciferase-expressing KRIB or 143B human osteosarcoma cell lines in athymic mice. Neither proteasome inhibitor reduced the growth of primary intramuscular KRIB tumors, however both drugs inhibited the growth of established pulmonary metastases created via intravenous inoculation with KRIB cells, which were significantly better vascularized than the primary tumors. Only ixazomib slowed metastases from KRIB primary tumors and inhibited the growth of 143B pulmonary and abdominal metastases, significantly enhancing the survival of mice intravenously injected with 143B cells. Taken together, these results suggest ixazomib exerts better single agent activity against osteosarcoma metastases than bortezomib. These data provide hope that incorporation of ixazomib, or other proteasome inhibitors that penetrate efficiently into solid tumors, into current regimens may improve outcomes for patients diagnosed with metastatic osteosarcoma. Full article
(This article belongs to the Special Issue Rare Childhood Malignancy)
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Review

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13 pages, 638 KiB  
Review
Infant Acute Myeloid Leukemia: A Unique Clinical and Biological Entity
by Charlotte Calvo, Odile Fenneteau, Guy Leverger, Arnaud Petit, André Baruchel and Françoise Méchinaud
Cancers 2021, 13(4), 777; https://doi.org/10.3390/cancers13040777 - 13 Feb 2021
Cited by 9 | Viewed by 5220
Abstract
Infant acute myeloid leukemia (AML) is a rare subgroup of AML of children <2 years of age. It is as frequent as infant acute lymphoblastic leukemia (ALL) but not clearly distinguished by study groups. However, infant AML demonstrates peculiar clinical and biological characteristics, [...] Read more.
Infant acute myeloid leukemia (AML) is a rare subgroup of AML of children <2 years of age. It is as frequent as infant acute lymphoblastic leukemia (ALL) but not clearly distinguished by study groups. However, infant AML demonstrates peculiar clinical and biological characteristics, and its prognosis differs from AML in older children. Acute megakaryoblastic leukemia (AMKL) is very frequent in this age group and has raised growing interest. Thus, AMKL is a dominant topic in this review. Recent genomic sequencing has contributed to our understanding of infant AML. These data demonstrated striking features of infant AML: fusion genes are able to induce AML transformation without additional cooperation, and unlike AML in older age groups there is a paucity of associated mutations. Mice modeling of these fusions showed the essential role of ontogeny in the infant leukemia phenotype compared to older children and adults. Understanding leukemogenesis may help in developing new targeted treatments to improve outcomes that are often very poor in this age group. A specific diagnostic and therapeutic approach for this age group should be investigated. Full article
(This article belongs to the Special Issue Rare Childhood Malignancy)
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15 pages, 949 KiB  
Review
DUX Hunting—Clinical Features and Diagnostic Challenges Associated with DUX4-Rearranged Leukaemia
by Jacqueline A. Rehn, Matthew J. O'Connor, Deborah L. White and David T. Yeung
Cancers 2020, 12(10), 2815; https://doi.org/10.3390/cancers12102815 - 30 Sep 2020
Cited by 13 | Viewed by 3209
Abstract
DUX4-rearrangement (DUX4r) is a recently discovered recurrent genomic lesion reported in 4–7% of childhood B cell acute lymphoblastic leukaemia (B-ALL) cases. This subtype has favourable outcomes, especially in children and adolescents treated with intensive chemotherapy. The fusion most commonly links [...] Read more.
DUX4-rearrangement (DUX4r) is a recently discovered recurrent genomic lesion reported in 4–7% of childhood B cell acute lymphoblastic leukaemia (B-ALL) cases. This subtype has favourable outcomes, especially in children and adolescents treated with intensive chemotherapy. The fusion most commonly links the hypervariable IGH gene to DUX4 a gene located within the D4Z4 macrosatellite repeat on chromosome 4, with a homologous polymorphic repeat on chromosome 10. DUX4r is cryptic to most standard diagnostic techniques, and difficult to identify even with next generation sequencing assays. This review summarises the clinical features and molecular genetics of DUX4r B-ALL and proposes prospective new diagnostic methods. Full article
(This article belongs to the Special Issue Rare Childhood Malignancy)
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