DNA polymerase β deficiency in the <i>p53</i> null cerebellum leads to medulloblastoma formation

Kim, Jusik,Kim, Jaemi,Lee, Youngsoo Elsevier 2018 Biochemical and biophysical research communication Vol.505 No.2

<P><B>Abstract</B></P> <P>Defects in DNA damage response or repair mechanisms during neurogenesis result in genomic instability, which is causative for several neural defects. These include brain tumors, particularly medulloblastoma, which occurs in the cerebellum with a high incidence in children. We generated an animal model with defective base excision repair during brain development through selective inactivation of DNA polymerase β (<I>Polb</I>) in neuroprogenitor cells. All of <I>Polb</I> conditional knockout mice developed medulloblastoma in a <I>p53</I> null background, similar to the <I>Xrcc1</I> and <I>p53</I> double deficient animal model. XRCC1 is a scaffolding protein which is involved in DNA damage repair and binds to POLB. In both animal models, the histopathological characteristics of the medulloblastoma were similar to those of human classic medulloblastoma. Brain tumor development was slower in the <I>Polb</I> and <I>p53</I> double null animals than in the <I>Xrcc1</I> and <I>p53</I> double knockout animals. Molecular marker analysis suggested that <I>Polb</I>- and <I>Xrcc1</I>-deficient medulloblastomas belonged to the SHHα subtype, underscoring the important role of genomic stability in preventing this devastating pediatric cerebellar tumor.</P> <P><B>Highlights</B></P> <P> <UL> <LI> DNA polymerase β inactivation leads to medulloblastoma formation in the <I>p53</I> null cerebellum. </LI> <LI> The DNA polymerase β null medulloblastoma is histopathologically similar to human medulloblastoma. </LI> <LI> DNA polymerase β and <I>Xrcc1</I> null medulloblastomas show the characteristics of the SHHα subtype. </LI> </UL> </P>

수아종에서 DNS Ploidy, P53, PCNA의 예후인자로서의 의의성에 관한 연구

송준혁,박윤관,정용구,정흥섭,서중근,이기찬,이훈갑 대한신경외과학회 1995 Journal of Korean neurosurgical society Vol.24 No.11

Medulloblastoma is a common intracranial neoplasm of childhood. Multiple clinical and therapeutic factors have been described to predict the outcome of patients with medulloblastoma. There were several studies about the usefulness of the DNA ploidy, the presence of mutation of p53 gene, and PCNA as predictors of the prognosis in the various type of intracranial tumors. The current study investigates the relationship between DNA ploidy, PCNA, mutation of p53 and the clinical course of the medulloblastoma patients. We analyzed the extent of resection, p53 mutation, PCNA, age, sex, and tumor stage as the prognostic indicator in 13 children with medulloblastoma. The patients' age and sex were not related to survival(p>0.1). The extent of resection was related to the patients' survival(p=0.03). The DNA ploidy was marginally related to the patients outcome(p=0.1) and this probably is due to the small number of our patients. There were no correlations between tumor stage, PCNA, p53 and patients' survival. The current study suggests that the prognosis is mainly influenced by the extent of the tumor resection in medulloblastoma patients. The DNA ploidy is weakly corellated with the outcome of the patients. Neither the mutation of p53 gene nor the PCNA were correlate with patients' survival.

Medulloblastoma: Current Perspectives and Recent Advances

( Jung Yoon Choi ) 대한뇌종양학회·대한신경종양학회·대한소아뇌종양학회 2023 Brain Tumor Research and Treatment Vol.11 No.1

Medulloblastoma is the most common embryonal tumor of the central nervous system in childhood. Combined multimodality approaches, including surgery, radiation, and chemotherapy, have improved the outcome of medulloblastoma. Advances in genomic research have shown that medulloblastoma is not a biologically or clinically discrete entity. Previously, the risk was divided according to histology, presence of metastasis, degree of resection, and age at diagnosis. Through the development of integrated genomics, new biology-based risk stratification methods have recently been proposed. It is also important to understand the genetic predisposition of patients with medulloblastoma. Therefore, treatment goal aimed to improve the survival rate with minimal additional adverse effects and reduced longterm sequelae. It is necessary to incorporate genetic findings into the standard of care, and clinical trials that reflect this need to be conducted.

RNA Binding Protein-Mediated Post-Transcriptional Gene Regulation in Medulloblastoma

Bish, Rebecca,Vogel, Christine Korean Society for Molecular and Cellular Biology 2014 Molecules and cells Vol.37 No.5

Medulloblastoma, the most common malignant brain tumor in children, is a disease whose mechanisms are now beginning to be uncovered by high-throughput studies of somatic mutations, mRNA expression patterns, and epigenetic profiles of patient tumors. One emerging theme from studies that sequenced the tumor genomes of large cohorts of medulloblastoma patients is frequent mutation of RNA binding proteins. Proteins which bind multiple RNA targets can act as master regulators of gene expression at the post-transcriptional level to co-ordinate cellular processes and alter the phenotype of the cell. Identification of the target genes of RNA binding proteins may highlight essential pathways of medulloblastomagenesis that cannot be detected by study of transcriptomics alone. Furthermore, a subset of RNA binding proteins are attractive drug targets. For example, compounds that are under development as anti-viral targets due to their ability to inhibit RNA helicases could also be tested in novel approaches to medulloblastoma therapy by targeting key RNA binding proteins. In this review, we discuss a number of RNA binding proteins, including Musashi1 (MSI1), DEAD (Asp-Glu-Ala-Asp) box helicase 3 X-linked (DDX3X), DDX31, and cell division cycle and apoptosis regulator 1 (CCAR1), which play potentially critical roles in the growth and/or maintenance of medulloblastoma.

Neurocognitive Function and Health-Related Quality of Life in Pediatric Korean Survivors of Medulloblastoma

Yoo, Hee Jung,Kim, Hyery,Park, Hyeon Jin,Kim, Dong-Seok,Ra, Young-Shin,Shin, Hee Young The Korean Academy of Medical Sciences 2016 JOURNAL OF KOREAN MEDICAL SCIENCE Vol.31 No.11

<P>The neurocognitive function and quality of life of 58 Korean survivors of childhood medulloblastoma were assessed after surgery, cranial radiation and chemotherapy. All patients were evaluated with a battery of neurocognitive function tests and the Pediatric Functional Assessment of Cancer Therapy-Brain Tumor Survivors, which consists of self-report questionnaires on quality of life. The mean full-scale intelligence quotient (IQ), verbal IQ, and performance IQ scores were 90.2, 97.1, and 84.16, respectively. The mean memory quotient (MQ) score was 86.78, which was within 1 standard deviation of the average score of 100. Processing speed, attention, and executive function showed mild to moderate deficits. Intelligence, memory, executive function, visuospatial function, and simple motor function were significantly lower in the patients diagnosed before 8 years of age compared with those diagnosed after 8. The cognitive deficits in the patients diagnosed at younger ages might be related to earlier exposure to craniospinal irradiation and chemotherapy. The patient and parent proxy evaluations of attention, fine motor function, and quality of life did not differ. We found significant neurocognitive changes in a wide range of neurocognitive functional domains in Korean survivors of childhood medulloblastoma. Long-term follow-up studies of survivors of childhood medulloblastoma beginning at the time of their first diagnosis are required to better understand the deficits exhibited by survivors of childhood medulloblastoma, so that intervention strategies and treatment refinements that reduce the long-term neurocognitive decline can be developed.</P>

Neurocognitive Function and Health-Related Quality of Life in Pediatric Korean Survivors of Medulloblastoma

유희정,김혜리,박현진,김동석,나영신,신희영 대한의학회 2016 Journal of Korean medical science Vol.31 No.11

The neurocognitive function and quality of life of 58 Korean survivors of childhood medulloblastoma were assessed after surgery, cranial radiation and chemotherapy. All patients were evaluated with a battery of neurocognitive function tests and the Pediatric Functional Assessment of Cancer Therapy-Brain Tumor Survivors, which consists of self-report questionnaires on quality of life. The mean full-scale intelligence quotient (IQ), verbal IQ, and performance IQ scores were 90.2, 97.1, and 84.16, respectively. The mean memory quotient (MQ) score was 86.78, which was within 1 standard deviation of the average score of 100. Processing speed, attention, and executive function showed mild to moderate deficits. Intelligence, memory, executive function, visuospatial function, and simple motor function were significantly lower in the patients diagnosed before 8 years of age compared with those diagnosed after 8. The cognitive deficits in the patients diagnosed at younger ages might be related to earlier exposure to craniospinal irradiation and chemotherapy. The patient and parent proxy evaluations of attention, fine motor function, and quality of life did not differ. We found significant neurocognitive changes in a wide range of neurocognitive functional domains in Korean survivors of childhood medulloblastoma. Long-term follow-up studies of survivors of childhood medulloblastoma beginning at the time of their first diagnosis are required to better understand the deficits exhibited by survivors of childhood medulloblastoma, so that intervention strategies and treatment refinements that reduce the long-term neurocognitive decline can be developed.

RNA Binding Protein-Mediated Post-Transcriptional Gene Regulation in Medulloblastoma

Rebecca Bish,Christine Vogel 한국분자세포생물학회 2014 Molecules and cells Vol.37 No.5

Medulloblastoma, the most common malignant brain tumor in children, is a disease whose mechanisms are now beginning to be uncovered by high-throughput studies of somatic mutations, mRNA expression patterns, and epigenetic profiles of patient tumors. One emerging theme from studies that sequenced the tumor genomes of large cohorts of medulloblastoma patients is frequent mutation of RNA binding proteins. Proteins which bind multiple RNA targets can act as master regulators of gene expression at the post-transcriptional level to co-ordinate cellular processes and alter the phenotype of the cell. Identification of the target genes of RNA binding proteins may highlight essential pathways of medulloblastomagenesis that cannot be detected by study of transcriptomics alone. Furthermore, a subset of RNA binding proteins are attractive drug targets. For example, compounds that are under development as anti-viral targets due to their ability to inhibit RNA helicases could also be tested in novel approaches to medulloblastoma therapy by targeting key RNA binding proteins. In this review, we discuss a number of RNA binding proteins, including Musashi1 (MSI1), DEAD (Asp-Glu-Ala-Asp) box helicase 3 X-linked (DDX3X), DDX31, and cell division cycle and apoptosis regulator 1 (CCAR1), which play potentially critical roles in the growth and/or mainte-nance of medulloblastoma.

The Roles of miRNAs in Medulloblastoma: A Systematic Review

Behrouz Mollashahi,Fateme Shaabanpour Aghamaleki,Abolfazl Movafagh 대한암예방학회 2019 Journal of cancer prevention Vol.24 No.2

Medulloblastoma is considered one of the most threatening malignant brain tumors with an extremely high mortality rate in children. In the medulloblastoma, there are several genes and mutations found to work in an unregulated manner that works together to push the cells into a cancerous state. With the discovery of non-coding RNAs such as microRNAs (miRNAs), it has been shown that a different layer of gene regulations may be disrupted which would cause cancer. This fact led scientists to put their focus on the role of miRNAs in cancer. A mature miRNA contains a seed sequence which gives the miRNA to identify and attach to the interest mRNA; this attachment may lead degradation of mRNA or suppress of translation of the mRNA. The expression of miRNAs in medulloblastoma shows that some of these non-coding RNAs are overexpressed (OncomiRs) which help cells to proliferate and keep their stemness features. On the other hand, there are other forms of these miRNAs which normally inhibit cell proliferation and promote cell differentiation (tumor suppressor). These are down-regulated during cancer progression. In this systematic review, we attempted to gather several important studies on miRNAs’ role in medulloblastoma tumors and the importance of these non-coding RNAs in the future study of cancer. (J Cancer Prev 2019;24:79-90)

Coexistence of Radiation-Induced Meningioma and Moyamoya Syndrome 10 Years after Irradiation against Medulloblastoma: a Case Report

Han, Ji Yeon,Choi, Jung Won,Wang, Kyu-Chang,Phi, Ji Hoon,Lee, Ji Yeoun,Chae, Jong-Hee,Park, Sung-Hye,Cheon, Jung-Eun,Kim, Seung-Ki KOREAN ACADEMY OF MEDICAL SCIENCE 2017 JOURNAL OF KOREAN MEDICAL SCIENCE Vol.32 No.11

<P>Radiotherapy is one of the standard treatments for medulloblastoma. However, therapeutic central nervous system irradiation in children may carry delayed side effects, such as radiation-induced tumor and vasculopathy. Here, we report the first case of coexisting meningioma and moyamoya syndrome, presenting 10 years after radiotherapy for medulloblastoma. A 13-year-old boy presented with an enhancing mass at the cerebral falx on magnetic resonance imaging (MRI) after surgery, radiotherapy (30.6 Gy craniospinal axis, 19.8 Gy posterior fossa) and chemotherapy against medulloblastoma 10 years ago, previously. The second tumor was meningioma. On postoperative day 5, he complained of right-sided motor weakness, motor dysphasia, dysarthria, and dysphagia. MRI revealed acute cerebral infarction in the left frontal lobe and both basal ganglia. MR and cerebral angiography confirmed underlying moyamoya syndrome. Four months after the meningioma surgery, the patient presented with headaches, dysarthria, and dizziness. Indirect bypass surgery was performed. He has been free from headaches since one month after the surgery. For patients who received radiotherapy for medulloblastoma at a young age, clinicians should consider the possibility of the coexistence of several complications. Careful follow up for development of secondary tumor and delayed vasculopathy is required.</P>

Coexistence of Radiation-Induced Meningioma and Moyamoya Syndrome 10 Years after Irradiation against Medulloblastoma: a Case Report

한지연,최정원,왕규창,피지훈,이지연,채종희,박성혜,천정은,김승기 대한의학회 2017 Journal of Korean medical science Vol.32 No.11

Radiotherapy is one of the standard treatments for medulloblastoma. However, therapeutic central nervous system irradiation in children may carry delayed side effects, such as radiation-induced tumor and vasculopathy. Here, we report the first case of coexisting meningioma and moyamoya syndrome, presenting 10 years after radiotherapy for medulloblastoma. A 13-year-old boy presented with an enhancing mass at the cerebral falx on magnetic resonance imaging (MRI) after surgery, radiotherapy (30.6 Gy craniospinal axis, 19.8 Gy posterior fossa) and chemotherapy against medulloblastoma 10 years ago, previously. The second tumor was meningioma. On postoperative day 5, he complained of right-sided motor weakness, motor dysphasia, dysarthria, and dysphagia. MRI revealed acute cerebral infarction in the left frontal lobe and both basal ganglia. MR and cerebral angiography confirmed underlying moyamoya syndrome. Four months after the meningioma surgery, the patient presented with headaches, dysarthria, and dizziness. Indirect bypass surgery was performed. He has been free from headaches since one month after the surgery. For patients who received radiotherapy for medulloblastoma at a young age, clinicians should consider the possibility of the coexistence of several complications. Careful follow up for development of secondary tumor and delayed vasculopathy is required.