The landscape of extrachromosomal circular DNA in medulloblastoma
Owen ChapmanJens LuebeckSameena WaniAshutosh TiwariMeghana S. PagadalaShanqing WangJon D. LarsonJoshua T. LangeIvy Tsz-Lo WongSiavash R. DehkordiSahaana ChandranMiriam AdamYingxi LinEdwin F. JuarezJames RobinsonSunita SridharDenise MalickiNicole G. CoufalMichael L. LevyJohn R. CrawfordScott L. PomeroyJeremy N. RichRichard H. ScheuermannHannah CarterJesse R. DixonPaul S. MischelErnest FraenkelRobert J. Wechsler‐ReyaVineet BafnaJill P. MesirovLukas Chávez
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SUMMARY Extrachromosomal circular DNA (ecDNA) is an important driver of aggressive tumor growth, promoting high oncogene copy number, intratumoral heterogeneity, accelerated evolution of drug resistance, enhancer rewiring, and poor outcome. ecDNA has been reported in medulloblastoma (MB), the most common malignant pediatric brain tumor, but the ecDNA landscape and its association with specific MB subgroups, its impact on enhancer rewiring, and its potential clinical implications, are not known. We assembled a retrospective cohort of 468 MB patient samples with available whole genome sequencing (WGS) data covering the four major MB subgroups WNT, SHH, Group 3 and Group 4. Using computational methods for the detection and reconstruction of ecDNA 1 , we find ecDNA in 82 patients (18%) and observe that ecDNA+ MB patients are more than twice as likely to relapse and three times as likely to die of disease. In addition, we find that individual medulloblastoma tumors often harbor multiple ecDNAs, each containing different amplified oncogenes along with co-amplified non-coding regulatory enhancers. ecDNA was substantially more prevalent among 31 analyzed patient-derived xenograft (PDX) models and cell lines than in our patient cohort. By mapping the accessible chromatin and 3D conformation landscapes of MB tumors that harbor ecDNA, we observe frequent candidate “enhancer rewiring” events that spatially link oncogenes with co-amplified enhancers. Our study reveals the frequency and diversity of ecDNA in a subset of highly aggressive tumors and suggests enhancer rewiring as a frequent oncogenic mechanism of ecDNAs in MB. Further, these results demonstrate that ecDNA is a frequent and potent driver of poor outcome in MB patients.OBJECTIVE Uniform cells with round, regular nuclei characterize the typical histologic aspect of medulloblastoma. Enlargement of nuclei distinguishes the large-cell medulloblastoma variant and is associated with a poor prognosis in pediatric medulloblastomas. The aim of the present study was to compare the size of nuclei between pediatric and adult medulloblastomas by a morphometric analysis. MATERIAL AND METHODS In 79 neurosurgical specimens of cerebellar medulloblastomas, the maximum nuclear diameter of the largest nuclei was measured. Measurements were performed with a digital-image analysis system. The measure of the maximum diameter was chosen in order to reduce the split cell error. RESULTS The difference between the mean values in children and adults was statistically significant (p = 0,001). The distribution of maximum values measured in each case had two distinct peaks in the two age groups, in 3.5% of adult cases and in more than 30% of pediatric cases the maximum nuclear size was superior to 12 microm. CONCLUSIONS The present results show that nuclei of tumor cells in pediatric medulloblastomas are larger than those in adult medulloblastomas and confirm that the phenotype of medulloblastoma is different in the two age groups. Distinct genetic events can, thus, underlie medulloblastoma in childhood and adult age, the prognostic role of genetic variables can differ by age.
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Medulloblastoma is the most frequent childhood brain tumor. Medulloblastoma affects the cerebellum, the brain region that regulates motor coordination and is also involved in certain cognitive functions. Medulloblastoma is a heterogeneous tumor, and recent advances in high-throughput genomic techniques have allowed medulloblastoma to be classified into four molecularly distinct subgroups: the SHH-group, WNT-group, group 3, and group 4 medulloblastoma.
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UNLABELLED Medulloblastoma, a primitive neuroectodermal tumor growing in cerebellum, is one of the most sensitive to radiation therapy childhood brain tumors, therefore, this method of treatments is justly considered to be the standard for the treatment of medulloblastoma. The outcome of this malignant brain tumor differs in standard and high-risk groups of patients. The aim of the work was to evaluate the survival rate for children with medulloblastoma according to two risk groups. PATIENTS AND METHODS Eighteen patients aged from 3 to 18 years with histological proven medulloblastoma treated with standard craniospinal and additional posterior fossa radiotherapy were investigated in our study. Nine patients with disseminated and partial removed medulloblastoma were assigned to the high-risk group and other 9 patients with local ant totally removed medulloblastoma were allocated to the standard risk group. RESULTS Radiological response of medulloblastoma to the radiation therapy was observed in 15 (83.3%) out of 18 patients: complete radiological response was observed in 6 (67%) out of 9 standard-risk patients and in only 1 (11.1%) out of 9 high-risk patients (p 0.05). The mean time to progression for all patients was 18.2 months: 28.9 months in standard and 7.4 months in high-risk group (p=0.02). The overall survival for all investigated patients was 25.8 months: 37.2 and 14.3 months in the standard and high-risk groups, respectively (p=0.01). Five years progression-free and overall survival rate for all patients was 16.7%: 0% in the high-risk group and 33.3 % in the standard-risk group (p>0.05). CONCLUSION In our study the difference in survival rate between standard and high-risk patients with medulloblastoma was shown. We observed a statistically significant longer time to progression and better overall survival in the standard-risk group. However, we did not find any significant differences in other survival indices (response, relapse rates, mortality, five years progression- free and overall survival) between those two risk groups.
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Objective: To investigate the CT,MRI and pathological examinations of the medulloblastoma in children,in order to improve the accuracy in early diagnosis,and provide reliable data for the clinic treatment before and after operation.Materials and Methods: Fifteen cases of pediatric medulloblastoma,with their age ranging from four to eleven years old,were provided by operation and pathological examination.Results: Nine cases of medulloblastoma were diagnosed by CT.Fourteen cases of medulloblastoma were diagnosed by MRI.One case of medulloblastoma or ependymoma were diagnosed.Fifteen cases of pediatric medulloblastoma were confirmed by pathological examination.Conclusion: MRI was superior to CT in determining the location and diagnosis of medulloblastoma.The early discovery and early treatment are the keys to prolonging the survial of pediatric patients with medulloblastoma~([1]).
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A case of a melanotic cerebellar tumor in a three year old child is described. The tumor has a close histological resemblance to the melanotic neuroectodermal tumor of infancy occurring extracranially. Despite this, the histological appearance, the site of involvement, the age incidence, and the malignant behavior of the tumor are similar to that of the usual medulloblastoma. Furthermore, the predominating cellular element of the tumor is indistinguishable from that of the medulloblastoma. The melanotic cerebellar tumor is, therefore, considered to be a variant of medulloblastoma and is designated as melanotic medulloblastoma.
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Though medulloblastoma is considered as a childhood brain tumor, it may occur less frequently in adolescents and rarely in adults. While desmoplastic medulloblastoma histologic variant is observed in approximately 15% of childhood cases, it constitutes more than 50% of adult cases. In this article, we discuss a desmoplastic medulloblastoma case in view of the current literature.
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Aberrant expression of protein arginine methyltransferases (PRMTs) has been implicated in a number of brain tumors, but the role of PRMT1 in medulloblastoma, the most common malignant pediatric brain tumor, remains unexplored
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