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Medulloblastoma genomics in the modern molecular era.

Published on May 1, 2020in Brain Pathology6.352
· DOI :10.1111/BPA.12804
Rahul Kumar1
Estimated H-index: 1
(St. Jude Children's Research Hospital),
Anthony P. Y. Liu4
Estimated H-index: 4
(St. Jude Children's Research Hospital),
Paul A. Northcott63
Estimated H-index: 63
(St. Jude Children's Research Hospital)
Abstract
Medulloblastoma (MB) represents a spectrum of biologically and clinically distinct entities. Initially described histopathologically as a small, round blue cell tumor arising in the cerebellum, MB has emerged as a paradigm for molecular classification in cancer. Recent advances in genomic, transcriptomic and epigenomic profiling of MB have further refined molecular classification and complemented conventional histopathological diagnosis. Herein, we review the main clinical and molecular features of the four consensus subgroups of MB (WNT, SHH, Group 3 and Group 4). We also highlight hereditary predisposition syndromes associated with increased risk of MB. Finally, we explore advances in the classification of the consensus molecular groups while also presenting cutting-edge frontiers in identifying intratumoral heterogeneity and cellular origins of MB.
  • References (116)
  • Citations (2)
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References116
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#1Lawrence A. Donehower (BCM: Baylor College of Medicine)H-Index: 68
#2Thierry Soussi (KI: Karolinska Institutet)H-Index: 63
Last. David A. Wheeler (BCM: Baylor College of Medicine)H-Index: 81
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Summary The TP53 tumor suppressor gene is frequently mutated in human cancers. An analysis of five data platforms in 10,225 patient samples from 32 cancers reported by The Cancer Genome Atlas (TCGA) enables comprehensive assessment of p53 pathway involvement in these cancers. More than 91% of TP53-mutant cancers exhibit second allele loss by mutation, chromosomal deletion, or copy-neutral loss of heterozygosity. TP53 mutations are associated with enhanced chromosomal instability, including incre...
6 CitationsSource
#1Volker Hovestadt (Broad Institute)H-Index: 39
#2Kyle S Smith (St. Jude Children's Research Hospital)H-Index: 3
Last. Paul A. Northcott (St. Jude Children's Research Hospital)H-Index: 63
view all 51 authors...
Medulloblastoma is a malignant childhood cerebellar tumour type that comprises distinct molecular subgroups. Whereas genomic characteristics of these subgroups are well defined, the extent to which cellular diversity underlies their divergent biology and clinical behaviour remains largely unexplored. Here we used single-cell transcriptomics to investigate intra- and intertumoral heterogeneity in 25 medulloblastomas spanning all molecular subgroups. WNT, SHH and Group 3 tumours comprised subgroup...
6 CitationsSource
#1Tanvi Sharma (DKFZ: German Cancer Research Center)H-Index: 10
#2Edward C. Schwalbe (Newcastle University)H-Index: 18
Last. Steven C. Clifford (Newcastle University)H-Index: 47
view all 23 authors...
In 2012, an international consensus paper reported that medulloblastoma comprises four molecular subgroups (WNT, SHH, Group 3, and Group 4), each associated with distinct genomic features and clinical behavior. Independently, multiple recent reports have defined further intra-subgroup heterogeneity in the form of biologically and clinically relevant subtypes. However, owing to differences in patient cohorts and analytical methods, estimates of subtype number and definition have been inconsistent...
3 CitationsSource
#1Maria C. Vladoiu (U of T: University of Toronto)H-Index: 3
#2Ibrahim El-Hamamy (OICR: Ontario Institute for Cancer Research)H-Index: 1
Last. Michael D. TaylorH-Index: 85
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Study of the origin and development of cerebellar tumours has been hampered by the complexity and heterogeneity of cerebellar cells that change over the course of development. Here we use single-cell transcriptomics to study more than 60,000 cells from the developing mouse cerebellum and show that different molecular subgroups of childhood cerebellar tumours mirror the transcription of cells from distinct, temporally restricted cerebellar lineages. The Sonic Hedgehog medulloblastoma subgroup tra...
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#1Theodoros Rampias (Academy of Athens)H-Index: 2
#2Dimitris Karagiannis (Academy of Athens)H-Index: 1
Last. Apostolos Klinakis (Academy of Athens)H-Index: 22
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Abstract Genome‐wide studies in tumor cells have indicated that chromatin‐modifying proteins are commonly mutated in human cancers. The lysine‐specific methyltransferase 2C (KMT2C/MLL3) is a putative tumor suppressor in several epithelia and in myeloid cells. Here, we show that downregulation of KMT2C in bladder cancer cells leads to extensive changes in the epigenetic status and the expression of DNA damage response and DNA repair genes. More specifically, cells with low KMT2C activity are defi...
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#1Andrey Korshunov (DKFZ: German Cancer Research Center)H-Index: 76
#2Felix Sahm (DKFZ: German Cancer Research Center)H-Index: 40
Last. Marcel Kool (DKFZ: German Cancer Research Center)H-Index: 66
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#1Andrew M. Heitzer (St. Jude Children's Research Hospital)H-Index: 1
#2Jason M. Ashford (St. Jude Children's Research Hospital)H-Index: 13
Last. Heather M. Conklin (St. Jude Children's Research Hospital)H-Index: 27
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Purpose Advantages to computerized cognitive assessment include increased precision of response time measurement and greater availability of alternate forms. Cogstate is a computerized cognitive battery developed to monitor attention, memory, and processing speed. Although the literature suggests the domains assessed by Cogstate are areas of deficit in children undergoing treatment for medulloblastoma, the validity of Cogstate in this population has not been previously investigated.
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#1Cathy Lee (UCSD: University of California, San Diego)H-Index: 9
#2Vasilisa A. Rudneva (St. Jude Children's Research Hospital)H-Index: 4
Last. Robert J. Wechsler-Reya (UCSD: University of California, San Diego)H-Index: 40
view all 17 authors...
Drugs that modify the epigenome are powerful tools for treating cancer, but these drugs often have pleiotropic effects, and identifying patients who will benefit from them remains a major clinical challenge. Here we show that medulloblastomas driven by the transcription factor Gfi1 are exquisitely dependent on the enzyme lysine demethylase 1 (Kdm1a/Lsd1). We demonstrate that Lsd1 physically associates with Gfi1, and that these proteins cooperate to inhibit genes involved in neuronal commitment a...
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#1Tobias Goschzik (University of Bonn)H-Index: 9
#2Edward C. Schwalbe (Northumbria University)H-Index: 18
Last. Steven C. Clifford (Newcastle University)H-Index: 47
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Summary Background Most children with medulloblastoma fall within the standard-risk clinical disease group defined by absence of high-risk features (metastatic disease, large-cell/anaplastic histology, and MYC amplification), which includes 50–60% of patients and has a 5-year event-free survival of 75–85%. Within standard-risk medulloblastoma, patients in the WNT subgroup are established as having a favourable prognosis; however, outcome prediction for the remaining majority of patients is impre...
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PURPOSE OF REVIEW: Molecular testing has become essential for the optimal workup of central nervous system (CNS) tumors. There is a vast array of testing from which to choose, and it can sometimes be challenging to appropriately incorporate findings into an integrated report. This article reviews various molecular tests and provides a concise overview of the most important molecular findings in the most commonly encountered CNS tumors. RECENT FINDINGS: Many molecular alterations in CNS tumors ha...
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#1David W. Ellison (St. Jude Children's Research Hospital)H-Index: 73
In this mini-symposium, four review articles describe recent advances in our understanding of the pathobiology of medulloblastoma. Medulloblastoma is the commonest malignant brain tumor of childhood and has been the subject of intense scientific investigation over several decades.
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