Abstract
The fifth edition of the WHO Classification of Tumors of the Central Nervous System (CNS), published in 2021, is the sixth version of the international standard for the classification of ...brain and spinal cord tumors. Building on the 2016 updated fourth edition and the work of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy, the 2021 fifth edition introduces major changes that advance the role of molecular diagnostics in CNS tumor classification. At the same time, it remains wedded to other established approaches to tumor diagnosis such as histology and immunohistochemistry. In doing so, the fifth edition establishes some different approaches to both CNS tumor nomenclature and grading and it emphasizes the importance of integrated diagnoses and layered reports. New tumor types and subtypes are introduced, some based on novel diagnostic technologies such as DNA methylome profiling. The present review summarizes the major general changes in the 2021 fifth edition classification and the specific changes in each taxonomic category. It is hoped that this summary provides an overview to facilitate more in-depth exploration of the entire fifth edition of the WHO Classification of Tumors of the Central Nervous System.
Gliomas are the most common CNS tumors in children and adolescents, and they show an extremely broad range of clinical behavior. The majority of pediatric gliomas present as benign, slow-growing ...lesions classified as grade I or II by the WHO classification of CNS tumors. These pediatric low-grade gliomas (LGGs) are fundamentally different from IDH-mutant LGGs occurring in adults, because they rarely undergo malignant transformation and show excellent overall survival under current treatment strategies. However, a significant fraction of gliomas develop over a short period of time and progress rapidly and are therefore classified as WHO grade III or IV high-grade gliomas (HGGs). Despite all therapeutic efforts, they remain largely incurable, with the most aggressive forms being lethal within months. Thus, the intentions of neurosurgeons, pediatric oncologists, and radiotherapists to improve care for pediatric patients with glioma range from increasing quality of life and preventing long-term sequelae in what is often a chronic, but rarely life-threatening disease (LGG), to uncovering effective treatment options to prolong patient survival in an almost universally fatal setting (HGG). The last decade has seen unprecedented progress in understanding the molecular biology underlying pediatric gliomas, fueling hopes to achieve both goals. Large-scale collaborative studies around the globe have cataloged genomic and epigenomic alterations in gliomas across ages, grades, and histologies. These studies have revealed biologic subgroups characterized by distinct molecular, pathologic, and clinical features, with clear relevance for patient management. In this review, we summarize hallmark discoveries that have expanded our knowledge in pediatric LGGs and HGGs, explain their role in tumor biology, and convey our current concepts on how these findings may be translated into novel therapeutic approaches.
Medulloblastoma, a malignant brain tumour primarily diagnosed during childhood, has recently been the focus of intensive molecular profiling efforts, profoundly advancing our understanding of ...biologically and clinically heterogeneous disease subgroups. Genomic, epigenomic, transcriptomic and proteomic landscapes have now been mapped for an unprecedented number of bulk samples from patients with medulloblastoma and, more recently, for single medulloblastoma cells. These efforts have provided pivotal new insights into the diverse molecular mechanisms presumed to drive tumour initiation, maintenance and recurrence across individual subgroups and subtypes. Translational opportunities stemming from this knowledge are continuing to evolve, providing a framework for improved diagnostic and therapeutic interventions. In this Review, we summarize recent advances derived from this continued molecular characterization of medulloblastoma and contextualize this progress towards the deployment of more effective, molecularly informed treatments for affected patients.
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, especially within Group 3 and Group 4. Herein, we aimed to reconcile the definition of Group 3/Group 4 MB subtypes through the analysis of a series of 1501 medulloblastomas with DNA-methylation profiling data, including 852 with matched transcriptome data. Using multiple complementary bioinformatic approaches, we compared the concordance of subtype calls between published cohorts and analytical methods, including assessments of class-definition confidence and reproducibility. While the lowest complexity solutions continued to support the original consensus subgroups of Group 3 and Group 4, our analysis most strongly supported a definition comprising eight robust Group 3/Group 4 subtypes (types I–VIII). Subtype II was consistently identified across all component studies, while all others were supported by multiple class-definition methods. Regardless of analytical technique, increasing cohort size did not further increase the number of identified Group 3/Group 4 subtypes. Summarizing the molecular and clinico-pathological features of these eight subtypes indicated enrichment of specific driver gene alterations and cytogenetic events amongst subtypes, and identified highly disparate survival outcomes, further supporting their biological and clinical relevance. Collectively, this study provides continued support for consensus Groups 3 and 4 while enabling robust derivation of, and categorical accounting for, the extensive intertumoral heterogeneity within Groups 3 and 4, revealed by recent high-resolution subclassification approaches. Furthermore, these findings provide a basis for application of emerging methods (e.g., proteomics/single-cell approaches) which may additionally inform medulloblastoma subclassification. Outputs from this study will help shape definition of the next generation of medulloblastoma clinical protocols and facilitate the application of enhanced molecularly guided risk stratification to improve outcomes and quality of life for patients and their families.
Malignancies are characterized by extensive global reprogramming of epigenetic patterns, including gains or losses in DNA methylation and changes to histone marks. Furthermore, high-resolution ...genome-sequencing efforts have discovered a wealth of mutations in genes encoding epigenetic regulators that have roles as 'writers', 'readers' or 'editors' of DNA methylation and/or chromatin states. In this Review, we discuss how these mutations have the potential to deregulate hundreds of targeted genes genome wide. Elucidating these networks of epigenetic factors will provide mechanistic understanding of the interplay between genetic and epigenetic alterations, and will inform novel therapeutic strategies.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Historical risk stratification criteria for medulloblastoma rely primarily on clinicopathological variables pertaining to age, presence of metastases, extent of resection, histological subtypes and ...in some instances individual genetic aberrations such as
MYC
and
MYCN
amplification. In 2010, an international panel of experts established consensus defining four main subgroups of medulloblastoma (WNT, SHH, Group 3 and Group 4) delineated by transcriptional profiling. This has led to the current generation of biomarker-driven clinical trials assigning WNT tumors to a favorable prognosis group in addition to clinicopathological criteria including
MYC
and
MYCN
gene amplifications. However, outcome prediction of non-WNT subgroups is a challenge due to inconsistent survival reports. In 2015, a consensus conference was convened in Heidelberg with the objective to further refine the risk stratification in the context of subgroups and agree on a definition of risk groups of non-infant, childhood medulloblastoma (ages 3–17). Published and unpublished data over the past 5 years were reviewed, and a consensus was reached regarding the level of evidence for currently available biomarkers. The following risk groups were defined based on current survival rates: low risk (>90 % survival), average (standard) risk (75–90 % survival), high risk (50–75 % survival) and very high risk (<50 % survival) disease. The WNT subgroup and non-metastatic Group 4 tumors with whole chromosome 11 loss or whole chromosome 17 gain were recognized as low-risk tumors that may qualify for reduced therapy. High-risk strata were defined as patients with metastatic SHH or Group 4 tumors, or
MYCN
-amplified SHH medulloblastomas. Very high-risk patients are Group 3 with metastases or SHH with
TP53
mutation. In addition, a number of consensus points were reached that should be standardized across future clinical trials. Although we anticipate new data will emerge from currently ongoing and recently completed clinical trials, this consensus can serve as an outline for prioritization of certain molecular subsets of tumors to define and validate risk groups as a basis for future clinical trials.
Extensive prior research focused on somatic copy-number alterations (SCNAs) affecting cancer genes, yet the extent to which recurrent SCNAs exert their influence through rearrangement of ...cis-regulatory elements (CREs) remains unclear. Here we present a framework for inferring cancer-related gene overexpression resulting from CRE reorganization (e.g., enhancer hijacking) by integrating SCNAs, gene expression data and information on topologically associating domains (TADs). Analysis of 7,416 cancer genomes uncovered several pan-cancer candidate genes, including IRS4, SMARCA1 and TERT. We demonstrate that IRS4 overexpression in lung cancer is associated with recurrent deletions in cis, and we present evidence supporting a tumor-promoting role. We additionally pursued cancer-type-specific analyses and uncovered IGF2 as a target for enhancer hijacking in colorectal cancer. Recurrent tandem duplications intersecting with a TAD boundary mediate de novo formation of a 3D contact domain comprising IGF2 and a lineage-specific super-enhancer, resulting in high-level gene activation. Our framework enables systematic inference of CRE rearrangements mediating dysregulation in cancer.
The recent publication of the 2016 World Health Organization Classification of Tumors of the Central Nervous System (2016 CNS WHO) represents a significant advance in the classification of human ...brain tumors 1. For the first time, a CNS WHO classification defines diagnostic entities by combining molecular and histological information. In doing so, the classification facilitates more precise diagnosis of well-understood entities and clearer designation of less-understood entities, which will in turn allow further study and likely future advances in their classifications.
Ependymal tumors are rare CNS tumors and may occur at any age, but their proportion among primary brain tumors is highest in children and young adults. Thus, the level of evidence of diagnostic and ...therapeutic interventions is higher in the pediatric compared with the adult patient population.The diagnosis and disease staging is performed by craniospinal MRI. Tumor classification is achieved by histological and molecular diagnostic assessment of tissue specimens according to the World Health Organization (WHO) classification 2016. Surgery is the crucial initial treatment in both children and adults. In pediatric patients with intracranial ependymomas of WHO grades II or III, surgery is followed by local radiotherapy regardless of residual tumor volume. In adults, radiotherapy is employed in patients with anaplastic ependymoma WHO grade III, and in case of incomplete resection of WHO grade II ependymoma. Chemotherapy alone is reserved for young children <12 months and for adults with recurrent disease when further surgery and irradiation are no longer feasible. A gross total resection is the mainstay of treatment in spinal ependymomas, and radiotherapy is reserved for incompletely resected tumors. Nine subgroups of ependymal tumors across different anatomical compartments (supratentorial, posterior fossa, spinal) and patient ages have been identified with distinct genetic and epigenetic alterations, and with distinct outcomes. These findings may lead to more precise diagnostic and prognostic assessments, molecular subgroup-adapted therapies, and eventually new recommendations pending validation in prospective studies.
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