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Smith et al. present M-PACT, a deep neural network leveraging low-input cell-free DNA methylation profiles to achieve robust classification of pediatric brain tumors and enable cellular deconvolution and sensitive copy-number variation detection.

Analysis of medulloblastomas in humans and mice shows that the functional consequences of ZIC1 mutations are exquisitely dependent on the cells of origin that give rise to different subgroups of medulloblastoma.

Genomic analysis of 491 medulloblastoma samples, including methylation profiling of 1,256 cases, effectively assigns candidate drivers to most tumours across all molecular subgroups.

Medulloblastoma, once thought to represent a single disease entity, is now recognized to comprise distinct subgroups that can be identified using histological, genetic and transcriptomic approaches. Northcott et al. present the evidence for the four recently defined subgroups of medulloblastoma, and highlight how stratification of tumours into these subgroups could have important clinical implications for patient prognosis, treatment and care.

Medulloblastoma has been the subject of numerous genomics and transcriptomics studies that have led to this disease being subclassified into various clinically meaningful groups and to advances in understanding the biology of these subgroups, with implications for treatment.

The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 cancer whole genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.

Whole-genome sequencing data for 2,778 cancer samples from 2,658 unique donors across 38 cancer types is used to reconstruct the evolutionary history of cancer, revealing that driver mutations can precede diagnosis by several years to decades.

Genomic studies of the paediatric brain tumour medulloblastoma have revealed four clinically distinct molecular subgroups; here active gene regulatory elements in 28 primary medulloblastoma tissues are mapped to reveal differentially regulated enhancers across the different subgroups, allowing insights into the transcription factors that characterize subgroup divergence and the cellular origin of the poorly characterized Group 3 and 4 subgroups.

Germline mutations in the Elongator complex gene ELP1 predispose individuals to the development of childhood medulloblastoma.

Multi-omic mapping shows that group 3 and group 4 medulloblastomas have a common, human-specific developmental origin in the cerebellar rhombic lip, providing a basis for their ambiguous molecular features and overlapping anatomical location, and for the difficulty of modelling these tumours in mice.

There’s an emerging body of evidence to show how biological sex impacts cancer incidence, treatment and underlying biology. Here, using a large pan-cancer dataset, the authors further highlight how sex differences shape the cancer genome.

Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.

In somatic cells the mechanisms maintaining the chromosome ends are normally inactivated; however, cancer cells can re-activate these pathways to support continuous growth. Here, the authors characterize the telomeric landscapes across tumour types and identify genomic alterations associated with different telomere maintenance mechanisms.

Whole-genome sequencing data from more than 2,500 cancers of 38 tumour types reveal 16 signatures that can be used to classify somatic structural variants, highlighting the diversity of genomic rearrangements in cancer.

A pan-cancer genomic analysis reports the effects of structural variations on chromatin domains (TADs). Most TAD disruptions do not result in appreciable changes in expression of nearby genes.

An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

The authors present SVclone, a computational method for inferring the cancer cell fraction of structural variants from whole-genome sequencing data.

Many tumours exhibit hypoxia (low oxygen) and hypoxic tumours often respond poorly to therapy. Here, the authors quantify hypoxia in 1188 tumours from 27 cancer types, showing elevated hypoxia links to increased mutational load, directing evolutionary trajectories.

Multi-omics datasets pose major challenges to data interpretation and hypothesis generation owing to their high-dimensional molecular profiles. Here, the authors develop ActivePathways method, which uses data fusion techniques for integrative pathway analysis of multi-omics data and candidate gene discovery.

The characterization of 4,645 whole-genome and 19,184 exome sequences, covering most types of cancer, identifies 81 single-base substitution, doublet-base substitution and small-insertion-and-deletion mutational signatures, providing a systematic overview of the mutational processes that contribute to cancer development.

In this study the authors consider the structural variants (SVs) present within cancer cases of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. They report hundreds of genes, including known cancer-associated genes for which the nearby presence of a SV breakpoint is associated with altered expression.

Cancers evolve as they progress under differing selective pressures. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, the authors present the method TrackSig the estimates evolutionary trajectories of somatic mutational processes from single bulk tumour data.

Analyses of genomes from 914 children, adolescents, and young adults provide a comprehensive resource of genomic alterations across a spectrum of common childhood cancers.

Characterization of medulloblastoma tissues using single-cell transcriptomics shows that the different molecular subtypes consist of distinct developmental phenotypes.

Understanding deregulation of biological pathways in cancer can provide insight into disease etiology and potential therapies. Here, as part of the PanCancer Analysis of Whole Genomes (PCAWG) consortium, the authors present pathway and network analysis of 2583 whole cancer genomes from 27 tumour types.

With the generation of large pan-cancer whole-exome and whole-genome sequencing projects, a question remains about how comparable these datasets are. Here, using The Cancer Genome Atlas samples analysed as part of the Pan-Cancer Analysis of Whole Genomes project, the authors explore the concordance of mutations called by whole exome sequencing and whole genome sequencing techniques.

Integrative analyses of transcriptome and whole-genome sequencing data for 1,188 tumours across 27 types of cancer are used to provide a comprehensive catalogue of RNA-level alterations in cancer.

Viral pathogen load in cancer genomes is estimated through analysis of sequencing data from 2,656 tumors across 35 cancer types using multiple pathogen-detection pipelines, identifying viruses in 382 genomic and 68 transcriptome datasets.

Analysis of cancer genome sequencing data has enabled the discovery of driver mutations. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium the authors present DriverPower, a software package that identifies coding and non-coding driver mutations within cancer whole genomes via consideration of mutational burden and functional impact evidence.

Some cancer patients first present with metastases where the location of the primary is unidentified; these are difficult to treat. In this study, using machine learning, the authors develop a method to determine the tissue of origin of a cancer based on whole sequencing data.

DNA methylation and copy number variant analyses across a large number of genetic mouse models of pediatric brain tumors reveal subtype-specific molecular alterations shared with the corresponding human diseases.

Medulloblastoma is the most common malignant brain tumour in children; having assembled over 1,000 samples the authors report that somatic copy number aberrations are common in medulloblastoma, in particular a tandem duplication of SNCAIP, a gene associated with Parkinson’s disease, which is restricted to subgroup 4α, and translocations of PVT1, which are restricted to Group 3.

We show that gain-of-function cancer mutations in the KBTBD4 E3 ligase promote neodegradation of substrates via a shape-complementarity-based mechanism, which converges with the mechanism of action of the UM171 molecular glue degrader and can be blocked by HDAC1/2 inhibitors.

Neurodevelopmental disorders normally arise from intrinsic brain abnormality. Here the authors show that a motor-learning deficit in 22q11 deletion syndrome may arise from improper development of the skull structure housing a part of the cerebellum.

A resource of preclinical pediatric brain tumor models with detailed molecular characterization provides a platform for the community to test novel therapeutic approaches.

Patient-derived xenografts provide a resource for basic and translational cancer research. Here, the authors generate multiple pediatric high-grade glioma xenografts, use omics technologies to show that they are representative of primary tumours and use them to assess therapeutic response.

Focusing on two ill-characterized subtypes of medulloblastoma (group 3 and group 4), this study identifies prevalent genomic structural variants that are restricted to these two subtypes and independently bring together coding regions of GFI1 family proto-oncogenes with active enhancer elements, leading to their mutually exclusive oncogenic activation.

Analysis of whole-genome sequencing data across 2,658 tumors spanning 38 cancer types shows that chromothripsis is pervasive, with a frequency of more than 50% in several cancer types, contributing to oncogene amplification, gene inactivation and cancer genome evolution.

Analysis of mitochondrial genomes (mtDNA) by using whole-genome sequencing data from 2,658 cancer samples across 38 cancer types identifies hypermutated mtDNA cases, frequent somatic nuclear transfer of mtDNA and high variability of mtDNA copy number in many cancers.

Efficient, large-scale genomic analysis is facilitated on the cloud by a computational tool with error-diagnosing and self-healing capabilities.

Michael Taylor, Marco Marra and colleagues analyze spatial tumor heterogeneity in 9 medulloblastomas, 16 high-grade gliomas and 10 renal cell carcinomas, using a combination of transcriptomic and genomic profiling of multiregional biopsies. They find that medulloblastomas have spatially homogeneous transcriptomes, whereas somatic mutations that affect genes suitable for targeted therapeutics are spatially heterogeneous.

Ependymoma is a type of neural tumour that arises throughout the central nervous system. Using comparative transcriptomics in mouse and human tumours, these authors home in on mutations that are specific to individual tumour subgroups. In doing so, they generate the first mouse model of ependymoma and demonstrate the power of interspecific genomic comparisons to interrogate cancer subgroups.

An analysis of mutations from over 7,000 cancers of diverse origins reveals the diversity of mutational processes underlying the development of cancer; more than 20 distinct mutational signatures are described, some of which are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are specific to individual tumour types.

Medulloblastoma is one of the most prevalent malignant brain tumors in children and has very poor prognosis. In this study, the authors show, using a mouse model of medulloblastoma, that Gfi1 promotes tumor growth by recruiting Lsd1, that this interaction inhibits genes involved in neuronal differentiation, and that Lsd1 may be a therapeutic target in Gfi1-activated tumors.

The Sonic Hedgehog subgroup of medulloblastoma are characterised by the high infiltration of tumour-associated macrophages (TAMs). Here, the authors show that TAM numbers in patients are associated with better prognosis and that, consistently, in a murine model of medulloblastoma, these TAMs have anti-tumoural properties.

This Review discusses recent genomic, epigenomic, transcriptomic and proteomic profiling studies of human medulloblastoma that have advanced our understanding of its disease subgroups. These efforts have provided new insights into the diverse biology of medulloblastomas that will hopefully lead to improved diagnosis and therapy.

Chromothripsis and chromoanasynthesis lead to locally clustered rearrangements affecting one or a few chromosomes, but their impact on cancer development and progression is unclear. Here the authors analyse the role of DNA repair factors in brain tumors by whole-genome sequencing of tumors from mouse models of medulloblastoma or high grade gliomas.