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We analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement signatures. Three rearrangement signatures, characterized by tandem duplications or deletions, appear associated with defective homologous-recombination-based DNA repair: one with deficient BRCA1 function, another with deficient BRCA1 or BRCA2 function, the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operating, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer. Whole-genome sequencing of tumours from 560 breast cancer cases provides a comprehensive genome-wide view of recurrent somatic mutations and mutation frequencies across both protein coding and non-coding regions; several mutational signatures in these cancer genomes are associated with BRCA1 or BRCA2 function and defective homologous-recombination-based DNA repair. Mutational signatures of breast cancers This study reports whole-genome sequencing of tumours and normal tissue from 560 breast cancer cases, providing a comprehensive genome-wide view of recurrent somatic mutations and mutation frequencies across both protein coding and non-coding regions. The authors analyse mutational signatures in these cancer genomes, including a new investigation of rearrangement mutational processes, and find several that are associated with BRCA1 or BRCA2 function and defective homologous-recombination-based DNA repair. They also find mutational signatures showing distinct DNA replication strand biases.

The Cancer Genome Atlas (TCGA) has used the latest sequencing and analysis methods to identify somatic variants across thousands of tumours. Here we present data and analytical results for point mutations and small insertions/deletions from 3,281 tumours across 12 tumour types as part of the TCGA Pan-Cancer effort. We illustrate the distributions of mutation frequencies, types and contexts across tumour types, and establish their links to tissues of origin, environmental/carcinogen influences, and DNA repair defects. Using the integrated data sets, we identified 127 significantly mutated genes from well-known (for example, mitogen-activated protein kinase, phosphatidylinositol-3-OH kinase, Wnt/β-catenin and receptor tyrosine kinase signalling pathways, and cell cycle control) and emerging (for example, histone, histone modification, splicing, metabolism and proteolysis) cellular processes in cancer. The average number of mutations in these significantly mutated genes varies across tumour types; most tumours have two to six, indicating that the number of driver mutations required during oncogenesis is relatively small. Mutations in transcriptional factors/regulators show tissue specificity, whereas histone modifiers are often mutated across several cancer types. Clinical association analysis identifies genes having a significant effect on survival, and investigations of mutations with respect to clonal/subclonal architecture delineate their temporal orders during tumorigenesis. Taken together, these results lay the groundwork for developing new diagnostics and individualizing cancer treatment. As part of The Cancer Genome Atlas Pan-Cancer effort, data analysis for point mutations and small indels from 3,281 tumours and 12 tumour types is presented; among the findings are 127 significantly mutated genes from cellular processes with both established and emerging links in cancer, and an indication that the number of driver mutations required for oncogenesis is relatively small. Genomic landscape of twelve tumour types As part of The Cancer Genome Atlas Pan-Cancer project, these authors present data analysis for point mutations and small indels from more than 3,000 tumours representing 12 tumour types. Among the findings are 127 significantly mutated genes from cellular processes with both established and emerging links to cancer, and an indication that the number of driver mutations required for oncogenesis is relatively small. Additional analyses also identify genes with significant impact on survival and a likely temporal order of mutational events during tumorigenesis.

Survey of postzygotic mosaic mutations (PZMs) in 5,947 trios with autism spectrum disorders (ASD) discovers differences in mutational properties between germline mutations and PZMs. Spatiotemporal analyses of the PZMs also revealed the association of the amygdala with ASD and implicated risk genes, including recurrent potential gain-of-function mutations in SMARCA4 . We systematically analyzed postzygotic mutations (PZMs) in whole-exome sequences from the largest collection of trios (5,947) with autism spectrum disorder (ASD) available, including 282 unpublished trios, and performed resequencing using multiple independent technologies. We identified 7.5% of de novo mutations as PZMs, 83.3% of which were not described in previous studies. Damaging, nonsynonymous PZMs within critical exons of prenatally expressed genes were more common in ASD probands than controls ( P < 1 × 10 −6 ), and genes carrying these PZMs were enriched for expression in the amygdala ( P = 5.4 × 10 −3 ). Two genes ( KLF16 and MSANTD2 ) were significantly enriched for PZMs genome-wide, and other PZMs involved genes ( SCN2A , HNRNPU and SMARCA4 ) whose mutation is known to cause ASD or other neurodevelopmental disorders. PZMs constitute a significant proportion of de novo mutations and contribute importantly to ASD risk.

Key Points Structural, biochemical and cell biology investigations of the nuclear pore complex (NPC) over the past 60 years have contributed to explaining its canonical features. Recently, in vitro and in situ investigations have converged to produce the first pseudo-atomic model of the NPC central core. It seems that nucleoporins, the building blocks of the NPC, are conformationally labile and locally adapt to serve multiple structural roles. A network of short linear motifs is essential for holding the scaffold of the NPC together and offers a novel and attractive scientific concept of how scaffolding might be regulated by post-translational modifications. Prospectively, these structural insights might trigger novel types of investigations that will shed light on the mechanism behind nucleocytoplasmic transport (as well as other functions of the NPC) and the disease-relevance of nucleoporin dysfunction. Nuclear pore complexes (NPCs) are large protein assemblies that form channels in the nuclear envelope and constitute major routes for nucleocytoplasmic communication. Insights into the complex structure of NPCs provide the basis for understanding their functions and reveal how the dysfunction of their structural components, nucleoporins, contributes to human disease. Nuclear pore complexes (NPCs) fuse the inner and outer nuclear membranes to form channels across the nuclear envelope. They are large macromolecular assemblies with a complex composition and diverse functions. Apart from facilitating nucleocytoplasmic transport, NPCs are involved in chromatin organization, the regulation of gene expression and DNA repair. Understanding the molecular mechanisms underlying these functions has been hampered by a lack of structural knowledge about the NPC. The recent convergence of crystallographic and biochemical in vitro analysis of nucleoporins (NUPs), the components of the NPC, with cryo-electron microscopic imaging of the entire NPC in situ has provided first pseudo-atomic view of its central core and revealed that an unexpected network of short linear motifs is an important spatial organization principle. These breakthroughs have transformed the way we understand NPC structure, and they provide an important base for functional investigations, including the elucidation of the molecular mechanisms underlying clinically manifested mutations of the nucleocytoplasmic transport system.

Analysis of a large cohort of EGFR -mutant lung cancer cell-free DNA samples along with longitudinal samples from a patient with EGFR -mutant lung cancer identifies pathways that inhibit EGFR-inhibitor response. Co-occurring genetic alterations influence clinical outcomes and underscore the need for combination therapies. A widespread approach to modern cancer therapy is to identify a single oncogenic driver gene and target its mutant-protein product (for example, EGFR-inhibitor treatment in EGFR -mutant lung cancers). However, genetically driven resistance to targeted therapy limits patient survival. Through genomic analysis of 1,122 EGFR -mutant lung cancer cell-free DNA samples and whole-exome analysis of seven longitudinally collected tumor samples from a patient with EGFR -mutant lung cancer, we identified critical co-occurring oncogenic events present in most advanced-stage EGFR -mutant lung cancers. We defined new pathways limiting EGFR-inhibitor response, including WNT/β-catenin alterations and cell-cycle-gene ( CDK4 and CDK6 ) mutations. Tumor genomic complexity increases with EGFR-inhibitor treatment, and co-occurring alterations in CTNNB1 and PIK3CA exhibit nonredundant functions that cooperatively promote tumor metastasis or limit EGFR-inhibitor response. This study calls for revisiting the prevailing single-gene driver-oncogene view and links clinical outcomes to co-occurring genetic alterations in patients with advanced-stage EGFR -mutant lung cancer.

Key Points The serine/threonine protein kinase mechanistic target of rapamycin (mTOR) is evolutionarily conserved and modulates protein synthesis, cell growth, and cellular autophagy in response to distinct intracellular and extracellular cues Altered mTOR signalling has been shown to play pathogenic roles in a number of neurological disorders, including epilepsy, autism, intellectual disability, neurodegenerative disorders, CNS tumours, and hypoxic–ischaemic brain injury Causative germline and somatic mutations in a number of genes encoding proteins involved in the mTOR signalling pathway have been identified in malformations of cortical development that cause epilepsy, intellectual disability, and autism Clinical trials with mTOR inhibitors, such as sirolimus and everolimus, have shown that suppression of aberrant mTOR activity is effective in neurodevelopmental disorders, such as tuberous sclerosis complex Future clinical trials of mTOR inhibitors are being considered in neurodegenerative disorders, such as Alzheimer disease and stroke Overactivation of the mechanistic target of rapamycin (mTOR) signalling pathway contributes to neurological disorders, including neurodevelopmental disorders, tuberous sclerosis complex, epilepsy, and tumours of the CNS. In this Review, Peter Crino discusses the pathophysiological role of mTOR in neurological diseases and provides an overview of clinical trials that have assessed the efficacy of mTOR inhibitors in these diseases. Defining the multiple roles of the mechanistic (formerly 'mammalian') target of rapamycin (mTOR) signalling pathway in neurological diseases has been an exciting and rapidly evolving story of bench-to-bedside translational research that has spanned gene mutation discovery, functional experimental validation of mutations, pharmacological pathway manipulation, and clinical trials. Alterations in the dual contributions of mTOR — regulation of cell growth and proliferation, as well as autophagy and cell death — have been found in developmental brain malformations, epilepsy, autism and intellectual disability, hypoxic–ischaemic and traumatic brain injuries, brain tumours, and neurodegenerative disorders. mTOR integrates a variety of cues, such as growth factor levels, oxygen levels, and nutrient and energy availability, to regulate protein synthesis and cell growth. In line with the positioning of mTOR as a pivotal cell signalling node, altered mTOR activation has been associated with a group of phenotypically diverse neurological disorders. To understand how altered mTOR signalling leads to such divergent phenotypes, we need insight into the differential effects of enhanced or diminished mTOR activation, the developmental context of these changes, and the cell type affected by altered signalling. A particularly exciting feature of the tale of mTOR discovery is that pharmacological mTOR inhibitors have shown clinical benefits in some neurological disorders, such as tuberous sclerosis complex, and are being considered for clinical trials in epilepsy, autism, dementia, traumatic brain injury, and stroke.

The authors identify EZH2 as a general underlying dependency of tumors with mutations in the SWI/SNF chromatin regulator complex, and they show that EZH2's pro-tumorigenic role may be dependent on non-catalytic activities. This may pose new opportunities and challenges for using EZH2 as a cancer therapy target. Human cancer genome sequencing has recently revealed that genes that encode subunits of SWI/SNF chromatin remodeling complexes are frequently mutated across a wide variety of cancers, and several subunits of the complex have been shown to have bona fide tumor suppressor activity 1 . However, whether mutations in SWI/SNF subunits result in shared dependencies is unknown. Here we show that EZH2, a catalytic subunit of the polycomb repressive complex 2 (PRC2), is essential in all tested cancer cell lines and xenografts harboring mutations of the SWI/SNF subunits ARID1A , PBRM1 , and SMARCA4 , which are several of the most frequently mutated SWI/SNF subunits in human cancer, but that co-occurrence of a Ras pathway mutation is correlated with abrogation of this dependence. Notably, we demonstrate that SWI/SNF-mutant cancer cells are primarily dependent on a non-catalytic role of EZH2 in the stabilization of the PRC2 complex, and that they are only partially dependent on EZH2 histone methyltransferase activity. These results not only reveal a shared dependency of cancers with genetic alterations in SWI/SNF subunits, but also suggest that EZH2 enzymatic inhibitors now in clinical development may not fully suppress the oncogenic activity of EZH2.

Environmental stresses increase genetic variation in bacteria, plants, and human cancer cells. The linkage between various environments and mutational outcomes has not been systematically investigated, however. Here, we established the influence of nutritional stresses commonly found in the biosphere (carbon, phosphate, nitrogen, oxygen, or iron limitation) on both the rate and spectrum of mutations in Escherichia coli. We found that each limitation was associated with a remarkably distinct mutational profile. Overall mutation rates were not always elevated, and nitrogen, iron, and oxygen limitation resulted in major spectral changes but no net increase in rate. Our results thus suggest that stress-induced mutagenesis is a diverse series of stress input-mutation output linkages that is distinct in every condition. Environment-specific spectra resulted in the differential emergence of traits needing particular mutations in these settings. Mutations requiring transpositions were highest under iron and oxygen limitation, whereas base-pair substitutions and indels were highest under phosphate limitation. The unexpected diversity of input-output effects explains some important phenomena in the mutational biases of evolving genomes. The prevalence of bacterial insertion sequence transpositions in the mammalian gut or in anaerobically stored cultures is due to environmentally determined mutation availability. Likewise, the much-discussed genomic bias towards transition base substitutions in evolving genomes can now be explained as an environment-specific output. Altogether, our conclusion is that environments influence genetic variation as well as selection.

Key Points Twin and familial studies reveal that autism spectrum disorder (ASD) traits are highly heritable. The genetic landscape of ASD is made of common and rare variants and can be different from one individual to another. Most of the ASD-risk genes are involved in chromatin remodelling, regulation of protein synthesis and degradation, or synaptic plasticity. In cellular and animal models, mutations in the ASD-risk genes lead to a distortion of typical neuronal connectivity by decreasing or increasing synapse strength or number. Compensatory mechanisms, such as genetic buffering and synaptic homeostasis, could modulate the severity of these mutations. Recent years have seen considerable interest in the genetics of autism spectrum disorder (ASD). In this Review, Thomas Bourgeron examines the genetic architecture of this disorder and how ASD-linked mutations might affect synaptic plasticity, before exploring the synaptic homeostasis hypothesis of ASD. Genetics studies of autism spectrum disorder (ASD) have identified several risk genes that are key regulators of synaptic plasticity. Indeed, many of the risk genes that have been linked to these disorders encode synaptic scaffolding proteins, receptors, cell adhesion molecules or proteins that are involved in chromatin remodelling, transcription, protein synthesis or degradation, or actin cytoskeleton dynamics. Changes in any of these proteins can increase or decrease synaptic strength or number and, ultimately, neuronal connectivity in the brain. In addition, when deleterious mutations occur, inefficient genetic buffering and impaired synaptic homeostasis may increase an individual's risk for ASD.

Leukemias bearing heterozygous mutations in the SRSF2 splicing-factor-encoding gene can be therapeutically targeted by pharmacologic inhibition of residual spliceosome function. Mutations in genes encoding splicing factors (which we refer to as spliceosomal genes) are commonly found in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) 1 , 2 , 3 . These mutations recurrently affect specific amino acid residues, leading to perturbed normal splice site and exon recognition 4 , 5 , 6 . Spliceosomal gene mutations are always heterozygous and rarely occur together with one another, suggesting that cells may tolerate only a partial deviation from normal splicing activity. To test this hypothesis, we engineered mice to express a mutated allele of serine/arginine-rich splicing factor 2 ( Srsf2 P95H )—which commonly occurs in individuals with MDS and AML—in an inducible, hemizygous manner in hematopoietic cells. These mice rapidly succumbed to fatal bone marrow failure, demonstrating that Srsf2 -mutated cells depend on the wild-type Srsf2 allele for survival. In the context of leukemia, treatment with the spliceosome inhibitor E7107 (refs. 7 , 8 ) resulted in substantial reductions in leukemic burden, specifically in isogenic mouse leukemias and patient-derived xenograft AMLs carrying spliceosomal mutations. Whereas E7107 treatment of mice resulted in widespread intron retention and cassette exon skipping in leukemic cells regardless of Srsf2 genotype, the magnitude of splicing inhibition following E7107 treatment was greater in Srsf2 -mutated than in Srsf2 -wild-type leukemia, consistent with the differential effect of E7107 on survival. Collectively, these data provide genetic and pharmacologic evidence that leukemias with spliceosomal gene mutations are preferentially susceptible to additional splicing perturbations in vivo as compared to leukemias without such mutations. Modulation of spliceosome function may thus provide a new therapeutic avenue in genetically defined subsets of individuals with MDS or AML.