Featured
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Valine tRNA levels and availability regulate complex I assembly in leukaemia
Restriction of dietary valine reduces growth of T cell acute lymphoblastic leukaemia through altered valine tRNA biogenesis and reduced translation of mRNAs that encode subunits of mitochondrial complex I.
- Palaniraja Thandapani
- , Andreas Kloetgen
- & Iannis Aifantis
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Spatial genomics enables multi-modal study of clonal heterogeneity in tissues
A technique using barcoded beads for DNA sequencing within tissue sections enables spatial resolution of tumour clonal heterogeneity and can be multiplexed with other analytical techniques for analysis of complex cellular phenotypes.
- Tongtong Zhao
- , Zachary D. Chiang
- & Fei Chen
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Mutant clones in normal epithelium outcompete and eliminate emerging tumours
The rarity of tumour formation despite the high proportion of cancer-driver mutations in epithelia is explained by the competitive fitness of tumour cells relative to that of surrounding mutant epithelial cells.
- B. Colom
- , A. Herms
- & P. H. Jones
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| Open AccessBiologically informed deep neural network for prostate cancer discovery
A biologically informed, interpretable deep learning model has been developed to evaluate molecular drivers of resistance to cancer treatment, predict clinical outcomes and guide hypotheses on disease progression.
- Haitham A. Elmarakeby
- , Justin Hwang
- & Eliezer M. Van Allen
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A body map of somatic mutagenesis in morphologically normal human tissues
Laser-capture microdissection and mini-bulk exome sequencing are combined to analyse somatic mutations in morphologically normal tissues from nine organs from five donors, revealing variation in mutation burdens, mutational signatures and clonal expansions.
- Ruoyan Li
- , Lin Di
- & Chen Wu
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A clinically applicable integrative molecular classification of meningiomas
Multi-omics datasets are integrated to generate a unified and clinically informed molecular classification of meningiomas.
- Farshad Nassiri
- , Jeff Liu
- & Gelareh Zadeh
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The mutational landscape of human somatic and germline cells
The authors report the mutational landscape of 29 cell types from microdissected biopsies from 19 organs and explore the mechanisms underlying mutation rates in normal tissues.
- Luiza Moore
- , Alex Cagan
- & Raheleh Rahbari
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Deficient H2A.Z deposition is associated with genesis of uterine leiomyoma
Analyses of samples from 728 women with uterine leiomyomas (uterine fibroids), and public data, show that somatic and germline mutations in the SRCAP histone-loading complex genes are associated with the condition.
- Davide G. Berta
- , Heli Kuisma
- & Lauri A. Aaltonen
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In silico saturation mutagenesis of cancer genes
A new computational approach to in silico mutagenesis screening allow comprehensive mapping of cancer driver mutations.
- Ferran Muiños
- , Francisco Martínez-Jiménez
- & Nuria Lopez-Bigas
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Clonal fitness inferred from time-series modelling of single-cell cancer genomes
Whole-genome sequencing of human cancer cells in patient-derived mouse xenograft models indicates a key role for TP53 in determining the fitness landscape of polyclonal cancer cell populations.
- Sohrab Salehi
- , Farhia Kabeer
- & Sohrab P. Shah
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Somatic mutation landscapes at single-molecule resolution
NanoSeq is used to detect mutations in single DNA molecules and analyses show that mutational processes that are independent of cell division are important contributors to somatic mutagenesis.
- Federico Abascal
- , Luke M. R. Harvey
- & Iñigo Martincorena
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Aneuploidy renders cancer cells vulnerable to mitotic checkpoint inhibition
Aneuploid cancer cell lines show increased dependence on the spindle assembly complex (SAC); initially they are resistant to SAC perturbations, but over time they accumulate chromosomal aberrations that impair their fitness.
- Yael Cohen-Sharir
- , James M. McFarland
- & Uri Ben-David
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Chromothripsis drives the evolution of gene amplification in cancer
Chromothripsis—a process during which chromosomes are ‘shattered’—drives the evolution of gene amplification and subsequent drug resistance in cancer cells.
- Ofer Shoshani
- , Simon F. Brunner
- & Don W. Cleveland
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Histone H1 loss drives lymphoma by disrupting 3D chromatin architecture
Mutations in histone H1 induce the remodelling of chromatin architecture to a more relaxed state, which leads to malignant transformation through changes in histone modifications and the expression of stem cell genes.
- Nevin Yusufova
- , Andreas Kloetgen
- & Ari M. Melnick
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| Open AccessA metastasis map of human cancer cell lines
A method in which pooled barcoded human cancer cell lines are injected into a mouse xenograft model enables simultaneous mapping of the metastatic potential of multiple cell lines, and shows that breast cancer cells that metastasize to the brain have altered lipid metabolism.
- Xin Jin
- , Zelalem Demere
- & Todd R. Golub
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Single-cell mutation analysis of clonal evolution in myeloid malignancies
The evolution of myeloid malignancies is investigated using combined single-cell sequencing and immunophenotypic analysis.
- Linde A. Miles
- , Robert L. Bowman
- & Ross L. Levine
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Pervasive chromosomal instability and karyotype order in tumour evolution
Chromosomal instability enables the continuous selection of somatic copy number alterations, which are established as ordered events that often occur in parallel, throughout tumour evolution and metastasis.
- Thomas B. K. Watkins
- , Emilia L. Lim
- & Charles Swanton
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Pervasive lesion segregation shapes cancer genome evolution
Mutagenic lesions such as those that give rise to cancer frequently segregate—unrepaired—during cell division, resulting in phasing of multiple alleles across generations of daughter cells and consequent tumour heterogeneity.
- Sarah J. Aitken
- , Craig J. Anderson
- & Martin S. Taylor
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Phase and context shape the function of composite oncogenic mutations
Composite mutations, of two or more nonsynonymous somatic mutations in the same cancer-associated gene, are present in nearly one in four human tumours.
- Alexander N. Gorelick
- , Francisco J. Sánchez-Rivera
- & Barry S. Taylor
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The mutational landscape of normal human endometrial epithelium
Whole-genome sequencing of normal human endometrial glands shows that most are clonal cell populations and frequently carry cancer driver mutations that occur early in life, and that parity has a protective effect.
- Luiza Moore
- , Daniel Leongamornlert
- & Michael R. Stratton
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Mechanisms and therapeutic implications of hypermutation in gliomas
Temozolomide therapy seems to lead to mismatch repair deficiency and hypermutation in gliomas, but not to an increase in response to immunotherapy.
- Mehdi Touat
- , Yvonne Y. Li
- & Keith L. Ligon
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Landscape and function of multiple mutations within individual oncogenes
Analysis of genomic data from more than 60,000 cancer samples uncovers frequent multiple driver mutations in individual oncogenes, which confer enhanced oncogenicity in combination.
- Yuki Saito
- , Junji Koya
- & Keisuke Kataoka
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A genomic and epigenomic atlas of prostate cancer in Asian populations
Genomic, transcriptomic and DNA methylation data from tissue samples from 208 Chinese patients with prostate cancer define the landscape of alterations in this population, and comparison with data from Western cohorts suggests that the disease may stratify into different molecular subtypes.
- Jing Li
- , Chuanliang Xu
- & Yinghao Sun
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Integrating genomic features for non-invasive early lung cancer detection
Circulating tumour DNA in blood is analysed to identify genomic features that distinguish early-stage lung cancer patients from risk-matched controls, and these are integrated into a machine-learning method for blood-based lung cancer screening.
- Jacob J. Chabon
- , Emily G. Hamilton
- & Maximilian Diehn
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| Open AccessPan-cancer analysis of whole genomes
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.
- Lauri A. Aaltonen
- , Federico Abascal
- & Christian von Mering
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| Open AccessThe evolutionary history of 2,658 cancers
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.
- Moritz Gerstung
- , Clemency Jolly
- & Christian von Mering
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| Open AccessAnalyses of non-coding somatic drivers in 2,658 cancer whole genomes
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.
- Esther Rheinbay
- , Morten Muhlig Nielsen
- & Christian von Mering
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| Open AccessGenomic basis for RNA alterations in cancer
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.
- Claudia Calabrese
- , Natalie R. Davidson
- & Christian von Mering
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| Open AccessPatterns of somatic structural variation in human cancer genomes
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.
- Yilong Li
- , Nicola D. Roberts
- & Christian von Mering
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Tobacco smoking and somatic mutations in human bronchial epithelium
Whole-genome sequencing of normal bronchial epithelium from 16 individuals shows that tobacco smoking increases genomic heterogeneity, mutational burden and driver mutations, whereas stopping smoking promotes replenishment of the epithelium with near-normal cells.
- Kenichi Yoshida
- , Kate H. C. Gowers
- & Peter J. Campbell
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The molecular landscape of ETMR at diagnosis and relapse
Analyses of primary and relapse samples of embryonal tumours with multilayered rosettes provide insights into the molecular mechanisms that underlie the development and opportunities for the treatment of this deadly disease.
- Sander Lambo
- , Susanne N. Gröbner
- & Marcel Kool
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Genetic predisposition to mosaic Y chromosome loss in blood
A genome-wide association study of mosaic loss of chromosome Y (LOY) in UK Biobank participants identifies 156 genetic determinants of LOY, showing that LOY is associated with cancer and non-haematological health outcomes.
- Deborah J. Thompson
- , Giulio Genovese
- & John R. B. Perry
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Longitudinal molecular trajectories of diffuse glioma in adults
The GLASS Consortium studies the evolutionary trajectories of 222 patients with a diffuse glioma to aid in our understanding of tumour progression and treatment failure
- Floris P. Barthel
- , Kevin C. Johnson
- & Roel G. W. Verhaak
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Circular ecDNA promotes accessible chromatin and high oncogene expression
Imaging and sequencing approaches are combined to show that extrachromosomal DNA (ecDNA) in cancer is circular and has unique chromatin structure that amplifies oncogene output.
- Sihan Wu
- , Kristen M. Turner
- & Paul S. Mischel
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| Open AccessPan-cancer whole-genome analyses of metastatic solid tumours
The mutational landscape of metastatic cancer genomes is analysed in a large-scale, pan-cancer study of metastatic solid tumours that includes whole-genome sequencing of 2,520 tumour–normal tissue pairs.
- Peter Priestley
- , Jonathan Baber
- & Edwin Cuppen
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Somatic mutations and clonal dynamics in healthy and cirrhotic human liver
Whole-genome sequencing of liver microdissections from five healthy individuals and nine with cirrhosis demonstrates the effects of liver disease on the genome, including increased rates of mutation, complex structural variation and different mutational signatures.
- Simon F. Brunner
- , Nicola D. Roberts
- & Peter J. Campbell
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The landscape of somatic mutation in normal colorectal epithelial cells
Genome sequencing of hundreds of normal colonic crypts from 42 individuals sheds light on mutational processes and driver mutations in normal colorectal epithelial cells.
- Henry Lee-Six
- , Sigurgeir Olafsson
- & Michael R. Stratton
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Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma
Highly recurrent hotspot r.3A>G mutations are identified in U1 splicesomal small nuclear RNAs in about 50% of Sonic hedgehog medulloblastomas, which result in disrupted RNA splicing and the activation of oncogenes.
- Hiromichi Suzuki
- , Sachin A. Kumar
- & Michael D. Taylor
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The U1 spliceosomal RNA is recurrently mutated in multiple cancers
A highly recurrent A>C somatic mutation in U1 small nuclear RNA, which alters the splicing pattern of genes that include known drivers of cancer, is identified in several types of tumour.
- Shimin Shuai
- , Hiromichi Suzuki
- & Lincoln D. Stein
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Spliceosomal disruption of the non-canonical BAF complex in cancer
A range of SF3B1 mutations promote tumorigenesis through the repression of BRD9, a core component of the non-canonical BAF complex, and correcting BRD9 mis-splicing in these SF3B1-mutant cells suppresses tumour growth.
- Daichi Inoue
- , Guo-Liang Chew
- & Robert K. Bradley
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Tumour lineage shapes BRCA-mediated phenotypes
Analysis of more than 17,000 tumours suggests that the contribution of germline and somatic mutations in the BRCA1 and BRCA2 genes to oncogenesis depends on tumour lineage.
- Philip Jonsson
- , Chaitanya Bandlamudi
- & Barry S. Taylor
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Somatic mutations and cell identity linked by Genotyping of Transcriptomes
Profiling of over 38,000 CD34+ cells from patients with CALR-mutated myeloproliferative neoplasms, using the ‘Genotyping of Transcriptomes’ procedure, reveals that the transcriptional output of these mutations depends upon native cell identity.
- Anna S. Nam
- , Kyu-Tae Kim
- & Dan A. Landau
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Growth dynamics in naturally progressing chronic lymphocytic leukaemia
Analysis of growth dynamics in a dataset from 107 patients with chronic lymphocytic leukaemia (CLL) reveals both exponential and logistic patterns of growth, which are associated with differences in genetic attributes and clinical outcomes.
- Michaela Gruber
- , Ivana Bozic
- & Catherine J. Wu
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Genome-wide cell-free DNA fragmentation in patients with cancer
Analyses of fragmentation patterns of cell-free DNA in the blood of patients with cancer and healthy individuals using a machine learning algorithm provide a proof-of principle approach for the early detection and screening of human cancer.
- Stephen Cristiano
- , Alessandro Leal
- & Victor E. Velculescu
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Epigenetic evolution and lineage histories of chronic lymphocytic leukaemia
A single-cell approach is used to follow the heritable stochastic changes to DNA methylation that occur in primary chronic lymphocytic leukaemia and healthy B cells, allowing the tracing of cell lineage histories and evolution during treatment with ibrutinib.
- Federico Gaiti
- , Ronan Chaligne
- & Dan A. Landau
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Next-generation characterization of the Cancer Cell Line Encyclopedia
The original Cancer Cell Line Encyclopedia (CCLE) is expanded with deeper characterization of over 1,000 cell lines, including genomic, transcriptomic, and proteomic data, and integration with drug-sensitivity and gene-dependency data.
- Mahmoud Ghandi
- , Franklin W. Huang
- & William R. Sellers
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NAD metabolic dependency in cancer is shaped by gene amplification and enhancer remodelling
NAD metabolic pathway choice in cancer is largely dependent on the tissue of origin, with implications for the development of precision treatments.
- Sudhir Chowdhry
- , Ciro Zanca
- & Paul S. Mischel
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Prioritization of cancer therapeutic targets using CRISPR–Cas9 screens
In a screen of 324 human cancer cell lines and utilising a systematic target prioritization framework, the Werner syndrome ATP-dependent helicase is shown to be a synthetic lethal target in tumours from multiple cancer types with microsatellite instability, providing a new target for cancer drug development.
- Fiona M. Behan
- , Francesco Iorio
- & Mathew J. Garnett
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WRN helicase is a synthetic lethal target in microsatellite unstable cancers
Depletion of the DNA helicase WRN induced double-stranded DNA breaks, and promoted apoptosis and cell cycle arrest selectively in cancers with microsatellite instability, indicating that WRN is a promising drug target for the treatment of these cancers.
- Edmond M. Chan
- , Tsukasa Shibue
- & Adam J. Bass