Featured
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Article
| Open Access
Genetic determinants of micronucleus formation in vivo
Genetic screening identifies a rich catalogue of regulators of micronucleus formation.
- D. J. Adams
- , B. Barlas
- & G. Balmus
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Article |
Deep whole-genome analysis of 494 hepatocellular carcinomas
The Chinese Liver Cancer Atlas project depicts a panoramic genomic landscape of hepatocellular carcinoma, covering candidate coding and non-coding drivers, mutational signatures, extrachromosomal circular DNA, subclonal catastrophic events and detailed evolutionary history.
- Lei Chen
- , Chong Zhang
- & Hongyang Wang
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Article |
Histone demethylase KDM5D upregulation drives sex differences in colon cancer
A murine colorectal cancer (CRC) model shows that mutant KRAS-STAT4-mediated upregulation of Y chromosome KDM5D contributes to the sex differences in KRAS-mutant CRC, providing an actionable therapeutic strategy for metastasis risk reduction for men afflicted with KRAS-mutant CRC.
- Jiexi Li
- , Zhengdao Lan
- & Ronald A. DePinho
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Article
| Open Access
ERα-associated translocations underlie oncogene amplifications in breast cancer
An analysis of 780 breast cancer genomes shows that focal amplifications are frequently preceded by dicentric chromosome formation from inter-chromosomal translocations associated with oestrogen receptor binding, which leads to chromosome bridge formation and breakage, initiating the amplification process.
- Jake June-Koo Lee
- , Youngsook Lucy Jung
- & Peter J. Park
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Article
| Open Access
Mitotic clustering of pulverized chromosomes from micronuclei
The CIP2A–TOPBP1 complex tethers fragmented chromosomes from micronuclei for asymmetric mitotic inheritance, explaining distinct patterns of chromosome rearrangements in cancers and genomic disorders.
- Yu-Fen Lin
- , Qing Hu
- & Peter Ly
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Article |
Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA
Measurements of subclonal expansion of ctDNA in the plasma before surgery may enable the prediction of future metastatic subclones, offering the possibility for early intervention in patients with non-small-cell lung cancer.
- Christopher Abbosh
- , Alexander M. Frankell
- & Charles Swanton
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Article |
BRD8 maintains glioblastoma by epigenetic reprogramming of the p53 network
BRD8 is identified as a specific epigenetic vulnerability for glioblastomas that harbour wild-type p53.
- Xueqin Sun
- , Olaf Klingbeil
- & Alea A. Mills
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Article |
Common and rare variant associations with clonal haematopoiesis phenotypes
Exome sequence data from 628,388 individuals was used to identify 24 risk loci in 40,208 carriers of clonal haematopoiesis of indeterminate potential and link them to other conditions including COVID-19, cardiovascular disease and cancer.
- Michael D. Kessler
- , Amy Damask
- & Eric Jorgenson
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Article
| Open Access
Ordered and deterministic cancer genome evolution after p53 loss
Malignant evolution enabled by p53 inactivation in mice proceeds through an ordered and predictable pattern of Trp53 loss of heterozygosity, accumulation of deletions, genome doubling and the emergence of gains and amplifications.
- Timour Baslan
- , John P. Morris IV
- & Scott W. Lowe
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Article |
Structure–function analysis of the SHOC2–MRAS–PP1C holophosphatase complex
- Jason J. Kwon
- , Behnoush Hajian
- & Andrew J. Aguirre
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Article |
Super-enhancer hypermutation alters oncogene expression in B cell lymphoma
Active super-enhancers are highly and specifically hypermutated in 92% of diffuse large B cell lymphoma samples and display signatures of activation-induced cytidine deaminase activity, leading to the dysregulation of genes encoding B cell developmental regulators and oncogenes.
- Elodie Bal
- , Rahul Kumar
- & Riccardo Dalla-Favera
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OCA-T1 and OCA-T2 are coactivators of POU2F3 in the tuft cell lineage
The POU2F3–OCA-T complex is the master regulator of tuft cell identity and a prominent molecular vulnerability of tuft-cell-like small-cell lung cancer.
- Xiaoli S. Wu
- , Xue-Yan He
- & Christopher R. Vakoc
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Article |
Silent mutations reveal therapeutic vulnerability in RAS Q61 cancers
A translationally silent KRASG60G mutation, preventing the formation of a cryptic splice donor site and enabling expression of KRAS(Q61K), reveals a vulnerability in RASQ61 cancers that are therapeutically exploitable in a mutant-selective manner.
- Yoshihisa Kobayashi
- , Chhayheng Chhoeu
- & Pasi A. Jänne
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Article
| Open Access
Mapping clustered mutations in cancer reveals APOBEC3 mutagenesis of ecDNA
An analysis of clustered substitutions and indels across 30 cancer types provides insight into the role of APOBEC3 in giving rise to clustered mutation events through its activity on extrachromosomal DNA.
- Erik N. Bergstrom
- , Jens Luebeck
- & Ludmil B. Alexandrov
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ecDNA hubs drive cooperative intermolecular oncogene expression
Extrachromosomal DNA (ecDNA) congregates in clusters called ecDNA hubs that promote intermolecular interactions between gene-regulatory regions and thereby amplify the expression of oncogenes such as MYC in cancer cell lines.
- King L. Hung
- , Kathryn E. Yost
- & Howard Y. Chang
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Article |
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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Article |
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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Article |
EGFR activation limits the response of liver cancer to lenvatinib
EGFR inhibition and lenvatinib treatment of liver cancer cells in vitro and in in vivo mouse models has potent anti-proliferative effects, and lenvatinib plus gefitinib treatment of 12 patients with advanced liver cancer resulted in meaningful clinical responses.
- Haojie Jin
- , Yaoping Shi
- & René Bernards
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Phase separation drives aberrant chromatin looping and cancer development
The NUP98–HOXA9 oncogenic fusion protein found in leukaemia undergoes phase separation in the nucleus, which helps to promote activation of leukaemic genes and to establish aberrant chromatin looping.
- Jeong Hyun Ahn
- , Eric S. Davis
- & Gang Greg Wang
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Article |
Epigenetic silencing by SETDB1 suppresses tumour intrinsic immunogenicity
A CRISPR–Cas9 screen of chromatin regulators in mouse tumour models treated with immune checkpoint blockade identifies SETDB1 as an epigenetic checkpoint protein that suppresses tumour-intrinsic immunogenicity.
- Gabriel K. Griffin
- , Jingyi Wu
- & Bradley E. Bernstein
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Article |
Identification of bacteria-derived HLA-bound peptides in melanoma
HLA peptidomic analysis identifies recurrent intracellular bacteria-derived peptides presented on HLA-I and HLA-II molecules in melanoma tumours, revealing how bacteria can modulate immune functions and responses to cancer therapies.
- Shelly Kalaora
- , Adi Nagler
- & Yardena Samuels
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Article |
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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Article |
Whole-genome doubling confers unique genetic vulnerabilities on tumour cells
Cancer cells that have undergone whole-genome doubling are more reliant than their near-diploid counterparts on DNA-replication factors, the spindle-assembly checkpoint and a mitotic kinesin protein, KIF18A.
- Ryan J. Quinton
- , Amanda DiDomizio
- & Neil J. Ganem
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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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The National Lung Matrix Trial of personalized therapy in lung cancer
Current outcomes are reported from the ongoing National Lung Matrix Trial, an umbrella trial for the treatment of non-small-cell lung cancer in which patients are triaged according to their tumour genotype and matched with targeted therapeutic agents.
- Gary Middleton
- , Peter Fletcher
- & Lucinda Billingham
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Article |
Oncometabolites suppress DNA repair by disrupting local chromatin signalling
Metabolites that are elevated in tumours inhibit the lysine demethylase KDM4B, resulting in aberrant hypermethylation of histone 3 lysine 9 and decreased homology-dependent DNA repair.
- Parker L. Sulkowski
- , Sebastian Oeck
- & Peter M. Glazer
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Article |
Mutational signature in colorectal cancer caused by genotoxic pks+ E. coli
Organoids derived from human intestinal cells that are co-cultured with bacteria carrying the genotoxic pks+ island develop a distinct mutational signature associated with colorectal cancer.
- Cayetano Pleguezuelos-Manzano
- , Jens Puschhof
- & Hans Clevers
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Article
| Open Access
The repertoire of mutational signatures in human cancer
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.
- Ludmil B. Alexandrov
- , Jaegil Kim
- & Christian von Mering
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Article |
Impaired cell fate through gain-of-function mutations in a chromatin reader
The histone-acetylation-reader protein ENL is mutated in a paediatric kidney cancer in such a way that it clusters at target genes, increasing the recruitment of the transcriptional machinery, enhancing transcription and deregulating cell fate during development.
- Liling Wan
- , Shasha Chong
- & C. David Allis
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Article |
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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Article |
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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Letter |
Coordinated alterations in RNA splicing and epigenetic regulation drive leukaemogenesis
Analyses of transcriptomes from patients with acute myeloid leukaemia identified frequently co-occurring mutations of IDH2 and SRSF2, which functional analyses showed to have distinct and coordinated leukaemogenic effects on the epigenome and RNA splicing.
- Akihide Yoshimi
- , Kuan-Ting Lin
- & Omar Abdel-Wahab
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Letter |
Inducing and exploiting vulnerabilities for the treatment of liver cancer
CDC7 inhibition selectively induces senescence in hepatocellular carcinoma cells with TP53 mutations, which enables the selective apoptotic cell death of these senescent cells using inhibitors of mTOR signalling.
- Cun Wang
- , Serena Vegna
- & René Bernards
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Letter |
The Drug Rediscovery protocol facilitates the expanded use of existing anticancer drugs
Clinical benefit was observed in 34% of a cohort of 215 patients with cancer who received treatment with anticancer drugs outside of their approved label, in the Drug Rediscovery protocol trial.
- D. L. van der Velden
- , L. R. Hoes
- & E. E. Voest
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Letter |
BORIS promotes chromatin regulatory interactions in treatment-resistant cancer cells
The CTCF paralogue BORIS is upregulated in transcriptionally reprogrammed neuroblastoma cells rendered resistant to targeted therapy, in which it promotes regulatory chromatin interactions that maintain the resistance phenotype.
- David N. Debruyne
- , Ruben Dries
- & Rani E. George
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Letter |
Distinct structural classes of activating FOXA1 alterations in advanced prostate cancer
Comprehensive genomic analyses and mechanistic studies uncover three structural, functional and clinical classes of activating FOXA1 mutations and locus rearrangements in prostate cancer.
- Abhijit Parolia
- , Marcin Cieslik
- & Arul M. Chinnaiyan
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Letter |
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
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The expanding landscape of ‘oncohistone’ mutations in human cancers
The characterization of missense histone mutations that occur across several cancer types provides insight into the potential role of these mutations in altering chromatin structure and potentially contributing to tumour development.
- Benjamin A. Nacev
- , Lijuan Feng
- & C. David Allis
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Letter |
Efficacy of MEK inhibition in patients with histiocytic neoplasms
A proof-of-concept clinical trial of patients with histiocytoses with MAPK-pathway mutations showed durable responses to treatment with the MEK1 and MEK2 inhibitor cobimetinib, which indicates that histiocytic neoplasms are dependent on MAPK signalling.
- Eli L. Diamond
- , Benjamin H. Durham
- & David M. Hyman
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Letter |
Neutrophils escort circulating tumour cells to enable cell cycle progression
The authors show that circulating tumour cells can be found in association with neutrophils, an interaction which supports their proliferation and their ability to seed metastasis.
- Barbara Maria Szczerba
- , Francesc Castro-Giner
- & Nicola Aceto
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Letter |
Heterozygous mutations cause genetic instability in a yeast model of cancer evolution
Repeated selection for adaptive mutations in a diploid yeast model results in increased genetic instability and sheds light on mechanisms of genetic instability that might contribute to tumorigenesis.
- Miguel C. Coelho
- , Ricardo M. Pinto
- & Andrew W. Murray
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Letter |
Autophagic cell death restricts chromosomal instability during replicative crisis
Cell death during replicative crisis involves autophagy induced by telomere dysfunction.
- Joe Nassour
- , Robert Radford
- & Jan Karlseder
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Article |
Accurate classification of BRCA1 variants with saturation genome editing
Germline BRCA1 loss-of-function variants are associated with predisposition to early-onset breast and ovarian cancer; here the authors use CRISPR/Cas9 genome editing to functionally assess thousands of BRCA1 variants in order to facilitate the clinical interpretation of these variants.
- Gregory M. Findlay
- , Riza M. Daza
- & Jay Shendure
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Article |
The genetic basis and cell of origin of mixed phenotype acute leukaemia
A large-scale genomics study shows that the cell of origin and founding mutations determine disease subtype and lead to the expression of multiple haematopoietic lineage-defining antigens in mixed phenotype acute leukaemia.
- Thomas B. Alexander
- , Zhaohui Gu
- & Charles G. Mullighan
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Article |
Necroptosis microenvironment directs lineage commitment in liver cancer
The tumour microenvironment determines which type of liver cancer develops, with transformed hepatocytes giving rise to intrahepatic cholangiocarcinoma or hepatocellular carcinoma depending or whether they are surrounded by cells undergoing necroptosis or apoptosis.
- Marco Seehawer
- , Florian Heinzmann
- & Lars Zender
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Letter |
Glucose-regulated phosphorylation of TET2 by AMPK reveals a pathway linking diabetes to cancer
Modulation of DNA 5-hydroxymethylcytosine by glucose reveals an AMPK–TET2–5hmC axis that links diabetes to cancer.
- Di Wu
- , Di Hu
- & Yujiang Geno Shi
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Letter |
Prediction of acute myeloid leukaemia risk in healthy individuals
Individuals who are at high risk of developing acute myeloid leukaemia can be identified years before diagnosis using genetic information from blood samples.
- Sagi Abelson
- , Grace Collord
- & Liran I. Shlush
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Letter |
Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling
Super enhancers regulate oncogenes and other molecular targets in ependymomas, and identification of these genes provides potential therapeutic targets.
- Stephen C. Mack
- , Kristian W. Pajtler
- & Jeremy N. Rich
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Letter |
Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth
The inactivation of DNA mismatch repair in cancer cells produces dynamic mutational profiles and generates neoantigens, which result in improved immune surveillance against these cells.
- Giovanni Germano
- , Simona Lamba
- & Alberto Bardelli
Targeting DCAF5 suppresses SMARCB1-mutant cancer by stabilizing SWI/SNF