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| Open AccessGeographic variation of mutagenic exposures in kidney cancer genomes
Whole-genome sequencing of 962 clear cell renal cell carcinomas from 11 countries shows geographic variations in somatic mutation profiles, including a mutational signature of unknown cause in 70% of cases from Japan.
- Sergey Senkin
- , Sarah Moody
- & Paul Brennan
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3D genomic mapping reveals multifocality of human pancreatic precancers
Quantitative multimodal 3D reconstruction of human pancreatic tissue at single-cell resolution reveals a high burden of multifocal, genetically heterogeneous pancreatic intraepithelial neoplasias in the normal adult pancreas.
- Alicia M. Braxton
- , Ashley L. Kiemen
- & Laura D. Wood
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Article
| Open AccessEvolutionary trajectories of small cell lung cancer under therapy
We uncover key processes of the genomic evolution of small cell lung cancer under therapy, identify the common ancestor as the source of clonal diversity at relapse and show central genomic patterns associated with drug response.
- Julie George
- , Lukas Maas
- & Roman K. Thomas
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| Open AccessAn atlas of epithelial cell states and plasticity in lung adenocarcinoma
Analyses of single epithelial cells from early-stage lung adenocarcinoma and normal lung identifies a population of intermediate cells that may have an increased likelihood of transforming to tumour cells after injury such as tobacco exposure.
- Guangchun Han
- , Ansam Sinjab
- & Humam Kadara
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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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Naturally occurring T cell mutations enhance engineered T cell therapies
A study examines the effects of mutations that occur naturally in T cell cancers, reporting that such mutations can potentially be exploited to increase the potency of T cell therapies.
- Julie Garcia
- , Jay Daniels
- & Jaehyuk Choi
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Distinct Hodgkin lymphoma subtypes defined by noninvasive genomic profiling
The potential use of circulating tumour DNA in classic Hodgkin lymphoma detection, classification and monitoring is defined.
- Stefan K. Alig
- , Mohammad Shahrokh Esfahani
- & Ash A. Alizadeh
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Article
| Open AccessEpigenetic regulation during cancer transitions across 11 tumour types
A pan-cancer epigenetic and transcriptomic atlas identifies epigenetic drivers associated with cancer transitions.
- Nadezhda V. Terekhanova
- , Alla Karpova
- & Li Ding
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Article
| Open AccessLong-molecule scars of backup DNA repair in BRCA1- and BRCA2-deficient cancers
Linked-read whole-genome sequencing reveals patterns of structural DNA variants that are specific to homologous recombination deficiency and can be used to distinguish between BRCA1- and BRCA2-deficient phenotypes.
- Jeremy Setton
- , Kevin Hadi
- & Marcin Imieliński
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Article
| Open AccessEvolutionary histories of breast cancer and related clones
By using phylogenetic analyses of multiple microdissected samples from both cancer and non-cancer lesions, unique evolutionary histories of breast cancers harbouring a common driver alteration are shown, providing new insight into how breast cancer evolves.
- Tomomi Nishimura
- , Nobuyuki Kakiuchi
- & Seishi Ogawa
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Cancer aneuploidies are shaped primarily by effects on tumour fitness
A study reports the development of an algorithm, BISCUT, that detects genomic loci under selective pressure by relying on the distribution of breakpoints across chromosome arms, and uses it to explore how aneuploidies affect tumorigenesis.
- Juliann Shih
- , Shahab Sarmashghi
- & Rameen Beroukhim
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Mitotic tethering enables inheritance of shattered micronuclear chromosomes
Chromothriptically produced pieces of a micronucleated chromosome are shown to be tethered together in mitosis by a protein complex consisting of MDC1, TOPBP1 and CIP2A, thus enabling their inheritance by a single daughter cell.
- Prasad Trivedi
- , Christopher D. Steele
- & Don W. Cleveland
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Article
| Open AccessHeritable transcriptional defects from aberrations of nuclear architecture
Micronuclei, which are common features of nuclei in cancer cells, can generate heritable sources of transcriptional suppression, a finding that establishes an inherent relationship between chromosomal instability and variation in chromatin state and gene expression.
- Stamatis Papathanasiou
- , Nikos A. Mynhier
- & David Pellman
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Article
| Open AccessDeterministic evolution and stringent selection during preneoplasia
We model occult preneoplasia by biallelic inactivation of TP53, a common early event in gastric cancer, in human gastric organoids, the results implying predictability in the earliest stages of tumorigenesis.
- Kasper Karlsson
- , Moritz J. Przybilla
- & Christina Curtis
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Article
| Open AccessERα-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 AccessWidespread somatic L1 retrotransposition in normal colorectal epithelium
This study illustrates long interspersed nuclear element-1 retrotransposition-induced somatic mosaicism in normal cells and provides insights into the genomic and epigenomic regulation of transposable elements over the human lifetime.
- Chang Hyun Nam
- , Jeonghwan Youk
- & Young Seok Ju
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Article
| Open AccessPan-cancer whole-genome comparison of primary and metastatic solid tumours
The genomic differences between primary and metastatic tumours are assessed across 23 cancer types using pan-cancer whole-genome analysis.
- Francisco Martínez-Jiménez
- , Ali Movasati
- & Arne Van Hoeck
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| Open AccessGenomic–transcriptomic evolution in lung cancer and metastasis
Computational and machine-learning approaches that integrate genomic and transcriptomic variation from paired primary and metastatic non-small cell lung cancer samples from the TRACERx cohort reveal the role of transcriptional events in tumour evolution.
- Carlos Martínez-Ruiz
- , James R. M. Black
- & Nicholas McGranahan
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| Open AccessExtrachromosomal DNA in the cancerous transformation of Barrett’s oesophagus
An analysis of whole-genome sequencing data from patients with Barrett’s oesophagus or oesophageal ademocarcinoma shows that extrachromosomal DNA (ecDNA) is strongly associated with cancer progression, and that a wide range of oncogenes are amplified on ecDNAs.
- Jens Luebeck
- , Alvin Wei Tian Ng
- & Paul S. Mischel
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Chromosomal fragile site breakage by EBV-encoded EBNA1 at clustered repeats
Epstein–Barr Virus (EBV) nuclear antigen 1 is shown to induce breakage of a fragile site on chromosome 11 by binding to a cluster of EBV-like imperfect palindromic repeats.
- Julia Su Zhou Li
- , Ammal Abbasi
- & Don W. Cleveland
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Article
| Open AccessThe evolution of non-small cell lung cancer metastases in TRACERx
A longitudinal evolutionary analysis of 126 lung cancer patients with metastatic disease reveals the timing of metastatic divergence, modes of dissemination and the genomic events subject to selection during the metastatic transition.
- Maise Al Bakir
- , Ariana Huebner
- & Charles Swanton
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Article
| Open AccessAntibodies against endogenous retroviruses promote lung cancer immunotherapy
In lung adenocarcinoma, antibodies against endogenous retroviruses promote anti-tumour activity, and expression of endogenous retroviruses can predict outcomes of immunotherapy.
- Kevin W. Ng
- , Jesse Boumelha
- & George Kassiotis
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Lung adenocarcinoma promotion by air pollutants
Combination of epidemiology, preclinical models and ultradeep DNA profiling of clinical cohorts unpicks the inflammatory mechanism by which air pollution promotes lung cancer
- William Hill
- , Emilia L. Lim
- & Charles Swanton
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Article
| Open AccessWhole-genome doubling drives oncogenic loss of chromatin segregation
Whole-genome doubling induces the loss of segregation of chromatin compartments, and can lead to tumour-promoting epigenetic and transcriptional modifications.
- Ruxandra A. Lambuta
- , Luca Nanni
- & Elisa Oricchio
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| Open AccessOvarian cancer mutational processes drive site-specific immune evasion
Multi-modal analysis of genomically unstable ovarian tumours characterizes the contribution of anatomical sites and mutational processes to evolutionary phenotypic divergence and immune resistance mechanisms.
- Ignacio Vázquez-García
- , Florian Uhlitz
- & Sohrab P. Shah
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| Open AccessRecurrent repeat expansions in human cancer genomes
An atlas explores the landscape of recurrent repeat expansions in human cancer genomes.
- Graham S. Erwin
- , Gamze Gürsoy
- & Michael P. Snyder
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Structural variants drive context-dependent oncogene activation in cancer
Results are presented that indicate that alterations to gene regulatory three-dimensional architecture are a critical mechanism that enables structural variant-based oncogene activation in cancer genomes and sheds light on the essential elements for such gene activation events.
- Zhichao Xu
- , Dong-Sung Lee
- & Jesse R. Dixon
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Genomic signature of Fanconi anaemia DNA repair pathway deficiency in cancer
Defective DNA interstrand crosslink repair in Fanconi anaemia drives extensive genomic rearrangements, thereby substantially increasing the risk of cancer development.
- Andrew L. H. Webster
- , Mathijs A. Sanders
- & Agata Smogorzewska
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Article
| Open AccessSpatial genomics maps the structure, nature and evolution of cancer clones
A workflow centred around base-specific in situ sequencing generates detailed maps of, and can phenotypically characterize, the unique set of subclones of cancers.
- Artem Lomakin
- , Jessica Svedlund
- & Lucy R. Yates
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Article
| Open AccessSingle-cell genomic variation induced by mutational processes in cancer
Single-cell whole-genome sequencing shows that 'foreground' cell-to-cell structural variation and alterations in copy number are associated with genomic diversity and evolution in triple-negative breast and high-grade serous ovarian cancers.
- Tyler Funnell
- , Ciara H. O’Flanagan
- & Samuel Aparicio
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| Open AccessThe co-evolution of the genome and epigenome in colorectal cancer
A study maps genetic and epigenetic heterogeneity of primary colorectal adenomas and cancers at single-clone resolution through spatial multi-omic profiling of individual glands and adjacent normal tissue.
- Timon Heide
- , Jacob Househam
- & Andrea Sottoriva
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Subtype-specific 3D genome alteration in acute myeloid leukaemia
Extensive genomic analyses of the chromatin architecture in acute myeloid leukaemia reveals several characteristics, including subtype-specific distal enhancers and silencers, that may represent new anticancer therapeutic targets.
- Jie Xu
- , Fan Song
- & Feng Yue
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| Open AccessPhenotypic plasticity and genetic control in colorectal cancer evolution
Intratumour genetic ancestry only infrequently affects gene expression traits and subclonal evolution in colorectal cancer, with most genetic intratumour variation having no detected phenotypic consequence and transcriptional plasticity being widespread within a tumour.
- Jacob Househam
- , Timon Heide
- & Trevor A. Graham
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Article
| Open AccessNuclear-embedded mitochondrial DNA sequences in 66,083 human genomes
A study examining DNA transfer from mitochondria to the nucleus using whole-genome sequences from 66,083 people shows that this is an ongoing dynamic process in normal cells with distinct roles in different types of cancer.
- Wei Wei
- , Katherine R. Schon
- & Patrick F. Chinnery
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A mechanism for oxidative damage repair at gene regulatory elements
The nuclear mitotic apparatus protein NuMA helps to protect genes from oxidative damage by occupying regions around transcription start sites, binding DNA repair factors and promoting transcription following damage.
- Swagat Ray
- , Arwa A. Abugable
- & Sherif F. El-Khamisy
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Failure of human rhombic lip differentiation underlies medulloblastoma formation
Derailed differentiation of human-specific progenitors of the developing cerebellar rhombic lip is the cause of group 4 medulloblastoma, the most common childhood brain tumour.
- Liam D. Hendrikse
- , Parthiv Haldipur
- & Michael D. Taylor
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Article
| Open AccessAfrican-specific molecular taxonomy of prostate cancer
A molecular taxonomy for prostate cancer reveals a subtype associated with copy-number loss found in African and European populations that predicts poor outcomes and two subtypes—one associated with high mutational noise and one with copy-number gain—specific to African populations.
- Weerachai Jaratlerdsiri
- , Jue Jiang
- & Vanessa M. Hayes
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| Open AccessOrdered 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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| Open AccessSpatially resolved clonal copy number alterations in benign and malignant tissue
Copy number variations inferred from spatial transcriptomics data in benign and malignant tissue reveal clonal architecture at the organ-wide level.
- Andrew Erickson
- , Mengxiao He
- & Joakim Lundeberg
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Article
| Open AccessMechanisms of APOBEC3 mutagenesis in human cancer cells
Endogenous APOBEC3 deaminases generate prevalent mutational signatures in human cancer cells, and APOBEC3A is the main driver of these mutations.
- Mia Petljak
- , Alexandra Dananberg
- & John Maciejowski
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Deep whole-genome ctDNA chronology of treatment-resistant prostate cancer
Deep whole-genome sequencing of serial blood samples and matched metastatic tissue reveals that circulating tumour DNA profiling enables detailed study of treatment-driven subclone dynamics, epigenomics and genome-wide somatic evolution in metastatic human cancers.
- Cameron Herberts
- , Matti Annala
- & Alexander W. Wyatt
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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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A pan-cancer compendium of chromosomal instability
Copy number signatures characterize different types of chromosomal instability and predict drug response.
- Ruben M. Drews
- , Barbara Hernando
- & Florian Markowetz
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| Open AccessSignatures of copy number alterations in human cancer
A new framework enables a pan-cancer reference set of copy number signatures derived from allele-specific profiles from different experimental assays.
- Christopher D. Steele
- , Ammal Abbasi
- & Nischalan Pillay
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| Open AccessThe renal lineage factor PAX8 controls oncogenic signalling in kidney cancer
The lineage transcription factor PAX8 is shown to play a pivotal part in determining cancer risk in clear cell renal cell carcinoma, providing insights into how genetic mutations lead to specific types of cancer.
- Saroor A. Patel
- , Shoko Hirosue
- & Sakari Vanharanta
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| Open AccessNeoantigen quality predicts immunoediting in survivors of pancreatic cancer
The human immune system naturally edits cancers of high-quality neoantigens.
- Marta Łuksza
- , Zachary M. Sethna
- & Vinod P. Balachandran
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| Open AccessSomatic mutation rates scale with lifespan across mammals
Whole-genome sequencing is used to analyse the landscape of somatic mutation in intestinal crypts from 16 mammalian species, revealing that rates of somatic mutation inversely scale with the lifespan of the animal across species.
- Alex Cagan
- , Adrian Baez-Ortega
- & Iñigo Martincorena
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| Open AccessSignatures of TOP1 transcription-associated mutagenesis in cancer and germline
Defective ribonucleotide excision repair causes ID4, an indel cancer signature characterized by deletions of 2–5 base pairs.
- Martin A. M. Reijns
- , David A. Parry
- & Andrew P. Jackson
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| Open AccessMapping 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