Tobacco smoking and somatic mutations in human bronchial epithelium

Nature, Journal Year: 2020, Volume and Issue: 578(7794), P. 266 - 272

Published: Jan. 29, 2020

Language: Английский

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Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes

Cell, Journal Year: 2021, Volume and Issue: 184(8), P. 2239 - 2254.e39

Published: April 1, 2021

Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin, drivers ITH across cancer types are poorly understood. To address this, we extensively characterize whole-genome sequences 2,658 samples spanning 38 types. Nearly all informative (95.1%) contain evidence distinct subclonal expansions with frequent branching relationships between subclones. We observe positive selection driver mutations most identify type-specific patterns gene mutations, fusions, structural variants, copy number alterations as well dynamic changes in mutational processes expansions. Our results underline importance its tumor evolution provide pan-cancer resource comprehensively annotated events from sequencing data.

Language: Английский

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Somatic mutation landscapes at single-molecule resolution

Nature, Journal Year: 2021, Volume and Issue: 593(7859), P. 405 - 410

Published: April 28, 2021

Language: Английский

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Adaptive mutability of colorectal cancers in response to targeted therapies

Science, Journal Year: 2019, Volume and Issue: 366(6472), P. 1473 - 1480

Published: Nov. 8, 2019

The emergence of drug resistance limits the efficacy targeted therapies in human tumors. prevalent view is that a fait accompli: when treatment initiated, cancers already contain drug-resistant mutant cells. Bacteria exposed to antibiotics transiently increase their mutation rates (adaptive mutability), thus improving likelihood survival. We investigated whether colorectal cancer (CRC) cells likewise exploit adaptive mutability evade therapeutic pressure. found epidermal growth factor receptor (EGFR)/BRAF inhibition down-regulates mismatch repair (MMR) and homologous recombination DNA-repair genes concomitantly up-regulates error-prone polymerases drug-tolerant (persister) MMR proteins were also down-regulated patient-derived xenografts tumor specimens during therapy. EGFR/BRAF induced DNA damage, increased mutability, triggered microsatellite instability. Thus, like unicellular organisms, pressures by enhancing mutability.

Language: Английский

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The genomics of oxidative DNA damage, repair, and resulting mutagenesis

Computational and Structural Biotechnology Journal, Journal Year: 2020, Volume and Issue: 18, P. 207 - 219

Published: Jan. 1, 2020

Reactive oxygen species are a constant threat to DNA as they modify bases with the risk of disrupting genome function, inducing instability and mutation. Such risks due primary oxidative damage also mediated by repair process. This leads delicate decision process for cell whether damaged base at specific genomic location or better leave it unrepaired. Persistent can disrupt but on other hand contribute gene regulation serving an epigenetic mark. When such processes out balance, pathophysiological conditions could get accelerated, because resulting mutagenic tightly linked ageing, inflammation, development multiple age-related diseases, cancer neurodegenerative disorders. Recent technological advancements novel data analysis strategies have revealed that damage, its repair, related mutations distribute heterogeneously over levels resolution. The involved mechanisms act in context sequence, interaction function chromatin. review addresses what we currently know about distribution intermediates, mutations. It will specifically focus various methodologies measure discuss mechanistic conclusions derived from different approaches. address consequences how gives rise mutations, instability,

Language: Английский

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Passenger hotspot mutations in cancer driven by APOBEC3A and mesoscale genomic features

Science, Journal Year: 2019, Volume and Issue: 364(6447)

Published: June 27, 2019

Cancer drivers require statistical modeling to distinguish them from passenger events, which accumulate during tumorigenesis but provide no fitness advantage cancer cells. The discovery of driver genes and mutations relies on the assumption that exact positional recurrence is unlikely by chance; thus, precise sharing across patients identifies drivers. Examining mutation landscape in genomes, we found many recurrent previously designated as are likely passengers. Our integrated bioinformatic biochemical analyses revealed these hotspot arise preference APOBEC3A, a cytidine deaminase, for DNA stem-loops. Conversely, APOBEC-signature not stem-loops enriched well-characterized may predict new This demonstrates mesoscale genomic features need be into computational models aimed at identifying linked diseases.

Language: Английский

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The genomic landscape of pediatric acute lymphoblastic leukemia

Nature Genetics, Journal Year: 2022, Volume and Issue: 54(9), P. 1376 - 1389

Published: Sept. 1, 2022

Language: Английский

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Mutational signatures: emerging concepts, caveats and clinical applications

Nature reviews. Cancer, Journal Year: 2021, Volume and Issue: 21(10), P. 619 - 637

Published: July 27, 2021

Language: Английский

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Whole-genome sequencing of 508 patients identifies key molecular features associated with poor prognosis in esophageal squamous cell carcinoma

Cell Research, Journal Year: 2020, Volume and Issue: 30(10), P. 902 - 913

Published: May 12, 2020

Language: Английский

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Mutational signatures are jointly shaped by DNA damage and repair

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: May 1, 2020

Abstract Cells possess an armamentarium of DNA repair pathways to counter damage and prevent mutation. Here we use C. elegans whole genome sequencing systematically quantify the contributions these factors mutational signatures. We analyse 2,717 genomes from wild-type 53 defective backgrounds, exposed 11 genotoxins, including UV-B ionizing radiation, alkylating compounds, aristolochic acid, aflatoxin B1, cisplatin. Combined genotoxic exposure deficiency alters mutation rates or signatures in 41% experiments, revealing how different alterations induced by same genotoxin are mended separate pathways. Error-prone translesion synthesis causes majority genotoxin-induced base substitutions, but averts larger deletions. Nucleotide excision prevents up 99% point mutations, almost uniformly across spectrum. Our data show that joint products suggest multiple underlie observed cancer genomes.

Language: Английский

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