Signatures of copy number alterations in human cancer

Nature, Journal Year: 2022, Volume and Issue: 606(7916), P. 984 - 991

Published: June 15, 2022

Abstract Gains and losses of DNA are prevalent in cancer emerge as a consequence inter-related processes replication stress, mitotic errors, spindle multipolarity breakage–fusion–bridge cycles, among others, which may lead to chromosomal instability aneuploidy 1,2 . These copy number alterations contribute initiation, progression therapeutic resistance 3–5 Here we present conceptual framework examine the patterns human that is widely applicable diverse data types, including whole-genome sequencing, whole-exome reduced representation bisulfite single-cell sequencing SNP6 microarray data. Deploying this 9,873 cancers representing 33 types from The Cancer Genome Atlas 6 revealed set 21 signatures explain 97% samples. Seventeen were attributed biological phenomena doubling, aneuploidy, loss heterozygosity, homologous recombination deficiency, chromothripsis haploidization. aetiologies four remain unexplained. Some harbour amplicon associated with extrachromosomal DNA, disease-specific survival proto-oncogene gains such MDM2 In contrast base-scale mutational signatures, no signature was many known exogenous risk factors. Our results synthesize global landscape by revealing diversity give rise these alterations.

Language: Английский

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COSMIC: a curated database of somatic variants and clinical data for cancer

Nucleic Acids Research, Journal Year: 2023, Volume and Issue: 52(D1), P. D1210 - D1217

Published: Nov. 1, 2023

Abstract The Catalogue Of Somatic Mutations In Cancer (COSMIC), https://cancer.sanger.ac.uk/cosmic, is an expert-curated knowledgebase providing data on somatic variants in cancer, supported by a comprehensive suite of tools for interpreting genomic data, discerning the impact alterations disease, and facilitating translational research. catalogue accessed used thousands cancer researchers clinicians daily, allowing them to quickly access information from immense pool curated over 29 thousand scientific publications large studies. Within last 4 years, COSMIC has substantially expanded its utility adding new resources: Mutational Signatures catalogue, Mutation Census, Actionability. To improve accessibility interoperability, have received stable identifiers that are associated with their coordinates GRCh37 GRCh38, export files reduced redundancy been made available download.

Language: Английский

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Mapping clustered mutations in cancer reveals APOBEC3 mutagenesis of ecDNA

Nature, Journal Year: 2022, Volume and Issue: 602(7897), P. 510 - 517

Published: Feb. 9, 2022

Clustered somatic mutations are common in cancer genomes and previous analyses reveal several types of clustered single-base substitutions, which include doublet- multi-base substitutions

Language: Английский

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Evolutionary histories of breast cancer and related clones

Nature, Journal Year: 2023, Volume and Issue: 620(7974), P. 607 - 614

Published: July 26, 2023

Recent studies have documented frequent evolution of clones carrying common cancer mutations in apparently normal tissues, which are implicated development1-3. However, our knowledge is still missing with regard to what additional driver events take place order, before one or more these tissues ultimately evolve cancer. Here, using phylogenetic analyses multiple microdissected samples from both and non-cancer lesions, we show unique evolutionary histories breast cancers harbouring der(1;16), a alteration found roughly 20% cancers. The approximate timing early was estimated the mutation rate measured epithelial cells. In der(1;16)(+) cancers, derivative chromosome acquired puberty late adolescence, followed by emergence ancestor patient's 30s, evolved. Replacing pre-existing mammary epithelium following years, occupied large area within premenopausal time diagnosis. Evolution independent founders ancestors common, contributing intratumour heterogeneity. number did not correlate histology, suggesting role local microenvironments and/or epigenetic events. A similar pattern also observed another case evolving an AKT1-mutated founder. Taken together, findings provide new insight into how evolves.

Language: Английский

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Assigning mutational signatures to individual samples and individual somatic mutations with SigProfilerAssignment

Bioinformatics, Journal Year: 2023, Volume and Issue: 39(12)

Published: Dec. 1, 2023

Analysis of mutational signatures is a powerful approach for understanding the mutagenic processes that have shaped evolution cancer genome. To evaluate operative in genome, one first needs to quantify their activities by estimating number mutations imprinted each signature.

Language: Английский

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Evolutionary trajectories of small cell lung cancer under therapy

Nature, Journal Year: 2024, Volume and Issue: 627(8005), P. 880 - 889

Published: March 13, 2024

Abstract The evolutionary processes that underlie the marked sensitivity of small cell lung cancer (SCLC) to chemotherapy and rapid relapse are unknown 1–3 . Here we determined tumour phylogenies at diagnosis throughout immunotherapy by multiregion sequencing 160 tumours from 65 patients. Treatment-naive SCLC exhibited clonal homogeneity distinct sites, whereas first-line platinum-based led a burst in genomic intratumour heterogeneity spatial diversity. We observed branched evolution shift ancestral clones underlying relapse. Effective radio- or induced re-expansion founder with acquired damage chemotherapy. Whereas TP53 RB1 alterations were exclusively part common ancestor, MYC family amplifications frequently not constituents clone. At relapse, emerging subclonal mutations affected key genes associated biology, harbouring CREBBP / EP300 underwent genome duplications. Gene-damaging co-alterations missense TP73 , FMN2 significantly shorter disease following In summary, uncover under therapy, identify ancestor as source diversity show central patterns resistance

Language: Английский

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Comprehensive analysis of mutational signatures reveals distinct patterns and molecular processes across 27 pediatric cancers

Nature Cancer, Journal Year: 2023, Volume and Issue: 4(2), P. 276 - 289

Published: Jan. 26, 2023

Abstract Analysis of mutational signatures can reveal underlying molecular mechanisms the processes that have imprinted somatic mutations found in cancer genomes. Here, we analyze single base substitutions and small insertions deletions pediatric cancers encompassing 785 whole-genome sequenced tumors from 27 molecularly defined subtypes. We identified only a number active cancers, compared with previously analyzed adult cancers. Further, report significant difference proportion showing homologous recombination repair defect previous analyses. In leukemias, an indel signature, not reported, characterized by long nonrepeat regions, affecting mainly intronic intergenic but also exons known genes. provide systematic overview COSMIC v.3 across which is highly relevant for understanding tumor biology enabling future research defining biomarkers treatment response.

Language: Английский

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3D genomic mapping reveals multifocality of human pancreatic precancers

Nature, Journal Year: 2024, Volume and Issue: 629(8012), P. 679 - 687

Published: May 1, 2024

Language: Английский

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The genomic landscape of 2,023 colorectal cancers

Nature, Journal Year: 2024, Volume and Issue: 633(8028), P. 127 - 136

Published: Aug. 7, 2024

Abstract Colorectal carcinoma (CRC) is a common cause of mortality 1 , but comprehensive description its genomic landscape lacking 2–9 . Here we perform whole-genome sequencing 2,023 CRC samples from participants in the UK 100,000 Genomes Project, thereby providing highly detailed somatic mutational this cancer. Integrated analyses identify more than 250 putative driver genes, many not previously implicated or other cancers, including several recurrent changes outside coding genome. We extend molecular pathways involved development, define four new subgroups microsatellite-stable based on features and show that these groups have independent prognostic associations. also characterize rare subgroups, some with potential clinical relevance, cancers both microsatellite chromosomal instability. demonstrate spectrum profiles across colorectum, which reflect aetiological differences. These include role Escherichia coli pks+ colibactin rectal 10 importance SBS93 signature 11–13 suggests diet smoking risk factor. Immune-escape mutations 14 are near-ubiquitous hypermutant tumours occur about half CRCs, often form HLA copy number changes. Many actionable, those associated (for example, BRCA1 IDH1 ), highlighting optimizing patient care.

Language: Английский

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Geographic variation of mutagenic exposures in kidney cancer genomes

Nature, Journal Year: 2024, Volume and Issue: 629(8013), P. 910 - 918

Published: May 1, 2024

Abstract International differences in the incidence of many cancer types indicate existence carcinogen exposures that have not yet been identified by conventional epidemiology make a substantial contribution to burden 1 . In clear cell renal carcinoma, obesity, hypertension and tobacco smoking are risk factors, but they do explain geographical variation its 2 Underlying causes can be inferred sequencing genomes cancers from populations with different rates detecting patterns somatic mutations. Here we sequenced 962 carcinomas 11 countries varying incidence. The mutation profiles differed between countries. Romania, Serbia Thailand, mutational signatures characteristic aristolochic acid compounds were present most cases, these rare elsewhere. Japan, signature unknown cause was found more than 70% cases less 2% A further ubiquitous exhibited higher loads kidney cancer. Known correlated consumption, no associated obesity or hypertension, suggesting non-mutagenic mechanisms action underlie factors. results this study multiple, geographically variable, mutagenic potentially affect tens millions people illustrate opportunities for new insights into causation through large-scale global genomics.

Language: Английский

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