SCENIC: single-cell regulatory network inference and clustering

Nature Methods, Journal Year: 2017, Volume and Issue: 14(11), P. 1083 - 1086

Published: Oct. 9, 2017

Language: Английский

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COSMIC: the Catalogue Of Somatic Mutations In Cancer

Nucleic Acids Research, Journal Year: 2018, Volume and Issue: 47(D1), P. D941 - D947

Published: Oct. 11, 2018

COSMIC, the Catalogue Of Somatic Mutations In Cancer (https://cancer.sanger.ac.uk) is most detailed and comprehensive resource for exploring effect of somatic mutations in human cancer. The latest release, COSMIC v86 (August 2018), includes almost 6 million coding across 1.4 tumour samples, curated from over 26 000 publications. addition to mutations, covers all genetic mechanisms by which promote cancer, including non-coding gene fusions, copy-number variants drug-resistance mutations. primarily hand-curated, ensuring quality, accuracy descriptive data capture. Building on our manual curation processes, we are introducing new initiatives that allow us prioritize key genes diseases, react more quickly comprehensively findings literature. Alongside improvements public website data-download systems, functionality COSMIC-3D allows exploration within three-dimensional protein structures, their structural functional impacts, implications druggability. parallel with COSMIC's deep broad variant coverage, Gene Census (CGC) describes a catalogue driving every form Currently describing 719 genes, CGC has recently introduced descriptions how each drives disease, summarized into 10 cancer Hallmarks.

Language: Английский

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Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients

Nature Medicine, Journal Year: 2017, Volume and Issue: 23(6), P. 703 - 713

Published: May 8, 2017

Language: Английский

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Detection and localization of surgically resectable cancers with a multi-analyte blood test

Science, Journal Year: 2018, Volume and Issue: 359(6378), P. 926 - 930

Published: Jan. 18, 2018

Earlier detection is key to reducing cancer deaths. Here, we describe a blood test that can detect eight common types through assessment of the levels circulating proteins and mutations in cell-free DNA. We applied this test, called CancerSEEK, 1005 patients with nonmetastatic, clinically detected cancers ovary, liver, stomach, pancreas, esophagus, colorectum, lung, or breast. CancerSEEK tests were positive median 70% types. The sensitivities ranged from 69 98% for five (ovary, esophagus) which there are no screening available average-risk individuals. specificity was greater than 99%: only 7 812 healthy controls scored positive. In addition, localized small number anatomic sites 83% patients.

Language: Английский

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New approach for understanding genome variations in KEGG

Nucleic Acids Research, Journal Year: 2018, Volume and Issue: 47(D1), P. D590 - D595

Published: Oct. 5, 2018

KEGG (Kyoto Encyclopedia of Genes and Genomes; https://www.kegg.jp/ or https://www.genome.jp/kegg/) is a reference knowledge base for biological interpretation genome sequences other high-throughput data. It an integrated database consisting three generic categories systems information, genomic information chemical additional human-specific category health information. pathway maps, BRITE hierarchies modules have been developed as molecular networks with Orthology nodes functional orthologs so that mapping procedures can be applied to any cellular organism. Unfortunately, however, this approach was inadequate representation in the category, where variations human genomes, especially disease-related variations, had considered. Thus, we introduced new gene variants are explicitly incorporated into what call 'network variants' recently released NETWORK database. This allows accumulation about perturbed caused not only by variants, but also viruses pathogens, environmental factors drugs. We expect will become another basic understanding disease mechanisms practical use clinical sequencing drug development.

Language: Английский

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The COSMIC Cancer Gene Census: describing genetic dysfunction across all human cancers

Nature reviews. Cancer, Journal Year: 2018, Volume and Issue: 18(11), P. 696 - 705

Published: Oct. 6, 2018

Language: Английский

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Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas

Cell Reports, Journal Year: 2018, Volume and Issue: 23(1), P. 239 - 254.e6

Published: April 1, 2018

Summary

DNA damage repair (DDR) pathways modulate cancer risk, progression, and therapeutic response. We systematically analyzed somatic alterations to provide a comprehensive view of DDR deficiency across 33 types. Mutations with accompanying loss heterozygosity were observed in over 1/3 genes, including TP53 BRCA1/2. Other prevalent included epigenetic silencing the direct genes EXO5, MGMT, ALKBH3 ∼20% samples. Homologous recombination (HRD) was present at varying frequency many types, most notably ovarian cancer. However, contrast cancer, HRD associated worse outcomes several other cancers. Protein structure-based analyses allowed us predict functional consequences rare, recurrent mutations. A new machine-learning-based classifier developed from gene expression data identify that phenocopy deleterious These frequent human cancers have may determine progression guide therapy.

Language: Английский

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Chemoresistance Evolution in Triple-Negative Breast Cancer Delineated by Single-Cell Sequencing

Cell, Journal Year: 2018, Volume and Issue: 173(4), P. 879 - 893.e13

Published: April 19, 2018

Language: Английский

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Pan-cancer whole-genome analyses of metastatic solid tumours

Nature, Journal Year: 2019, Volume and Issue: 575(7781), P. 210 - 216

Published: Oct. 23, 2019

Abstract Metastatic cancer is a major cause of death and associated with poor treatment efficacy. A better understanding the characteristics late-stage required to help adapt personalized treatments, reduce overtreatment improve outcomes. Here we describe largest, our knowledge, pan-cancer study metastatic solid tumour genomes, including whole-genome sequencing data for 2,520 pairs normal tissue, analysed at median depths 106× 38×, respectively, surveying more than 70 million somatic variants. The characteristic mutations lesions varied widely, that reflect those primary types, high rates duplication events (56%). Individual were relatively homogeneous, vast majority (96%) driver being clonal up 80% tumour-suppressor genes inactivated bi-allelically by different mutational mechanisms. Although genomes showed similar landscape tumours, find could contribute responsiveness therapy or resistance in individual patients. We implement an approach review clinically relevant associations their potential actionability. For 62% patients, identify genetic variants may be used stratify patients towards therapies either have been approved are clinical trials. This demonstrates importance comprehensive genomic profiling precision medicine cancer.

Language: Английский

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Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease

New England Journal of Medicine, Journal Year: 2020, Volume and Issue: 383(27), P. 2628 - 2638

Published: Oct. 27, 2020

Adult-onset inflammatory syndromes often manifest with overlapping clinical features. Variants in ubiquitin-related genes, previously implicated autoinflammatory disease, may define new disorders.We analyzed peripheral-blood exome sequence data independent of phenotype and inheritance pattern to identify deleterious mutations genes. Sanger sequencing, immunoblotting, immunohistochemical testing, flow cytometry, transcriptome cytokine profiling were performed. CRISPR-Cas9-edited zebrafish used as an vivo model assess gene function.We identified 25 men somatic affecting methionine-41 (p.Met41) UBA1, the major E1 enzyme that initiates ubiquitylation. (The UBA1 lies on X chromosome.) In such patients, fatal, treatment-refractory syndrome develops late adulthood, fevers, cytopenias, characteristic vacuoles myeloid erythroid precursor cells, dysplastic bone marrow, neutrophilic cutaneous pulmonary inflammation, chondritis, vasculitis. Most these patients met criteria for (relapsing polychondritis, Sweet's syndrome, polyarteritis nodosa, or giant-cell arteritis) a hematologic condition (myelodysplastic multiple myeloma) both. Mutations found more than half hematopoietic stem including cells but not lymphocytes fibroblasts. p.Met41 resulted loss canonical cytoplasmic isoform expression novel, catalytically impaired initiated at p.Met67. Mutant showed decreased ubiquitylation activated innate immune pathways. Knockout homologue caused systemic inflammation.Using genotype-driven approach, we disorder connects seemingly unrelated adult-onset syndromes. We named this VEXAS (vacuoles, enzyme, X-linked, autoinflammatory, somatic) syndrome. (Funded by NIH Intramural Research Programs EU Horizon 2020 Innovation Program.).

Language: Английский

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