ESMO Recommendations on clinical reporting of genomic test results for solid cancers DOI Creative Commons
Joris van de Haar, Paul Roepman, Fabrice André

и другие.

Annals of Oncology, Год журнала: 2024, Номер 35(11), С. 954 - 967

Опубликована: Июль 9, 2024

•These Recommendations cover the preparation of genomic reports to inform clinical decisions for patients with solid cancers.•Recommendations are based on consensus from a multidisciplinary group experts after reviewing available evidence.•The manuscript provides guidance structuring reports, and optimal presentation content each section.•These recommendations relevant most next-generation sequencing assays utilised in practice research.•Recommendations categorised into priority levels (A, B) adapt diverse laboratory contexts. BackgroundGenomic tumour profiling has crucial role management cancers, as it helps selecting prioritising therapeutic interventions prognostic predictive biomarkers, well identifying markers hereditary cancers. Harmonised approaches interpret results testing needed support physicians their decision making, prevent inequalities precision medicine maximise patient benefit cancer options.MethodsThe European Society Medical Oncology (ESMO) Translational Research Precision Medicine Working Group assembled international propose preparing These aim foster best practices integrating within settings. After review evidence, several rounds surveys focused discussions were conducted reach recommendation statements. Only reported. Recommendation statements graded two tiers importance: level A (required maintain common standards reporting) B (optional but necessary achieve ideal practice).ResultsGenomics should present key information front page(s) followed by supplementary one or more appendices. Reports be structured sections: (i) sample details; (ii) assay data analysis characteristics; (iii) sample-specific performance quality control; (iv) alterations functional annotation; (v) actionability assessment matching potential therapy indications; (vi) summary main findings. Specific prepare these sections made.ConclusionsWe set aimed at genomics enhance physician comprehension Communication between ordering professionals reporting is minimise uncertainties optimise impact tests care. Genomic options. The practice). Genomics made. We

Язык: Английский

Ensembl 2024 DOI Creative Commons
Peter W. Harrison,

M Ridwan Amode,

Olanrewaju Austine-Orimoloye

и другие.

Nucleic Acids Research, Год журнала: 2023, Номер 52(D1), С. D891 - D899

Опубликована: Ноя. 11, 2023

Abstract Ensembl (https://www.ensembl.org) is a freely available genomic resource that has produced high-quality annotations, tools, and services for vertebrates model organisms more than two decades. In recent years, there been dramatic shift in the landscape, with large increase number phylogenetic breadth of reference genomes, alongside major advances pan-genome representations higher species. order to support these efforts accelerate downstream research, continues focus on scaling rapid annotation new genome assemblies, developing methods comparative analysis, expanding depth quality our annotations. This year we have continued expansion global biodiversity doubling annotated genomes Rapid Release site over 1700, driven by close collaboration projects such as Darwin Tree Life. We also strengthened key agricultural species, including first regulatory builds farmed animals, updated tools resources scientific community, notably Variant Effect Predictor. data, software, are available.

Язык: Английский

Процитировано

287
COSMIC: a curated database of somatic variants and clinical data for cancer DOI Creative Commons
Zbysław Sońdka,

Nidhi Bindal Dhir,

Denise Carvalho‐Silva

и другие.

Nucleic Acids Research, Год журнала: 2023, Номер 52(D1), С. D1210 - D1217

Опубликована: Ноя. 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.

Язык: Английский

Процитировано

208
CADD v1.7: using protein language models, regulatory CNNs and other nucleotide-level scores to improve genome-wide variant predictions DOI Creative Commons
Max Schubach, Thorben Maaß, Lusiné Nazaretyan

и другие.

Nucleic Acids Research, Год журнала: 2024, Номер 52(D1), С. D1143 - D1154

Опубликована: Янв. 5, 2024

Machine Learning-based scoring and classification of genetic variants aids the assessment clinical findings is employed to prioritize in diverse studies analyses. Combined Annotation-Dependent Depletion (CADD) one first methods for genome-wide prioritization across different molecular functions has been continuously developed improved since its original publication. Here, we present our most recent release, CADD v1.7. We explored integrated new annotation features, among them state-of-the-art protein language model scores (Meta ESM-1v), regulatory variant effect predictions (from sequence-based convolutional neural networks) sequence conservation (Zoonomia). evaluated version on data sets derived from ClinVar, ExAC/gnomAD 1000 Genomes variants. For coding effects, tested 31 Deep Mutational Scanning (DMS) ProteinGym and, prediction, used saturation mutagenesis reporter assay promoter enhancer sequences. The inclusion features further overall performance CADD. As with previous releases, all sets, v1.7 scores, scripts on-site an easy-to-use webserver are readily provided via https://cadd.bihealth.org/ or https://cadd.gs.washington.edu/ community.

Язык: Английский

Процитировано

138
ChIP-Atlas 3.0: a data-mining suite to explore chromosome architecture together with large-scale regulome data DOI Creative Commons
Zhaonan Zou, Tazro Ohta, Shinya Oki

и другие.

Nucleic Acids Research, Год журнала: 2024, Номер 52(W1), С. W45 - W53

Опубликована: Май 16, 2024

Abstract ChIP-Atlas (https://chip-atlas.org/) presents a suite of data-mining tools for analyzing epigenomic landscapes, powered by the comprehensive integration over 376 000 public ChIP-seq, ATAC-seq, DNase-seq and Bisulfite-seq experiments from six representative model organisms. To unravel intricacies chromatin architecture that mediates regulome-initiated generation transcriptional phenotypic diversity within cells, we report 3.0 enhances clarity incorporating additional tracks genomic features newly consolidated ‘annotation track’ section. The include chromosomal conformation (Hi-C eQTL datasets), regulatory elements (ChromHMM FANTOM5 enhancers), variants associated with diseases phenotypes (GWAS SNPs ClinVar variants). These annotation are easily accessible alongside other experimental tracks, facilitating better elucidation underlying diversification traits. Furthermore, ‘Diff Analysis,’ new online tool, compares query epigenome data to identify differentially bound, accessible, methylated regions using ATAC-seq DNase-seq, datasets, respectively. Diff Analysis coupled continuous expansion, renders robust resource mining landscape mechanisms, thereby offering valuable perspectives, particularly genetic disease research drug discovery.

Язык: Английский

Процитировано

38
Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity DOI
Meng‐Ju Wu, Hiroshi Kondo, Ashwin V. Kammula

и другие.

Science, Год журнала: 2024, Номер 385(6705)

Опубликована: Июль 11, 2024

(

Язык: Английский

Процитировано

24
A molecular glue degrader of the WIZ transcription factor for fetal hemoglobin induction DOI
Pamela Y. Ting, Sneha Borikar,

John Ryan Kerrigan

и другие.

Science, Год журнала: 2024, Номер 385(6704), С. 91 - 99

Опубликована: Июль 4, 2024

Sickle cell disease (SCD) is a prevalent, life-threatening condition attributable to heritable mutation in β-hemoglobin. Therapeutic induction of fetal hemoglobin (HbF) can ameliorate complications and has been intently pursued. However, safe effective small-molecule inducers HbF remain elusive. We report the discovery dWIZ-1 dWIZ-2, molecular glue degraders WIZ transcription factor that robustly induce erythroblasts. Phenotypic screening cereblon (CRBN)-biased chemical library revealed as previously unknown repressor HbF. degradation mediated by recruitment WIZ(ZF7) CRBN dWIZ-1, resolved crystallography ternary complex. Pharmacological was well tolerated induced humanized mice cynomolgus monkeys. These findings establish globally accessible therapeutic strategy for SCD.

Язык: Английский

Процитировано

22
Integrating single-cell multi-omics and prior biological knowledge for a functional characterization of the immune system DOI
Philipp Schäfer, Daniel Dimitrov, Eduardo J. Villablanca

и другие.

Nature Immunology, Год журнала: 2024, Номер 25(3), С. 405 - 417

Опубликована: Фев. 27, 2024

Язык: Английский

Процитировано

18
Cell state-dependent allelic effects and contextual Mendelian randomization analysis for human brain phenotypes DOI Creative Commons
Alexander Haglund, Verena Zuber,

Maya Abouzeid

и другие.

Nature Genetics, Год журнала: 2025, Номер unknown

Опубликована: Янв. 10, 2025

Abstract Gene expression quantitative trait loci are widely used to infer relationships between genes and central nervous system (CNS) phenotypes; however, the effect of brain disease on these inferences is unclear. Using 2,348,438 single-nuclei profiles from 391 disease-case control brains, we report 13,939 whose correlated with genetic variation, which 16.7–40.8% (depending cell type) showed disease-dependent allelic effects. Across 501 colocalizations for 30 CNS traits, 23.6% had a dependency, even after adjusting status. To estimate unconfounded outcomes, repeated analysis using nondiseased brains ( n = 183) reported an additional 91 not present in larger mixed dataset, demonstrating enhanced interpretation disease-associated variants. Principled implementation single-cell Mendelian randomization control-only identified 140 putatively causal gene–trait associations, 11 were replicated UK Biobank, prioritizing candidate peripheral biomarkers predictive outcomes.

Язык: Английский

Процитировано

3
Enhancer-driven cell type comparison reveals similarities between the mammalian and bird pallium DOI
Nikolai Hecker, Niklas Kempynck, David Mauduit

и другие.

Science, Год журнала: 2025, Номер 387(6735)

Опубликована: Янв. 2, 2025

Combinations of transcription factors govern the identity cell types, which is reflected by genomic enhancer codes. We used deep learning to characterize these codes and devised three metrics compare types in telencephalon across amniotes. To this end, we generated single-cell multiome spatially resolved transcriptomics data chicken telencephalon. Enhancer orthologous nonneuronal γ-aminobutyric acid–mediated (GABAergic) show a high degree similarity amniotes, whereas excitatory neurons mammalian neocortex avian pallium exhibit varying degrees similarity. mesopallial are most similar those deep-layer neurons. With study, present generally applicable approaches on basis regulatory sequences.

Язык: Английский

Процитировано

3
Exome sequencing identifies genes for socioeconomic status in 350,770 individuals DOI Creative Commons
Xinrui Wu, Yang Liu, Bang‐Sheng Wu

и другие.

Proceedings of the National Academy of Sciences, Год журнала: 2025, Номер 122(2)

Опубликована: Янв. 7, 2025

Socioeconomic status (SES) is a critical factor in determining health outcomes and influenced by genetic environmental factors. However, our understanding of the structure SES remains incomplete. Here, we conducted large-scale exome study markers (household income, occupational status, educational attainment, social deprivation) 350,770 individuals. For rare coding variants, identified 56 significant associations gene-based collapsing tests, unveiling 7 additional SES-associated genes ( NRN1 , CCDC36 RHOB EP400 NCAM1, TPTEP2-CSNK1E LINC02881 ). Exome-wide single common variant analysis revealed nine lead single-nucleotide polymorphisms (SNPs) associated with household income 34 SNPs EduYears, replicating previous GWAS findings. The gene–environment correlations had substantial impact on SES, as indicated significantly increased P values several after controlling for geographic regions. Furthermore, observed pleiotropic effects factors wide range outcomes, such cognitive function, psychosocial diabetes. This highlights contribution variants to their phenotypes.

Язык: Английский

Процитировано

2