A5033761850- Cancer Genomics and Diagnostics
- Genomics and Rare Diseases
- Genomics and Chromatin Dynamics
- Genomic variations and chromosomal abnormalities
- Genetic factors in colorectal cancer
- CRISPR and Genetic Engineering
- Pluripotent Stem Cells Research
- Single-cell and spatial transcriptomics
- RNA modifications and cancer
- Bioinformatics and Genomic Networks
- Genomics and Phylogenetic Studies
- Chromosomal and Genetic Variations
- Cancer Immunotherapy and Biomarkers
- Evolution and Genetic Dynamics
- Cancer-related molecular mechanisms research
- Genetic Associations and Epidemiology
- Telomeres, Telomerase, and Senescence
- Epigenetics and DNA Methylation
- Lung Cancer Treatments and Mutations
- Renal and related cancers
- RNA Research and Splicing
- DNA Repair Mechanisms
- Molecular Biology Techniques and Applications
- Nutrition, Genetics, and Disease
- Cancer, Hypoxia, and Metabolism
European Bioinformatics Institute
2021-2025
AstraZeneca (Spain)
2025
University of Tübingen
2018-2024
University College London
2024
Royal National Orthopaedic Hospital
2024
Genomics England
2024
Boston Children's Hospital
2024
Centre for Genomic Regulation
2017-2023
Wellcome Sanger Institute
2022
Universitat Pompeu Fabra
2017-2021
Tumor behavior is intricately dependent on the oncogenic properties of cancer cells and their multi-cellular interactions. To understand these dependencies within wider microenvironment, we studied over 270,000 single-cell transcriptomes 100 microdissected whole exomes from 12 patients with kidney tumors, prior to validation using spatial transcriptomics. Tissues were sampled multiple regions tumor core, tumor-normal interface, normal surrounding tissues, peripheral blood. We find that...
DNA mismatch repair deficiency (MMRd) is associated with a high tumor mutational burden (TMB) and sensitivity to immune checkpoint blockade (ICB) therapy. Nevertheless, most MMRd tumors do not durably respond ICB critical questions remain about immunosurveillance TMB in these tumors. In the present study, we developed autochthonous mouse models of lung colon cancer. Surprisingly, did display increased T cell infiltration or response, which showed be result substantial intratumor...
Genetic screens in cancer cell lines inform gene function and drug discovery. More comprehensive screen datasets with multi-omics data are needed to enhance opportunities functionally map genetic vulnerabilities. Here, we construct a second-generation of dependencies by annotating 930 multi-omic analyze relationships between molecular markers derived from CRISPR-Cas9 screens. We identify dependency-associated expression beyond driver genes, observe many addiction driven gain rather than...
Abstract Characterization of somatic mutations at single-cell resolution is essential to study cancer evolution, clonal mosaicism and cell plasticity. Here, we describe SComatic, an algorithm designed for the detection in transcriptomic ATAC-seq (assay transposase-accessible chromatin sequence) data sets directly without requiring matched bulk or DNA sequencing data. SComatic distinguishes from polymorphisms, RNA-editing events artefacts using filters statistical tests parameterized on...
Osteosarcoma is the most common primary cancer of bone, with a peak incidence in children and young adults. Using multi-region whole-genome sequencing, we find that chromothripsis an ongoing mutational process, occurring subclonally 74% osteosarcomas. Chromothripsis generates highly unstable derivative chromosomes, evolution which drives acquisition oncogenic mutations, clonal diversification, intra-tumor heterogeneity across diverse sarcomas carcinomas. In addition, characterize new...
Cactophilic Drosophila species provide a valuable model to study gene–environment interactions and ecological adaptation. buzzatii mojavensis are two cactophilic that belong the repleta group, but have very different geographical distributions primary host plants. To investigate genomic basis of adaptation, we sequenced genome developmental transcriptome D. compared its gene content with other noncactophilic in same subgenus. The newly (161.5 Mb) comprises 826 scaffolds (>3 kb) contains...
Definitive radiochemotherapy (RCTX) with curative intent is one of the standard treatment options in patients locally advanced head and neck squamous cell carcinoma (HNSCC). Despite this intensive therapy protocol, disease recurrence remains an issue. Therefore, we tested predictive capacity liquid biopsies as a novel biomarker during RCTX HNSCC.We sequenced tumour samples 20 HNSCC to identify driver mutations. Subsequently, performed longitudinal analysis circulating DNA (ctDNA) dynamics...
Abstract Telomere fusions (TFs) can trigger the accumulation of oncogenic alterations leading to malignant transformation and drug resistance. Despite their relevance in tumour evolution, our understanding patterns consequences TFs human cancers remains limited. Here, we characterize rates spectrum somatic across >30 cancer types using whole-genome sequencing data. are pervasive tumours with varying markedly within types. In addition end-to-end fusions, find that mechanistically link...
Accurate detection of somatic structural variants (SVs) and copy number aberrations (SCNAs) is critical to inform the diagnosis treatment human cancers. Here, we describe SAVANA, a computationally efficient algorithm designed for joint analysis SVs, SCNAs, tumour purity ploidy using long-read sequencing data. SAVANA relies on machine learning distinguish true SVs from artefacts provide prediction errors individual SVs. Using high-depth Illumina nanopore whole-genome data 99 tumours matched...
Recent advancements in single-cell RNA sequencing (scRNA-seq) have significantly impacted clinical oncology. However, the accurate interpretation of scRNA-seq data remains challenging due to limitations current methodologies distinguishing between different cell types within a tissue sample. Despite substantial efforts construct comprehensive atlases, differentiating malignant from non-malignant cells is still time-consuming process. Current approaches primarily rely on marker genes, gene...
In recent years, next-generation sequencing (NGS) has become a cornerstone of clinical genetics and diagnostics. Many applications require high precision, especially if rare events such as somatic mutations in cancer or genetic variants causing diseases need to be identified. Although random errors can modeled statistically deep minimizes their impact, systematic remain problem even at depth coverage. Understanding source is crucial increase precision NGS applications. this work, we studied...
Mosaic mutations acquired during early embryogenesis can lead to severe early-onset genetic disorders and cancer predisposition, but are often undetectable in blood samples. The rate mutational spectrum of embryonic mosaic (EMMs) have only been studied few tissues, their contribution is unknown. Therefore, we investigated how frequent occur across all germ layers tissues.Mosaic mutation detection 49 normal tissues from 570 individuals (Genotype-Tissue Expression (GTEx) cohort) was performed...
Immune checkpoint inhibitors (ICI) have significantly improved overall survival in melanoma patients. However, 60% experience severe adverse events and early response markers are lacking. Circulating tumour DNA (ctDNA) is a promising biomarker for treatment-response recurrence detection. The prospective PET/LIT study included 104 patients with palliative combined or adjuvant ICI. Tumour-informed sequencing panels to monitor 30 patient-specific variants were designed 321 liquid biopsies of 87...
Abstract Cancers develop through somatic mutagenesis, however germline genetic variation can markedly contribute to tumorigenesis via diverse mechanisms. We discovered and phased 88 million single nucleotide variants, short insertions/deletions, large structural variants in whole genomes from 2,642 cancer patients, employed this genomic resource study determinants of mutagenesis across 39 types. Our analyses implicate damaging a variety predisposition DNA damage response genes with specific...
Mendelian diseases have shown to be an and efficient model for connecting genotypes phenotypes elucidating the function of genes. Whole-exome sequencing (WES) accelerated study rare in families, allowing directly pinpointing causal mutations genic regions without need linkage analysis. However, low diagnostic rates 20–30% reported multiple WES disease studies point improved variant pathogenicity classification prioritization methods. Here, we present exome Disease Variant Analysis (eDiVA;...
Abstract Profilin 1—encoded by PFN1— is a small actin-binding protein with tumour suppressive role in various adenocarcinomas and pagetic osteosarcomas. However, its contribution to development not fully understood. Using fix live cell imaging, we report that 1 inactivation results multiple mitotic defects, manifested prominently anaphase bridges, multipolar spindles, misaligned lagging chromosomes, cytokinesis failures. Accordingly, next-generation sequencing technologies highlighted...
Despite the overall efficacy of immune checkpoint blockade (ICB) for mismatch repair deficiency (MMRD) across tumor types, a sizable fraction patients with MMRD still do not respond to ICB. We performed mutational signature analysis panel sequencing data (n = 95) from cases treated discover that T>C rich single base substitution (SBS) signatures, SBS26 and SBS54 COSMIC Mutational Signatures catalog, identify significantly shorter survival. Tumors high burden show over expression enriched...
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Collaborative efforts, such as the Human Cell Atlas, are rapidly accumulating large amounts of single-cell data. To ensure that atlases representative human genetic diversity, we need to determine ancestry donors from whom data generated. Self-reporting race and ethnicity, although important, can be biased is not always available for datasets already collected. Here, introduce scAI-SNP, a tool infer directly genomics train identified 4.5 million ancestry-informative single-nucleotide...
<title>Abstract</title> Accurate detection of somatic structural variants (SVs) and copy number aberrations (SCNAs) is critical to inform the diagnosis treatment human cancers. Here, we describe SAVANA, a computationally efficient algorithm designed for joint analysis SVs, SCNAs, tumour purity ploidy using long-read sequencing data. SAVANA relies on machine learning distinguish true SVs from artefacts provide prediction errors individual SVs. Using high-depth Illumina nanopore whole-genome...
Osteosarcoma is the most common primary cancer of bone with a peak incidence in children and young adults. Despite progress, genomic aberrations underpinning osteosarcoma evolution remain poorly understood. Using multi-region whole-genome sequencing, we find that chromothripsis an ongoing mutational process, occurring subclonally 74% tumours. Chromothripsis drives acquisition oncogenic mutations generates highly unstable derivative chromosomes, which clonal diversification intra-tumour...
Rare variants are thought to play an important role in the etiology of complex diseases and may explain a significant fraction missing heritability genetic disease studies. Next-generation sequencing facilitates association rare coding or regulatory regions with large cohorts at genome-wide scale. However, variant studies (RVAS) still lack power when small medium-sized if variation explains phenotypic variance. Here we present novel Bayesian Association Test using Integrated Nested Laplace...
Abstract DNA mismatch repair deficiency (MMRd) in human cancer is associated with high tumor mutational burden (TMB), frameshift mutation-derived neoantigens, increased T cell infiltration, and remarkable responsiveness to immune checkpoint blockade (ICB) therapy. Nevertheless, about half of MMRd tumors do not respond ICB for unclear reasons. While line transplant models have reinforced the importance TMB response, critical questions remain regarding role immunosurveillance evolution induced...
Abstract Whole-genome sequencing (WGS) of human cancers has revealed that structural variation, which refers to the rearrangement genome leading deletion, amplification reshuffling DNA segments ranging from a few hundred bp entire chromosomes, is key mutational process in cancer evolution. Notably, pan-cancer analyses have both simple and complex forms variation are pervasive across diverse cancers, often underpin drug resistance metastasis. To date, study genomes relied on analysis...