A5069950937- Cancer Genomics and Diagnostics
- Molecular Biology Techniques and Applications
- Circular RNAs in diseases
- Lung Cancer Treatments and Mutations
- Genetic factors in colorectal cancer
- Single-cell and spatial transcriptomics
- Evolution and Genetic Dynamics
- MicroRNA in disease regulation
- Glioma Diagnosis and Treatment
- Sarcoma Diagnosis and Treatment
- RNA modifications and cancer
- Neurofibromatosis and Schwannoma Cases
- Cancer-related gene regulation
- DNA Repair Mechanisms
- CRISPR and Genetic Engineering
- SARS-CoV-2 and COVID-19 Research
- Epigenetics and DNA Methylation
- Vascular Malformations Diagnosis and Treatment
- Bacteriophages and microbial interactions
- Genetics, Bioinformatics, and Biomedical Research
- Renal and related cancers
- Renal cell carcinoma treatment
- Neuroblastoma Research and Treatments
- Bladder and Urothelial Cancer Treatments
- Mitochondrial Function and Pathology
Wellcome Sanger Institute
2018-2025
Granta Design (United Kingdom)
2018
Queen Mary University of London
2009-2015
Analysis Group (United States)
2014
The mutational burden of aging As people age, they accumulate somatic mutations in healthy cells. About 25% cells normal, sun-exposed skin harbor cancer driver mutations. What about tissues not exposed to powerful mutagens like ultraviolet light? Martincorena et al. performed targeted gene sequencing normal esophageal epithelium from nine human donors varying age (see the Perspective by Chanock). mutation rate was lower esophagus than skin, but there a strong positive selection clones...
Abstract The rates and patterns of somatic mutation in normal tissues are largely unknown outside humans 1–7 . Comparative analyses can shed light on the diversity mutagenesis across species, long-standing hypotheses about evolution their role cancer ageing. Here we performed whole-genome sequencing 208 intestinal crypts from 56 individuals to study landscape 16 mammalian species. We found that was dominated by seemingly endogenous mutational processes all including 5-methylcytosine...
We report genetic aberrations that activate the ERK/MAP kinase pathway in 100% of posterior fossa pilocytic astrocytomas, with a high frequency gene fusions between KIAA1549 and BRAF among these tumours. These were identified from analysis focal copy number gains at 7q34, detected using Affymetrix 250K 6.0 SNP arrays. PCR sequencing confirmed presence five KIAA1549-BRAF fusion variants, along single SRGAP3 RAF1. The resulting genes lack auto-inhibitory domains RAF1, which are replaced...
Genetic profiles of the bladder Depending on environment individual, human can be exposed to carcinogens as they are flushed through body. Lawson et al. and Li examined genetic composition laser-dissected microbiopsies from normal cancer cells collected urothelium, a specialized epithelium lining lower urinary tract (see Perspective by Rozen). These complementary studies identified mutational landscape urothelium various sequencing strategies high heterogeneity within between individuals...
Abstract Mutation accumulation in somatic cells contributes to cancer development and is proposed as a cause of aging. DNA polymerases Pol ε δ replicate during cell division. However, some cancers, defective proofreading due acquired POLE / POLD1 exonuclease domain mutations causes markedly elevated mutation burdens with distinctive mutational signatures. Germline familial predisposition. Here, we sequenced normal tissue tumor from individuals germline mutations. Increased characteristic...
Starting from the zygote, all cells in human body continuously acquire mutations. Mutations shared between different imply a common progenitor and are thus naturally occurring markers for lineage tracing1,2. Here we reconstruct extensive phylogenies of normal tissues three adult individuals using whole-genome sequencing 511 laser capture microdissections. Reconstructed embryonic progenitors same generation phylogeny often contribute to extents body. The degree this asymmetry varies...
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...
Monitoring the spread of SARS-CoV-2 and reconstructing transmission chains has become a major public health focus for many governments around world. The modest mutation rate rapid prevents reconstruction from consensus genome sequences, but within-host genetic diversity could theoretically help identify close contacts. Here we describe patterns in 1181 samples sequenced to high depth duplicate. 95.1% show mutations at detectable allele frequencies. Analyses mutational spectra revealed strong...
Introduction Detection and monitoring of circulating tumor DNA (ctDNA) is rapidly becoming a diagnostic, prognostic predictive tool in cancer patient care. A growing number gene targets have been identified as diagnostic or actionable, requiring the development reliable technology that provides analysis multiple genes parallel. We developed InVision™ liquid biopsy platform which utilizes enhanced TAm-Seq™ (eTAm-Seq™) technology, an amplicon-based next generation sequencing method for...
Understanding the molecular determinants that underpin clinical heterogeneity of non-muscle-invasive bladder cancer (NMIBC) is essential for prognostication and therapy development. Stage T1 disease in particular presents a high risk progression requires improved understanding. We present detailed multi-omics study containing gene expression, copy number, mutational profiles show relationships to immune infiltration, recurrence, muscle invasion. compare expression genomic subtypes derived...
The epigenetic landscape of cancer is regulated by many factors, but primarily it derives from the underlying genome sequence. Chromothripsis a catastrophic localized shattering event that drives, and often initiates, evolution. We characterized five esophageal adenocarcinoma organoids with chromothripsis using long-read sequencing transcriptome epigenome profiling. Complex structural variation subclonal variants meant haplotype-aware de novo methods were required to generate contiguous...
Gene fusions involving members of the RAF family protein kinases have recently been identified as characteristic aberrations low-grade astrocytomas, most common tumors central nervous system in children. While it has shown that these cause constitutive activation ERK/MAPK pathway, very little is known about their formation. Here, we present a detailed analysis gene fusion breakpoints from well-characterized cohort 43 astrocytomas. Our findings show rearrangements generate may be simple or...
Pilocytic astrocytomas are slow-growing tumors that usually occur in the cerebellum or midline along hypothalamic/optic pathways. The most common genetic alterations pilocytic activate ERK/MAPK signal transduction pathway, which is a major driver of proliferation but also believed to induce senescence these tumors. Here, we have conducted detailed investigation microRNA and gene expression, together with pathway analysis, improve our understanding regulatory mechanisms astrocytomas. were...
Abstract Progressive dysfunction of mitochondria, organelles responsible for energy provision to cells, is a major hallmark ageing. How the steadily accrues over lifetime remains unclear, given transient nature free radical damage and high turnover mitochondria. Here, we leveraged whole-genome sequencing data from single-cell derived foetal adult haematopoietic stem/progenitor cell colonies study clonal dynamics selection in mitochondrial genomes throughout life. We found that genetic drift...
Primary human cells cultured in organoid format have great promise as potential regenerative cellular therapies. However, their immunogenicity and mutational profile remain unresolved, impeding effective long-term translation to the clinic. In this study we report, for first time, generation of leukocyte antigen (HLA)-I HLA-II knock-out expandable primary cholangiocyte organoids (PCOs) using CRISPR-Cas9 a 'universal' low-immunogenic therapy bile duct disorders. HLA-edited PCOs (ePCOs)...
Abstract Cancer predisposition syndromes mediated by recessive cancer genes generate tumors via somatic variants (second hits) in the unaffected allele. Second hits may or not be sufficient for neoplastic transformation. Here we performed whole-genome and whole-exome sequencing on 479 tissue biopsies from a child with neurofibromatosis type 1, multisystem cancer-predisposing syndrome constitutive monoallelic NF1 inactivation. We identified multiple independent driver histologically normal...
Monitoring the spread of SARS-CoV-2 and reconstructing transmission chains has become a major public health focus for many governments around world. The modest mutation rate rapid prevents reconstruction from consensus genome sequences, but within-host genetic diversity could theoretically help identify close contacts. Here we describe patterns in 1,181 samples sequenced to high depth duplicate. 95% show mutations at detectable allele frequencies. Analyses mutational spectra revealed strong...
Abstract As we age, many tissues become colonised by microscopic clones carrying somatic driver mutations ( 1–10 . Some of these represent a first step towards cancer whereas others may contribute to ageing and other diseases. However, our understanding the clonal landscapes human tissues, their impact on risk, disease, remains limited due challenge detecting present in small numbers cells. Here, introduce new version nanorate sequencing (NanoSeq) 11 , duplex method with error rates <5...
Abstract Mutations that occur in the cell lineages of sperm or eggs can be transmitted to offspring. In humans, positive selection driver mutations during spermatogenesis is known increase birth prevalence certain developmental disorders. Until recently, characterising extent this has been limited by error rates sequencing technologies. Using duplex method NanoSeq, we sequenced 81 bulk samples from individuals aged 24 75 years. Our findings revealed a linear accumulation 1.67 (95% CI =...