A5079438475- Epigenetics and DNA Methylation
- Nutrition, Genetics, and Disease
- Bioinformatics and Genomic Networks
- Cancer Genomics and Diagnostics
- Genetic factors in colorectal cancer
- Hyperglycemia and glycemic control in critically ill and hospitalized patients
- Pancreatic function and diabetes
- Acute Lymphoblastic Leukemia research
- Diabetes Management and Research
- Diabetes and associated disorders
- Single-cell and spatial transcriptomics
- Acute Myeloid Leukemia Research
- Developmental Biology and Gene Regulation
- Hematopoietic Stem Cell Transplantation
- Genomics and Rare Diseases
- Metabolism and Genetic Disorders
- RNA modifications and cancer
- Metabolism, Diabetes, and Cancer
- interferon and immune responses
- melanin and skin pigmentation
- CRISPR and Genetic Engineering
- dental development and anomalies
- Chronic Myeloid Leukemia Treatments
- Evolution and Genetic Dynamics
- Immunodeficiency and Autoimmune Disorders
Institute of Cancer Research
2021-2024
Genomics (United Kingdom)
2021-2024
Human Technopole
2023-2024
University College London
2013-2022
CRUK Lung Cancer Centre of Excellence
2017-2022
London Cancer
2017-2021
Cancer Institute (WIA)
2019
Great Ormond Street Hospital
2009-2017
Genomics England
2013
Garvan Institute of Medical Research
2012
Abstract Genetic and epigenetic variation, together with transcriptional plasticity, contribute to intratumour heterogeneity 1 . The interplay of these biological processes their respective contributions tumour evolution remain unknown. Here we show that genetic ancestry only infrequently affects gene expression traits subclonal in colorectal cancer (CRC). Using spatially resolved paired whole-genome transcriptome sequencing, find the majority variation is not strongly heritable but rather...
Abstract Colorectal malignancies are a leading cause of cancer-related death 1 and have undergone extensive genomic study 2,3 . However, DNA mutations alone do not fully explain malignant transformation 4–7 Here we investigate the co-evolution genome epigenome colorectal tumours at single-clone resolution using spatial multi-omic profiling individual glands. We collected 1,370 samples from 30 primary cancers 8 concomitant adenomas generated 1,207 chromatin accessibility profiles, 527 whole...
Abstract In cancer, evolutionary forces select for clones that evade the immune system. Here we analyzed >10,000 primary tumors and 356 immune-checkpoint-treated metastases using dN/dS, ratio of nonsynonymous to synonymous mutations in immunopeptidome, measure selection cohorts individuals. We classified as edited when antigenic were removed by negative escaped antigenicity was covered up aberrant modulation. Only immune-edited predation linked CD8 T cell infiltration. Immune-escaped...
Inflammatory bowel disease [IBD] presenting in early childhood is extremely rare. More recently, progress has been made to identify children with monogenic forms of IBD predominantly very life. In this study, we describe the heterogeneous phenotypes and genotypes patients before age 2 years establish phenotypic features associated underlying monogenicity.Phenotype data 62 onset over past 20 were reviewed. Children without previously established genetic diagnosis prospectively recruited for...
Aging is associated with reduced fitness and increased myeloid bias of the hematopoietic stem cell (HSC) compartment, causing risk immune compromise, anemia, malignancy. We show that mitochondrial membrane potential (MMP) can be used to prospectively isolate chronologically old HSCs transcriptional features functional attributes characteristic young HSCs, including a high rate transcription balanced lineage-affiliated programs. Strikingly, MMP stronger determinant quantitative qualitative...
Intellectual disability and cerebellar atrophy occur together in a large number of genetic conditions are frequently associated with microcephaly and/or epilepsy. Here we report the identification causal mutations Sorting Nexin 14 (SNX14) found seven affected individuals from three unrelated consanguineous families who presented recessively inherited moderate-severe intellectual disability, ataxia, early-onset atrophy, sensorineural hearing loss, distinctive association progressively...
Abstract The dominant mutational signature in colorectal cancer genomes is C > T deamination (COSMIC Signature 1) and, a small subgroup, mismatch repair signatures 6 and 44). Mutations common driver genes are often not consistent with those signatures. Here we perform whole-genome sequencing of normal colon crypts from patients, matched to previous multi-omic tumour dataset. We analyse that were distant vs adjacent the cancer. In contrast healthy individuals, patients have high incidence...
Abstract Patients with estrogen receptor–positive breast cancer receive adjuvant endocrine therapies (ET) that delay relapse by targeting clinically undetectable micrometastatic deposits. Yet, up to 50% of patients even decades after surgery through unknown mechanisms likely involving dormancy. To investigate genetic and transcriptional changes underlying tumor awakening, we analyzed late longitudinally profiled a rare cohort treated long-term neoadjuvant ETs until progression. Next,...
Pigmented hypertrichotic dermatosis with insulin-dependent diabetes (PHID) syndrome is a recently described autosomal recessive disorder associated predominantly antibody negative, mellitus. In order to identify the genetic basis of PHID and study its relationship glucose metabolism, we performed homozygosity mapping in five unrelated families followed by candidate gene sequencing. Five loss-of-function mutations were identified SLC29A3 which encodes member highly conserved protein family...
<h3>Background</h3> Multiple monogenetic conditions with partially overlapping phenotypes can present inflammatory bowel disease (IBD)-like intestinal inflammation. With novel genotype-specific therapies emerging, establishing a molecular diagnosis is becoming increasingly important. <h3>Design</h3> We have introduced targeted next-generation sequencing (NGS) technology as prospective screening tool in children very early onset IBD (VEOIBD). evaluated the coverage of 40 VEOIBD genes two...
<h3>Background</h3> Primary ciliary dyskinesia (PCD) is a rare, genetically heterogeneous ciliopathy disorder affecting cilia and sperm motility. A range of ultrastructural defects the axoneme underlie disease, which characterised by chronic respiratory symptoms obstructive lung infertility body axis laterality defects. We applied next-generation sequencing approach to identify gene responsible for this phenotype in two consanguineous families. <h3>Methods results</h3> Data from whole-exome...
ETV6-RUNX1 is associated with childhood acute B-lymphoblastic leukemia (cALL) functioning as a first-hit mutation that initiates clinically silent pre-leukemia in utero. Because lineage commitment hierarchies differ between embryo and adult, the impact of oncogenes cell-context dependent, we hypothesized affiliation cALL reflects its origins progenitor unique to embryonic life. We characterize first emerging B cells first-trimester human embryos, identifying developmentally restricted...
Abstract Both Tbx1 and retinoic acid (RA) are key players in embryonic pharyngeal development; loss of produces DiGeorge syndrome‐like phenotypes mouse models as does disruption homeostasis. We have demonstrated that perturbation levels the avian embryo altered expression. In vitamin A‐deficient quails, which lack endogenous acid, expression patterns were disrupted early development was subsequently lost all tissues. “Gain‐of‐function” experiments where RA‐soaked beads grafted into region...
It is believed that mouse dentition determined by a prepatterning of the oral epithelium into molar (proximal) and incisor (distal) regions. The LIM homeodomain protein Islet1 (ISL1) involved in regulation differentiation many cell types organs. During odontogenesis, we find to be exclusively expressed epithelial cells developing incisors but not during development. Early expression presumptive coincident with Bmp4, which acts induce Msx1 underlying mesenchyme. To define role ISL1...
HADH encodes for the enzyme 3-hydroxyacyl-coenzyme A dehydrogenase (HADH) and catalyses penultimate reaction in beta-oxidation of fatty acids. All previously reported patients with mutations gene hyperinsulinemic hypoglycemia (HH) showed raised plasma hydroxybutyrylcarnitine urinary 3-hydroxyglutarate.The aims study were: 1) to report a novel mutation not associated abnormal acylcarnitine or organic acid profile; 2) observation severe protein-sensitive HH three mutations.The index case...
Primary ovarian insufficiency (POI) is a distressing cause of infertility in young women. POI heterogeneous with only few causative genes having been discovered so far. Our objective was to determine the genetic consanguineous Lebanese family two affected sisters presenting primary amenorrhoea and an absence any pubertal development. Multipoint parametric linkage analysis performed. Whole-exome sequencing done on proband. Linkage identified locus chromosome 7 where exome successfully...
Abstract Kinase signaling fuels growth of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Yet its role in initiation is unclear and has not been shown primary human hematopoietic cells. We previously described activating mutations interleukin-7 receptor alpha (IL7RA) poor-prognosis “ph-like” BCP-ALL. Here we show that expression activated mutant IL7RA CD34 + stem progenitor cells induces a preleukemic state transplanted immunodeficient NOD/LtSz- scid IL2Rγ null mice, characterized...