Thomas J. Mitchell
A5087549268- Cancer Genomics and Diagnostics
- Renal cell carcinoma treatment
- Renal and related cancers
- Music Technology and Sound Studies
- Hippo pathway signaling and YAP/TAZ
- Ovarian cancer diagnosis and treatment
- Single-cell and spatial transcriptomics
- Cancer Mechanisms and Therapy
- Epigenetics and DNA Methylation
- RNA modifications and cancer
- CRISPR and Genetic Engineering
- Protein Degradation and Inhibitors
- Music and Audio Processing
- Evolution and Genetic Dynamics
- Multiple Myeloma Research and Treatments
- Microtubule and mitosis dynamics
- Radiomics and Machine Learning in Medical Imaging
- Chromosomal and Genetic Variations
- Speech and Audio Processing
- MRI in cancer diagnosis
- Advanced Breast Cancer Therapies
- Cancer, Hypoxia, and Metabolism
- Cancer-related molecular mechanisms research
- RNA and protein synthesis mechanisms
- Tactile and Sensory Interactions
University of Cambridge
2015-2025
Advisory Board Company (United States)
2024-2025
University of Oklahoma
2024-2025
Liverpool School of Tropical Medicine
2025
University Hospitals Bristol NHS Foundation Trust
2025
The University of Texas MD Anderson Cancer Center
2025
Cambridge University Hospitals NHS Foundation Trust
2018-2024
Wellcome Sanger Institute
2016-2024
University of Oxford
2003-2024
University of the West of England
2006-2024
Cancer develops through a process of somatic evolution
Messenger RNA encodes cellular function and phenotype. In the context of human cancer, it defines identities malignant cells diversity tumor tissue. We studied 72,501 single-cell transcriptomes renal tumors normal tissue from fetal, pediatric, adult kidneys. matched childhood Wilms with specific fetal cell types, thus providing evidence for hypothesis that are aberrant cells. carcinoma, we identified a canonical cancer transcriptome little-known subtype proximal convoluted tubular cell....
The evolutionary features of clear-cell renal cell carcinoma (ccRCC) have not been systematically studied to date. We analyzed 1,206 primary tumor regions from 101 patients recruited into the multi-center prospective study, TRACERx Renal. observe up 30 driver events per and show that subclonal diversification is associated with known prognostic parameters. By resolving patterns event ordering, co-occurrence, mutual exclusivity at clone level, we deterministic nature clonal evolution. ccRCC...
Clear cell renal carcinoma (ccRCC) is characterized by near-universal loss of the short arm chromosome 3, deleting several tumor suppressor genes. We analyzed whole genomes from 95 biopsies across 33 patients with clear carcinoma. find hotspots point mutations in 5′ UTR TERT, targeting a MYC-MAX-MAD1 repressor associated telomere lengthening. The most common structural abnormality generates simultaneous 3p and 5q gain (36% patients), typically through chromothripsis. This event occurs...
Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin, drivers ITH across cancer types are poorly understood. To address this, we extensively characterize whole-genome sequences 2,658 samples spanning 38 types. Nearly all informative (95.1%) contain evidence distinct subclonal expansions with frequent branching relationships between subclones. We observe positive selection driver mutations most...
Genomic havoc from one fateful mistake Many human tumors display scrambled genomes that arise two distinct mutational processes. The first, the chromosome breakage-fusion-bridge (BFB) cycle, produces gene amplification and genomic instability. second, chromothripsis, generates massive, clustered rearrangements in or a few chromosomes. Umbreit et al. hypothesized these processes are mechanistically related tested this idea by recreating essential steps of BFB cycle cultured cells (see...
Immune landscape of the human kidney Single-cell RNA sequencing has begun to shed light on full cellular diversity specific organs. However, these studies rarely examine organ-specific immune cells. Stewart et al. sequenced healthy adult and fetal samples at a single-cell level define heterogeneity in epithelial, myeloid, lymphoid From this dataset, they identified zonation cells, with relevance disease varied perturbations that occur different tumor settings. This profiling generates...
Abstract Age-related change in human haematopoiesis causes reduced regenerative capacity 1 , cytopenias 2 immune dysfunction 3 and increased risk of blood cancer 4–6 but the reason for such abrupt functional decline after 70 years age remains unclear. Here we sequenced 3,579 genomes from single cell-derived colonies haematopoietic cells across 10 subjects 0 to 81 age. Haematopoietic stem or multipotent progenitors (HSC/MPPs) accumulated a mean 17 mutations per year birth lost 30 base pairs...
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 The multiple myeloma (MM) genome is heterogeneous and evolves through preclinical post-diagnosis phases. Here we report a catalog hierarchy of driver lesions using sequences from 67 MM genomes serially collected 30 patients together with public exome datasets. Bayesian clustering defines at least 7 genomic subgroups distinct sets co-operating events. Focusing on whole sequencing data, complex structural events emerge as major drivers, including chromothripsis novel replication-based...
Abstract Mutations in fumarate hydratase (FH) cause hereditary leiomyomatosis and renal cell carcinoma 1 . Loss of FH the kidney elicits several oncogenic signalling cascades through accumulation oncometabolite 2 However, although long-term consequences loss have been described, acute response has not so far investigated. Here we generated an inducible mouse model to study chronology kidney. We show that leads early alterations mitochondrial morphology release DNA (mtDNA) into cytosol, where...
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...
Abstract Purpose: Although Src family kinase (SFK) inhibitors are now in clinical trials for the treatment of androgen-independent prostate cancer (AIPC), there no studies relating SFK activation to patient survival. This study was designed determine if up-regulated with development AIPC and patients could be selected who were more likely respond therapy. Experimental Design: A unique cohort matched tumor samples, taken before hormone deprivation therapy following relapse, used by...
A childhood tumor—from the beginning Many adult cancers arise from clonal expansions of mutant cells in normal tissue. These premalignant are defined by somatic mutations shared cancers. Whether pediatric originate a similar way is unknown. Coorens et al. studied Wilms tumor, kidney cancer. Phylogenetic analyses revealed large clones histologically and functionally tissue long before tumor development. Thus, like tumors, appears to bed. Science , this issue p. 1247
Purpose: Cyclin E1 (CCNE1) amplification is associated with primary treatment resistance and poor outcome in high-grade serous ovarian cancer (HGSC). Here, we explore approaches to target CCNE1-amplified cancers potential strategies overcome targeted agents.Experimental Design: To examine dependency on CDK2 HGSC, utilized siRNA conditional shRNA gene suppression, chemical inhibition using dinaciclib, a small-molecule inhibitor. High-throughput compound screening was used identify selective...
The evolution and progression of multiple myeloma its precursors over time is poorly understood. Here, we investigate the landscape timing mutational processes shaping in a large cohort 89 whole genomes 973 exomes. We identify eight processes, including signature caused by exposure to melphalan. Reconstructing chronological activity each signature, estimate that initial transformation germinal center B-cell usually occurred during first 2
Amplification of cyclin E1 (CCNE1) is associated with poor outcome in breast, lung, and other solid cancers, the most prominent structural variant primary treatment failure high-grade serous ovarian cancer (HGSC). We have previously shown that CCNE1-amplified tumors show amplicon-dependent sensitivity to CCNE1 suppression. Here, we explore targeting CDK2 as a novel therapeutic strategy cancers mechanisms resistance.We examined effect suppression using RNA interference small-molecule...