Henry Lee-Six
A5038294012- Cancer Genomics and Diagnostics
- Genetic factors in colorectal cancer
- Colorectal Cancer Treatments and Studies
- Lung Cancer Treatments and Mutations
- Radiomics and Machine Learning in Medical Imaging
- Cancer Immunotherapy and Biomarkers
- Epigenetics and DNA Methylation
- Colorectal Cancer Screening and Detection
- Nutrition, Genetics, and Disease
- Renal and related cancers
- Genomics and Rare Diseases
- DNA Repair Mechanisms
- Ferroptosis and cancer prognosis
- RNA modifications and cancer
- Cancer-related molecular mechanisms research
- Acute Myeloid Leukemia Research
- Genomics and Phylogenetic Studies
- Single-cell and spatial transcriptomics
- Evolution and Genetic Dynamics
- Bioinformatics and Genomic Networks
- Genomics and Chromatin Dynamics
- Chromosomal and Genetic Variations
- Esophageal Cancer Research and Treatment
- Immunotherapy and Immune Responses
- Diet and metabolism studies
Wellcome Sanger Institute
2017-2025
Cambridge University Hospitals NHS Foundation Trust
2024-2025
University of Cambridge
2024
Cancer develops through a process of somatic evolution
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...
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...
Inflammatory bowel disease (IBD) is a chronic inflammatory associated with increased risk of gastrointestinal cancers. We whole-genome sequenced 446 colonic crypts from 46 IBD patients and compared these to 412 41 non-IBD controls our previous publication on the mutation landscape normal colon. The average rate affected epithelial cells 2.4-fold that healthy colon, this increase mostly driven by acceleration mutational processes ubiquitously observed in In contrast where clonal expansions...
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...
Abstract Before squamous cell lung cancer develops, precancerous lesions can be found in the airways. From longitudinal monitoring, we know that only half of such become cancer, whereas a third spontaneously regress. Although recent studies have described presence an active immune response high-grade lesions, mechanisms underpinning clinical regression remain unknown. Here, show host surveillance is strongly implicated lesion regression. Using bronchoscopic biopsies from human subjects, find...
Abstract Cellular DNA damage caused by reactive oxygen species is repaired the base excision repair (BER) pathway which includes glycosylase MUTYH. Inherited biallelic MUTYH mutations cause predisposition to colorectal adenomas and carcinoma. However, mechanistic progression from germline MUTYH-Associated Polyposis (MAP) incompletely understood. Here, we sequence normal tissue DNAs 10 individuals with MAP. Somatic substitution mutation rates in intestinal epithelial cells were elevated 2...
Abstract APOBEC mutational signatures SBS2 and SBS13 are common in many human cancer types. However, there is an incomplete understanding of its stimulus, when it occurs the progression from normal to cell enzymes responsible. Here we whole-genome sequenced 342 microdissected epithelial crypts small intestines 39 individuals found that SBS2/SBS13 mutations were present 17% crypts, more frequent than most other tissues. Crypts with often had immediate crypt neighbors without SBS2/SBS13,...
Several risk factors have been established for colorectal cancer, yet their direct mutagenic effects in patients' tumors remain to be elucidated. Here, we leveraged whole-exome sequencing data from 900 cancer cases that had occurred three U.S.-wide prospective studies with extensive dietary and lifestyle information. We found an alkylating signature was previously undescribed then showed the existence of a similar mutational process normal colonic crypts. This is associated high intakes...
Abstract Lynch Syndrome (LS) is an autosomal dominant disease conferring a high risk of colorectal cancer due to germline heterozygous mutations in DNA mismatch repair (MMR) gene. Although cancers LS patients show elevated somatic mutation burdens, information on rates normal tissues and understanding the trajectory from cell limited. Here we whole genome sequence 152 crypts neoplastic epithelial 10 patients. In repertoire mutational processes similar that found wild type individuals. A...
Abstract We present SVclone, a computational method for inferring the cancer cell fraction of structural variant (SV) breakpoints from whole-genome sequencing data. SVclone accurately determines allele frequencies both SV breakends, then simultaneously estimates and copy number. assess performance using in silico mixtures real samples, at known proportions, created two clonal metastases same patient. find that SVclone’s is comparable to single-nucleotide variant-based methods, despite having...
Abstract The type and genomic context of cancer mutations depend on their causes. These causes have been characterized using signatures that represent mutation types co-occur in the same tumours. However, it remains unclear how processes change during evolution due to lack reliable methods reconstruct evolutionary trajectories mutational signature activity. Here, as part ICGC/TCGA Pan-Cancer Analysis Whole Genomes (PCAWG) Consortium, which aggregated whole-genome sequencing data from 2658...
Abstract The colorectal adenoma-carcinoma sequence has provided a paradigmatic framework for understanding the successive somatic genetic changes and consequent clonal expansions leading to cancer. As most cancer types, however, of earliest phases neoplastic change, which may occur in morphologically normal tissue, is comparatively limited because difficulty detecting mutations cells. Each crypt small clone cells derived from single recently-existing stem cell. Here, we whole genome...
<div>Abstract<p>Approximately 10% of children with cancer harbor a mutation in predisposition gene. In the kidney Wilms tumor, prevalence is as high 30%. Certain predispositions are associated defined histological and clinical features, suggesting differences tumorigenesis. To investigate this, we assembled cohort 137 whom 71 had pathogenic germline or mosaic variant. We examined 237 neoplasms (including two secondary leukemias), utilizing whole-genome sequencing, RNA genome-wide...
<p>Contains Supplementary Figures 1-9. Figure 1 shows age of diagnosis children and indel burden rearrangement for tumours from predisposed versus those with sporadic disease. 2 genomic evidence novel predispositions. 3 global methylation patterns. 4 differential gene expression. 5 mutational signatures. 6 histological subtypes across predispositions somatic drivers. 7 polyclonal clonal enrichment 11p LOH in normal kidneys. 8 phylogenies multiple neoplasms either WT1 or TRIM28 9 non...