Biology subjects

Thomson, J. P.

Publications and source records attributed to Thomson, J. P..

5 recordsLinked to original sources

bioRxiv2025

Combined genomic and molecular analysis defines prognostic markers of relapse in stage IA-IC1 clear cell ovarian carcinoma

ObjectiveClear cell ovarian carcinoma (CCOC) is generally associated with a favourable prognosis, but up to 30% of low-stage cases relapse within five years. The benefit of adjuvant chemotherapy for low-stage CCOC (FIGO stage IA-IC1) remains uncertain. This study aimed to identify molecular and immune markers associated with relapse in a well-characterized CCOC cohort. MethodsUsing the Edinburgh Ovarian Cancer Database, we identified 85 CCOC cases. Targeted DNA sequencing assessed genomic alterations and tumour immune infiltration was evaluated using CD3 and CD8 immunohistochemistry on tissue microarrays. Tumours were stratified by stage (IA-IC1, IC2-II, III-IV), and both univariate and multivariate analysis applied for progression-free survival (PFS) included stage, age, genomic features, and immune markers. ResultsCommon genomic alterations included ARID1A (49%) and PIK3CA (42%) mutations, PIK3-AKT pathway perturbations (60%), and mismatch repair-related mutational signatures (25.9%). Genomic and molecular features were not significantly associated with tumour stage; however, low-stage tumours (IA-IC1) were enriched in CD3+ (40% cases) and CD8+ (29% cases) tumour-infiltrating lymphocytes (TILs) compared to higher-stage tumours (IC2-II: 13%/7%; III-IV: 9%/0% cases). In univariate analysis, low CD3+ TIL levels were significantly associated with reduced progression-free survival (HR = 4.4, P = 0.042, 95% CI 1.1-18). ARID1A wild-type status was linked to poorer PFS but only in low-stage tumours HR = 7.2, P = 0.088; 95% CI 0.74-72). Notably, the combination of ARID1A wild-type status and CD3+ depletion identified a high-risk subgroup among low-stage CCOC cases (HR = 11.7, P = 0.050; 95% CI 1-138), highlighting potential as a composite risk marker set. ConclusionsCombined ARID1A mutation and low CD3+ve TIL levels are suggestive of higher recurrence risk in low-stage CCOC patients. These findings support further investigation of targeted therapies or immune checkpoint inhibitors in larger CCOC cohorts. HighlightsO_LIWe report a well-characterized CCOC cohort with rich clinical, genomic and molecular data. C_LIO_LICommon mutations included ARID1A (49%) and PIK3CA (42%), with MSI in 9%, showing no significant enrichment across tumour stages. C_LIO_LILow-stage CCOC has higher levels of CD3+ & CD8+ tumour infiltrating leukocytes than in advanced-stage disease. C_LIO_LIARID1A wild-type tumours with CD3+ TIL depletion represent a high-risk subgroup of low-stage CCOC. C_LIO_LIFindings support further study and highlight potential markers for recurrence risk. C_LI

cancer biology↗

bioRxiv2024

Divergent trajectories to structural diversity impact patient survival in high grade serous ovarian cancer

Deciphering the structural variation across tumour genomes is crucial to determine the events driving tumour progression and better understand tumour adaptation and evolution. High grade serous ovarian cancer (HGSOC) is an exemplar tumour type showing extreme, but poorly characterised structural diversity. We comprehensively describe the mutational landscape driving HGSOC, exploiting a large (N=324), deeply whole genome sequenced dataset. We reveal two divergent evolutionary trajectories, affecting patient survival and involving differing genomic environments. One involves homologous recombination repair deficiency (HRD) while the other is dominated by whole genome duplication (WGD) with frequent chromothripsis, breakage-fusion-bridges and extra-chromosomal DNA. These trajectories contribute to structural variation hotspots, containing novel candidate driver genes with significantly altered expression. While structural variation predominantly drives tumorigenesis, we also find high mtDNA mutation loads associated with shorter patient survival, and acting in combination with alterations in the nuclear genome to impact prognosis and suggesting new strategies for patient stratification.

cancer biology↗

bioRxiv2020

Macrovesicular steatosis in nonalcoholic fatty liver disease is a consequence of purine nucleotide cycle driven fumarate accumulation

SummaryNonalcoholic fatty liver disease (NAFLD) affects ~88% of obese individuals and is characterised by hepatic lipid accumulation. Mitochondrial metabolic dysfunction is a feature of NAFLD. We used a human pluripotent stem cell-based system to determine how mitochondrial dysfunction is linked to hepatic lipid accumulation. We induced lipid accumulation in hepatocyte-like cells (HLCs) using lactate, pyruvate and octanoate (LPO). Transcriptomic analysis revealed perturbation of mitochondrial respiratory pathways in LPO exposed cells. Using 13C isotopic tracing, we identified truncation of the TCA cycle in steatotic HLCs. We show that increased purine nucleotide cycle (PNC) activity fuels fumarate accumulation and drives lipid accumulation in steatotic cells. These findings provide new insights into the pathogenesis of hepatic steatosis and may lead to an improved understanding of the metabolic and transcriptional rewiring associated with NAFLD.Competing Interest StatementProfessor David Hay is a founder, shareholder and director in Stemnovate Limited.View Full Text

biochemistry↗

bioRxiv2019

DNA methylation directs polycomb-dependent 3D genome re- organisation in naive pluripotency

The DNA hypomethylation that occurs when embryonic stem cells (ESCs) are directed to the ground state of naive pluripotency by culturing in 2i conditions results in redistribution of polycomb (H3K27me3) away from its target loci. Here we demonstrate that 3D genome organisation is also altered in 2i. We found chromatin decompaction at polycomb target loci as well as loss of long-range polycomb interactions. By preventing DNA hypomethylation during the transition to the ground-state, we are able to restore the H3K27me3 distribution, and polycomb-mediated 3D genome organisation that is characteristic of primed ESCs grown in serum, to ESCs in 2i. However, these cells retain the functional characteristics of 2i ground state ESCs. Our findings demonstrate the central role of DNA methylation in shaping major aspects of 3D genome organisation but caution against assuming causal roles for the epigenome and 3D genome in gene regulation and function in ESCs.

cell biology↗

bioRxiv2017

Methyl donor deficient diets cause distinct alterations in lipid metabolism but are poorly representative of human NAFLD

Non-alcoholic fatty liver disease (NAFLD) is a global health issue. Dietary methyl donor restriction is used to induce a NAFLD/non-alcoholic steatohepatitis (NASH) phenotype in rodents, however the extent to which this model reflects human NAFLD remains incompletely understood. To address this, we undertook hepatic transcriptional profiling of methyl donor restricted rodents and compared these to published human NAFLD datasets.\n\nAdult C57BL/6J mice were maintained on control, choline deficient (CDD) or methionine/choline deficient (MCDD) diets for four weeks; the effects on methyl donor and lipid biology were investigated by bioinformatic analysis of hepatic gene expression profiles followed by a cross-species comparison with human expression data of all stages of NAFLD.\n\nCompared to controls, expression of the very low density lipoprotein (VLDL) packaging carboxylesterases (Ces1d, Ces1f, Ces3b) and the NAFLD risk allele Pnpla3 were suppressed in MCDD; with Pnpla3 and the liver predominant Ces isoform, Ces3b, also suppressed in CDD. With respect to 1-carbon metabolism, down-regulation of Chka, Chkb, Pcty1a, Gnmt and Ahcy with concurrent upregulation of Mat2a suggests a drive to maintain S-adenosylmethionine levels. There was minimal similarity between global gene expression patterns in either dietary intervention and any stage of human NAFLD, however some common transcriptomic changes in inflammatory, fibrotic and proliferative mediators were identified in MCDD, NASH and HCC.\n\nIn conclusion, this study suggests suppression of VLDL assembly machinery may contribute to hepatic lipid accumulation in these models, but that CDD and MCDD rodent diets are minimally representative of human NAFLD at the transcriptional level.\n\nSummary statementWe used transcriptional profiling of methyl donor restricted rodents to examine effects on methyl donor and lipid biology. We report novel mechanisms for lipid accumulation in this model and describe significant disparity between both dietary interventions and human disease.

molecular biology↗