Biology subjects

Gourley, C.

Publications and source records attributed to Gourley, C..

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

Structural variants at the BRCA1/2 loci are a common source of homologous repair deficiency in high grade serous ovarian carcinoma

Around half of high grade serous ovarian carcinomas (HGSOC) show homologous recombination repair deficiency (HRD), often caused by germline or somatic single nucleotide variant (SNV) mutations or small indels disrupting BRCA1/2. We have uniformly processed the largest collection of whole genome sequencing (WGS) data from HGSOC samples to date (N=205), comprehensively characterising the somatic mutational landscape, and expression at the BRCA1/2 loci. We discover that large structural variants (SV) are a frequent but unappreciated source of BRCA1/2 disruption in these tumours. Somatic structural variation at these loci is dominated by multi-megabase deletions that span the entirety of BRCA1 (median = 4.9Mb) or BRCA2 (median = 6.2Mb), independently affecting a substantial proportion of patients (16%) in addition to those affected by damaging germline or somatic short variants, within the BRCA1/2 coding sequences (24%). In common with previous studies, we show that the presence of damaging somatic SNVs or short indels in BRCA1 (OR=10, 95% CI 1.8-103, p=0.002, adj p=0.027 and BRCA2 (OR=17, 95% CI 2.1-816), p=0.002, adj.p=0.021) was found to influence HRD. For the first time we also study the compound effect of SV and SNV or short indel mutations at both loci, demonstrating that SVs often contribute to compound deficiencies involving SNVs or indels, with large somatic deletions contributing to these compound deficiencies in 15/205 (7%) of samples. Notably the strongest risk of HRD (OR=19 (2.4-896), p=6.6x10-3, adj P=8.5x10-3) is generated by combined large deletions at BRCA1 and BRCA2 in the absence of SNVs or indels, affecting 3% of patients. Overall, we show that HRD is a complex phenotype in HGSOC tumours, affected by the patterns of shorter variants such as SNVs and indels, SVs, methylation and expression seen at multiple loci, and we construct a successful (ROC AUC = 0.75) predictive model of HRD using such variables. In addition, HRD impacts patient survival when conferred by mechanisms other than through the well-understood short variants at BRCA1/2, currently exploited in the clinic. These results alter our understanding of the mutational landscape at the BRCA1/2 loci in highly rearranged tumours, and increase the number of patients predicted to benefit from therapies exploiting HRD in tumours such as PARP inhibition.

cancer biology↗

bioRxiv2019

Infection-driven activation of transglutaminase 2 boosts glucose uptake and hexosamine biosynthesis

Transglutaminase 2 (TG2) is a ubiquitous enzyme with transamidating activity. We report here that the expression and activity of TG2 are enhanced in cells infected with the obligate intracellular bacteria Chlamydia trachomatis. Genetic or pharmacological inhibition of TG2 activity impair bacterial development. We show that TG2 increases glucose import by up-regulating the transcription of the glucose transporter genes GLUT-1 and GLUT-3. Furthermore, TG2 activation drives one specific glucose-dependent pathway in the host, i.e. hexosamine biosynthesis. Mechanistically, we identify the glucosamine:fructose-6-phosphate amidotransferase (GFPT) among the substrates of TG2. GFPT modification by TG2 increases its enzymatic activity, resulting in higher levels of UDP-N-acetylglucosamine biosynthesis. As a consequence, TG2 activation results in increased protein O-GlcNAcylation. The correlation between TG2 transamidating activity and O-GlcNAcylation is disrupted in infected cells because host hexosamine biosynthesis is being exploited by the bacteria, in particular to assist their division. In conclusion, our work establishes TG2 as a key player in controlling glucose-derived metabolic pathways in mammalian cells, themselves hijacked by C. trachomatis to sustain their own metabolic needs.

microbiology↗

bioRxiv2017

Copy-number signatures and mutational processes in ovarian carcinoma

Tumours with profound copy-number aberration elude molecular stratification due to their genomic complexity. By representing this complexity as a mixture of copy-number signatures, we provide molecular explanations for differing clinical outcomes. Here we present a method for copy-number signature identification, deriving eight signatures in 117 shallow whole-genome sequenced high-grade serous ovarian cancers (HGSOC), which validated on independent cohorts of 95 deep whole-genome sequenced, and 402 SNP array-profiled cases. Three copy-number signatures predicted longer overall survival, while the others predicted poorer outcome. We found evidence for the mutational processes giving rise to copy-number change for six of the eight signatures via correlations with other genomic features. Our results provide insights into the pathogenesis of HGSOC by uncovering multiple mutational processes that shape genomes following TP53 mutation. Importantly, our work shows that most HGSOC have a mixture of mutational processes suggesting that targeting a single mutator phenotype may be therapeutically suboptimal.

cancer biology↗