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Rye, T.

Publications and source records attributed to Rye, T..

2 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↗
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↗