Spatial transcriptomic analysis reveals coordinated gene expression in ovarian clear cell carcinoma and adjacent endometriosis in UK and Japanese patients

Abstract

PurposeOvarian clear cell carcinoma (OCCC) is strongly associated with endometriosis and shows geographic variation in incidence. We investigated whether OCCC and adjacent endometriosis exhibit distinct transcriptional states and whether these patterns differ between United Kingdom (UK) and Japanese cohorts. Experimental DesignWe performed whole-transcriptome spatial profiling on specimens from 16 OCCC cases (8 UK, 8 Japan) in which tumor and endometriosis were both present. Gene expression was analyzed in tumor, endometriosis and stroma. ARID1A status was assessed by immunohistochemistry. ResultsMedian age was 59 years (range 26-82). 13/16 cases (81.3%) had early-stage disease. Tissue compartment rather than cohort of origin was the dominant source of variation across endometriosis and tumor regions. Endometriosis was enriched for inflammatory and immune-related pathways compared to tumor, whilst there was greater representation of chromatin and protein-DNA complex assembly pathways in tumor regions. These patterns were conserved across both cohorts and after stratification by ARID1A status. Mesenchymal-associated gene expression scores also significantly differed across stroma, endometriosis and tumor with clear compartmental separation. Cell type deconvolution analyses showed clear compositional differences between stromal and epithelial disease compartments. ConclusionsOCCC and coexisting endometriosis are transcriptionally distinct, with the dominant contrast being compartmental rather than geographic. ARID1A alone is unlikely to account for the principal spatial transcriptional states identified here. Further analyses will be required to ascertain whether these differences reflect genuine biological differences between OCCC and coexisting endometriosis or represent different stages of endometriosis-associated tumorigenesis. Translational RelevanceOvarian clear cell carcinoma often arises in association with endometriosis, yet the biological transition between these lesions remains poorly understood. Using spatial transcriptomics in matched tumor and adjacent endometriosis from Japanese and UK cohorts, we showed that endometriosis is characterized by inflammatory and antigen-presentation features, whereas tumor regions showed chromatin-organization and oncogenic transcriptional states. These patterns were largely maintained irrespective of ARID1A status and geographic background. In addition, spatial deconvolution suggested differences in local immune composition, with tumor regions showing relatively greater neutrophil- and T cell-associated signals. Together, our data suggest that OCCC and coexisting endometriosis share a spatially linked tissue context, but that tumor regions have distinct transcriptional profile and microenvironment that may be involved in the malignant transformation and inform interpretation of molecular classification in endometriosis-associated OCCC.