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

Kuroda T, Takafumi Kuroda, Gaia Giannone, Giannone G, Darren Ennis, Hasan Mirza, Daniel Marks, Marks D, Louis Flood, Flood L, Sisley M, Mary Sisley, Ryan Griffin, Griffin R, Desai S, S. Desai, McDermott J, Jacqueline McDermott, Lambie N, Nathalie Lambie, Nei Fukasawa, Fukasawa N, Takako Kiyokawa, Kiyokawa T, Masayuki Shimoda, Shimoda M, Saito M, Misato Saito, Takuhiro Koba, Koba T, Ryosuke Saito, Saito R, Kawabata A, Ayako Kawabata, Takenaka M, Masataka Takenaka, Valabrega G, Giorgio Valabrega, Nik Matthews, Matthews N, Laura A. Tookman, Tookman LA, Nozomu Yanaihara, Yanaihara N, Aikou Okamoto, Okamoto A, Iain A. McNeish
In: bioRxiv · 2026 · doi:10.64898/2026.05.29.728698 · W7163144110
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Spatial transcriptomic analysis of ovarian clear cell carcinoma and adjacent endometriosis in UK and Japanese patients revealed distinct, conserved transcriptional states between tumor and endometriosis, dominated by compartmental rather than geographic differences.

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This study used whole-transcriptome spatial transcriptomics on matched specimens from 16 ovarian clear cell carcinoma cases with adjacent endometriosis (8 from the UK and 8 from Japan) to profile gene expression in tumor, endometriosis, and stroma, with ARID1A status assessed by immunohistochemistry. Across cases, tissue compartment rather than geographic cohort explained most transcriptional variation: endometriosis regions were enriched for inflammatory and immune-related pathways, while tumor regions showed greater representation of chromatin and protein–DNA complex assembly pathways, with mesenchymal-associated scores also separating across compartments. Cell-type deconvolution indicated distinct stromal versus epithelial compositional differences and relatively higher neutrophil- and T cell-associated signals in tumor regions; these patterns were largely conserved across cohorts and after stratification by ARID1A status. The authors note that further analyses are needed to determine whether observed differences reflect genuine biological divergence between OCCC and coexisting endometriosis or differences in endometriosis-associated tumorigenesis stage. This paper is centrally about endometriosis—matched spatially resolved transcriptomic comparisons of adjacent endometriosis and ovarian clear cell carcinoma to characterize their distinct inflammatory/immune versus tumor chromatin/oncogenic states.

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Abstract

Abstract Purpose Ovarian 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 Design We 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. Results Median 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. Conclusions OCCC 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 Relevance Ovarian 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.
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Abstract

Purpose Ovarian 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 Design We 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.

Results

Median 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.

Conclusions

OCCC 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 Relevance Ovarian 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. Competing Interest Statement GG reports fees as invited speaker for pharma_and, MIT and College SPA, all outside the scope of research reported in this manuscript. LAT reports advisory boards for AstraZeneca, Clovis Oncology, GSK; consulting fees and honoraria from AstraZeneca, Clovis Oncology, GSK, MSD, Pharma_and; travel and sponsorship from MSD, Pharma&, Abbvie, all outside the scope of research reported in this manuscript. IMcN reports advisory boards for GSK, pharma&, AstraZeneca, Abvie, Roche and BioNTech; honoraria and travel support from GSK, all outside the scope of research reported in this manuscript. All other authors report no conflicts of interest.

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