Abstract Introduction: Ovarian clear cell carcinoma (OCCC) is the second most common histological subtype of epithelial ovarian cancer (EOC), accounting for 5–25% of cases, with higher prevalence in East Asian populations. A significant proportion (25–70%) of OCCC cases are associated with concurrent endometriosis (EMs), suggesting a potential pathogenic link. While EMs has historically been implicated in OCCC and endometrioid carcinoma development, emerging evidence points to shared genetic alterations and a possible endometrial epithelial origin. Here, we aimed to identify the cellular origin of OCCC using integrated multi-omics approaches. Methods: We performed single-cell RNA sequencing (scRNA-seq) on OCCC and healthy endometrium specimens and integrated these data with publicly available datasets to trace the putative cell-of-origin. Bulk RNA-seq analysis of OCCC, high-grade serous ovarian carcinoma, endometrioid uterine carcinoma, normal fallopian tube, and endometrium were used further validation. Flow cytometry and multiplex immunohistochemistry (mIHC) were employed to confirm the spatial-temporal distribution of candidate origin cells in endometrial organoids and human endometrial tissues. Results: scRNA-seq revealed transcriptional similarities between OCCC and endometrial lumenal cells. A cell-type classification model identified lumenal cells as the most probable origin of OCCC, a finding corroborated by bulk RNA-seq. Flow cytometry and mIHC confirmed the presence of lumenal cell populations in secretory-phase endometrium and hormone-treated endometrial organoids, supporting their potential as OCCC progenitors. Conclusion: Our study demonstrated that OCCC likely arises from endometrial lumenal cells, distinguishing it from other ovarian cancer subtypes. These findings provide new insights into OCCC pathogenesis and highlight potential targets for early detection and intervention. Citation Format: Can Cui, Michelle Kwan Yee. Siu, Runying Long, Lingshan Hung, Ruiqian Zhang, Stephanie Si. Liu, Tina Na. Wei, Xintong Li, Jianlin Li, Annie Nga-Yin. Cheung, Philip Chi Ngong. Chiu, William Shu Biu. Yeung, Kui Liu, Haonan Lu, Karen Kar Loen Chan. Elucidating the endometrial epithelial cell origin of ovarian clear cell carcinoma with integrated multi-omics analysis abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85 (18Suppl): Abstract nr A075.
Cui et al. (2025) studied this question.