Abstract IntroductionRecent studies have revealed pervasive mutations in cancer-related genes within many normal tissues, including the endometrium. Endometriosis-associated ovarian cancer (EAOC) is hypothesized to arise from endometriotic lesions seeded from the endometrium to the ovary, although direct evidence supporting this origin has been lacking. This study aimed to identify the clonal origin of EAOC in the endometrium by detecting shared somatic mutations between EAOC tumors and endometrial clones. MethodsWe performed high-density sampling of histologically normal endometrial tissues from 6 patients diagnosed with EAOC (5-32 sample/patient, 84 samples in total) and conducted whole-exome sequencing. The resulting somatic mutation profiles were compared with those of the matched EAOC tumors from the same patients. ResultsEndometrial samples harbored a median of 28.5 (range 6-74) somatic mutations. In 78 of 84 histologically normal endometrial samples (93%), one or more of known driver gene mutations involving PIK3CA, PIK3R1, KRAS, PPP2R1A, ARHGAP35 and FBXW7 were identified, with an average of 2.4 mutations/sample (range 0-7). PIK3CA mutations were the most common, detected in 44 of 84 samples (52%), followed by ARHGAP35 mutations (25/84, 30%). Notably, in two cases, we identified an endometrial sample sharing multiple somatic mutations with the EAOC tumors. In Case 1 (74 y/o, ovarian clear cell carcinoma), one of 32 endometrial samples shared 16 mutations with the tumor, including alterations in PTEN, PIK3CA, and KRAS. In Case 2 (31 y/o, bilateral ovarian endometrioid carcinoma), one of 6 endometrial samples shared 11 mutations with the tumor, including in PIK3CA, AKT1, PPP2R1A and CTNNB1. Phylogenetic analysis using whole-genome sequencing estimated that the most recent common ancestor of the cancer diverged from the normal endometrial clone in their early 20s in both cases. In Case 1, the tumor acquired additional copy number alterations not present in the endometrial ancestor, suggesting their potential role in carcinogenesis. By contrast, in Case 2 no clear genetic differences were detected between the ancestral endometrial clone and the ovarian tumor, suggesting that the transition from normal tissue to cancer may be driven by non-genetic events. ConclusionWe demonstrated that at least some EAOC tumors originate from an ancestral clone in the histologically normal endometrium. This ancestral clone had already acquired multiple driver events contributing to carcinogenesis. Our findings provide new insights into the early events underlying EAOC development. Citation Format: Koichi Watanabe, Nobuyuki Kakiuchi, Kosuke Ieiri, Hirona Maeda, Tomonori Hirano, Mana Taki, Koji Yamanoi, Ryusuke Murakami, Masaki Mandai, Seishi Ogawa, . Identification of the clonal origin of endometriosis-associated ovarian cancer in normal endometrium abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3529.
Watanabe et al. (Fri,) studied this question.