Abstract 3895: Clonal expansion in normal endometrium and its association with endometriosis-associated ovarian cancer
Authors: Koichi Watanabe, Nobuyuki Kakiuchi, Kosuke Ieiri, Maeda Hirona, Tomonori Hirano, Mana Taki, Koji Yamanoi, Ryusuke Murakami, Ken Yamaguchi, Junzo Hamanishi, Masaki Mandai, Seishi Ogawa
Journal: Cancer Research (2025)

[Introduction] Recent studies have revealed pervasive mutations affecting cancer-related genes in many normal tissues, including the endometrium, suggesting their role in cancer development. Endometriosis-associated ovarian cancer (EAOC) is thought to develop from endometriosis lesions seeded from endometrium to the ovary, although no solid evidence supports this. In this study, we sought to identify the clonal origin of EAOC by demonstrating ancestral clones of EAOC in the endometrium by detecting shared mutations between EAOC and endometrial clones. [Methods] We performed high-density sampling of endometrial tissues from 5 patients diagnosed with EAOC (5-32 sample/patient, 78 samples in total) and performed whole exome sequencing, and compared the somatic mutations with those of the EAOC tumors from the same patients. [Results] The median number of somatic mutations in endometrial samples was 29/sample (range 6-74). In 74 of 78 endometrial samples (95%), one or more of known driver gene mutations such as PIK3CA, PIK3R1, KRAS, PPP2R1A, ARHGAP35 and FBXW7 were identified, with an average of 2.3/sample (range 0-6). PIK3CA mutations were the most common, identified in 42 of 78 samples (54%), followed by ARHGAP35 mutations (25/78, 32%). Some of the adjacent endometrial samples shared multiple mutations, including driver mutations, indicating large clonal expansion over several millimeters. In one case with clear cell carcinoma in a 74-year-old woman, one of 32 endometrial samples shared 16 somatic mutations, including those affecting PTEN, PIK3CA, KRAS and FOXA2, with the ovarian tumor, indicating that this ovarian tumor originated from the endometrium. We confirmed that this endometrial tissue was histologically normal. Based on the phylogenetic analysis using whole genome sequencing, the most recent cancer founder was estimated to have diverged from the normal endometrial clones at approximately 20 years of age. No additional driver alterations were acquired in the main trunk except for multiple copy number alterations, suggesting their role in the progression from precancer to cancer. [Conclusion] We demonstrated that at least some EAOC tumors originate from an ancestor in the endometrium, in which a number of driver events are acquired to contribute to carcinogenesis. Our findings provide new insight into early events during the development of EAOC. Citation Format: Koichi Watanabe, Nobuyuki Kakiuchi, Kosuke Ieiri, Maeda Hirona, Tomonori Hirano, Mana Taki, Koji Yamanoi, Ryusuke Murakami, Ken Yamaguchi, Junzo Hamanishi, Masaki Mandai, Seishi Ogawa. Clonal expansion in normal endometrium and its association with endometriosis-associated ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3895.