Molecular evidence for a clonal relationship between synchronous uterine endometrioid carcinoma and ovarian clear cell carcinoma: a new example of "precursor escape"?

Synchronous endometrial and ovarian carcinomas (SEOCs) that share the same endometrioid histology are generally considered as the result of metastatic spread from one organ to another. However, SEOCs with different histologies are regarded as distinct primary lesions that arise independently from each other. This study was undertaken to compare the mutational landscape of SEOCs with different histologies to confirm or refute the hypothesis of an independent origin. Four patients with synchronous uterine endometrioid carcinoma (UEMC) and ovarian clear cell carcinoma (OCCC) were examined. UEMCs were accompanied by endometrial hyperplasia/endometrioid intraepithelial neoplasia, whereas endometriosis was evident in two cases. Paired UEMC and OCCC specimens were subjected to mutation analysis with massively parallel sequencing. Surprisingly, we found that 50% (2/4) of paired SEOCs with different histologies shared the same somatic mutations, some of which localized in cancer driver genes. Clonality analyses indicated that these tumors were clonally related to each other. Notably, 75% (3/4) of the study patients had Lynch syndrome. The cancer-specific survival figures of patients with synchronous UEMCs and OCCCs were more favorable than those observed in a historical cohort of patients with isolated stage 2/3 OCCCs. Taken together, we set forth a potential explanation that considers clonally related SEOCs as a result of “precursor escape” — whereby precursor cells of endometrial cancer spread beyond the uterus to reach the pelvis and eventually evolve into an OCCC under an increasing mutational burden. Key messages • SEOCs characterized by different histologies are rare. • All cases of SEOCs were accompanied by endometrial hyperplasia. • Fifty percent of SEOCs were clonally related to each other. • Shared mutations in cancer driver genes were evident among SEOCs. • Clonally related SEOCs may be a result of “precursor escape.” • Lynch syndrome is highly prevalent in patients with UEMC and synchronous OCCC. • The prognosis of synchronous UEMC and OCCC was favorable. Similar content being viewed by others

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We are grateful to Wei-Yang Chang and Jung-Erh Yang for their excellent technical assistance. We thank the members of the Division of Gynecology Oncology for their invaluable help with patient care. The authors acknowledge the statistical assistance provided by the Clinical Trial Center, Chang Gung Memorial Hospital, Linkou, Taiwan — which is funded by the Ministry of Health and Welfare of Taiwan (grant MOHW109-TDU-B-212-114005). Funding This study was financially supported by grants (CMRPG3H0353, CMRPG3J0411/3J0401, CRRPG3F0041/2/3, CMRPG3H1151/2) from the Chang Gung Foundation and the Ministry of Science and Technology (106-2314-B-182-053-MY2 and MOST108-2320-B-182-036-MY3). Author information Authors and Affiliations Contributions Conceptualization: [Ren-Chin Wu, Angel Chao], Methodology: [Cindy Hsuan Weng, Chin-Jung Wang, Hung-Hsueh Chou, An-Shine Chao, Chyong-Huey Lai], Formal analysis and investigation: [Ren-Chin Wu, Shu-Jen Chen, Hua-Chien Chen, Kien Thiam Tan, Yun-Shien Lee, Shih-Sin Huang, Lan-Yan Yang], Writing — original draft preparation: [Cindy Hsuan Weng, Ren-Chin Wu, Angel Chao]; Writing — review and editing: [Cindy Hsuan Weng, Ren-Chin Wu, Angel Chao], Funding acquisition: [Ren-Chin Wu, Angel Chao], Resources: [Shu-Jen Chen, Hua-Chien Chen, Kien Thiam Tan], Supervision: [Chyong-Huey Lai] Corresponding authors Ethics declarations Ethics approval and consent to participate Ethical approval was granted by the Institutional Review Board (IRB) of Chang Gung Memorial Hospital (IRB No. 201601562B0). Owing to the retrospective nature of the study, the IRB waived the need for written informed consent for retrieval of formalin-fixed paraffin-embedded tissues. Consent for publication Not applicable. Conflict of interest Shu-Jen Chen, Hua-Chien Chen, and Kien Thiam Tan are employees of ACT Genomics, Co. Ltd. All other authors have no conflicts of interest to declare. Additional information Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Supplementary Information ESM 1 (download XLSX ) (XLSX 43 kb) Rights and permissions About this article Cite this article Weng, C.H., Wu, RC., Chen, SJ. et al. Molecular evidence for a clonal relationship between synchronous uterine endometrioid carcinoma and ovarian clear cell carcinoma: a new example of “precursor escape”?. J Mol Med 99, 959–966 (2021). https://doi.org/10.1007/s00109-021-02064-4 Received: Revised: Accepted: Published: Version of record: Issue date: DOI: https://doi.org/10.1007/s00109-021-02064-4