{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T23:39:42Z","timestamp":1785281982569,"version":"3.55.0"},"reference-count":30,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T00:00:00Z","timestamp":1760572800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Catholic Medical Center Research Foundation in the program year of 2020"},{"name":"IITP (Institute of Information and Communications Technology Planning and Evaluation)-ICAN","award":["IITP-2025-RS-2024-00438263"],"award-info":[{"award-number":["IITP-2025-RS-2024-00438263"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background\/Objectives: Uterine leiomyomas (ULs) and breast fibroadenomas (FAs) are the most common benign tumors in women, both arising in hormone-responsive mesenchymal tissues and often co-occurring during reproductive years. Despite their shared hormonal sensitivity and frequent MED12 mutations, their downstream molecular evolution remains poorly characterized. This study aimed to investigate whether ULs and FAs, though initiated by similar genetic alterations, diverge in their oncogenic trajectories, thereby addressing the molecular basis for their distinct clinical behaviors. Methods: We performed whole-exome sequencing (WES) on 15 uterine leiomyomas and 7 publicly available fibroadenomas with matched normal controls to compare somatic mutations, copy number alterations (CNAs), and mutational signatures. All UL samples were derived from Korean patients who underwent surgical treatment at a tertiary hospital between 2017 and 2019. Somatic variants were analyzed using MuTect2 and Strelka2. FACETS was used to estimate copy number changes in individual samples, and GISTIC2 to identify recurrent and statistically significant copy number alterations across patient cohorts. Mutational processes were inferred using SigProfiler. Microsatellite instability status was determined with MSIsensor2. The study was approved by the Institutional Review Board (UC17SNSI0092). Results: Comparative whole-exome sequencing of 15 ULs and 7 FAs from matched tumor-normal samples in an East Asian cohort confirmed both tumor types harbor identical MED12 p.G44D mutations, establishing shared molecular initiation. However, post-initiation evolution diverged dramatically: ULs exhibited chromosomal instability with 15 copy number amplifications, 6 of which affected oncogenes, but relatively modest point mutations. In contrast, FAs remained chromosomally stable but hypermutated, harboring 1.47\u00d7 more variants than ULs despite lower tumor purity. Notably, one histologically benign FA harbored multiple loss-of-function mutations plus an EGFR gain-of-function mutation typically associated with malignant breast cancer, challenging traditional benign-malignant classifications. Conclusions: Despite sharing a common initiating mutation in MED12, ULs and FAs evolve through fundamentally distinct genomic pathways. UL evolves through chromosomal instability, whereas FA evolves through a mutator phenotype, with important implications for understanding tumor biology and molecular-based risk stratification. These findings support a paradigm of tissue-specific oncogenic evolution and underscore the potential clinical utility of genomic profiling in distinguishing benign tumors with atypical molecular features.<\/jats:p>","DOI":"10.3390\/jcm14207325","type":"journal-article","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T11:39:34Z","timestamp":1760701174000},"page":"7325","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Tissue-Specific Genomic Evolution Despite Shared MED12 Mutations in Benign Tumors"],"prefix":"10.3390","volume":"14","author":[{"given":"Jeong","family":"Namkung","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Eunpyeong St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, 1021 Tongil-ro, Eunpyeong-gu, Seoul 03312, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang Ho","family":"Park","sequence":"additional","affiliation":[{"name":"Clinical Research Laboratory, Uijeongbu St. Mary\u2019s Hoapital, The Catholic University of Korea, 271 Cheonbo-ro, Uijeongbu-si 11765, Gyeonggi-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayoung","family":"Hwang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Korea University College of Medicine, 73 Goryeodae-ro, Seongbuk-gu, Seoul 02841, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5900-8395","authenticated-orcid":false,"given":"Hae","family":"Seo","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Korea University College of Medicine, 73 Goryeodae-ro, Seongbuk-gu, Seoul 02841, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9001-6388","authenticated-orcid":false,"given":"Jooyoung","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Korea University College of Medicine, 73 Goryeodae-ro, Seongbuk-gu, Seoul 02841, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3569-4351","authenticated-orcid":false,"given":"Moonyoung","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Korea University College of Medicine, 73 Goryeodae-ro, Seongbuk-gu, Seoul 02841, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyunkyung","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Uijeongbu St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, 271 Cheonbo-ro, Uijeongbu-si 11765, Gyeonggi-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8614-0973","authenticated-orcid":false,"given":"Jungmin","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Korea University College of Medicine, 73 Goryeodae-ro, Seongbuk-gu, Seoul 02841, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2167-7243","authenticated-orcid":false,"given":"Jae Yen","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Seoul St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Yuk, J.S., Yang, S.W., Yoon, S.H., Kim, M.H., Seo, Y.S., Lee, Y., Joo, Y., Kim, J., Yoon, S.Y., and Cho, H. 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