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Nuclear atypia is one of hallmarks in LMS, however, it also occurs in 2 clinically benign variants, including smooth muscle tumors with fumarate hydratase alteration (SMT\u2010FH) and leiomyoma with bizarre nuclei (LM\u2010BN). In addition to nuclear atypia, many well recognized biomarkers used for LMS are also frequently overexpressed in LM\u2010BN, and the histogenesis and molecular natures for LM\u2010BN and LMS remain largely unknown. To characterize the molecular profiling of LMS, SMT\u2010FH, and LM\u2010BN, we performed integrated comprehensive genomic profiling including whole\u2010genome sequencing (WGS) and RNA sequencing and genomic microarray analyses to assess genome\u2010wide copy number alterations (CNAs) and immunohistochemistry (IHC) in all 3 tumor types. We found that both LM\u2010BN and LMS showed genomic instability and harbored extensive CNAs throughout the whole genome. By contrast, the SMT\u2010FH presented its characteristic 1q43\u201044 deletions in all cases tested, with minimal CNAs in the rest of genomic regions. Further analyses revealed that LMS and LM\u2010BN groups showed similar patterns of CNAs that are tended to cluster together and separated from the SMT\u2010FH group. The integrated molecular profiling enabled the detection of novel and traditional biomarkers and showed excellent discrimination between LM\u2010BN and LMS. Our study suggests that LM\u2010BN, despite having similar nuclear atypia to SMT\u2010FH, showed similar genomic instability but distinct genomic alterations with its malignant counterpart of LMS. The integrated molecular profiling is of clinical importance in characterizing these rare uterine smooth muscle tumors.<\/jats:p>","DOI":"10.1111\/cas.14775","type":"journal-article","created":{"date-parts":[[2020,12,18]],"date-time":"2020-12-18T21:41:31Z","timestamp":1608327691000},"page":"2046-2059","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Integrated histologic and molecular analysis of uterine leiomyosarcoma and 2 benign variants with nuclear atypia"],"prefix":"10.1111","volume":"112","author":[{"given":"Tingting","family":"Gao","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology General Hospital Ningxia Medical University Ningxia China"},{"name":"Department of Pathology Northwestern University Feinberg School of Medicine Chicago IL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian 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