1. Integrated histologic and molecular analysis of uterine leiomyosarcoma and 2 benign variants with nuclear atypia
- Author
-
Serdar E. Bulun, Yanli Ban, Jian-Jun Wei, Ping Yin, Yinuo Li, Xinyan Lu, Brian S. Finkelman, Tingting Gao, and Chunfang Ha
- Subjects
Adult ,Leiomyosarcoma ,0301 basic medicine ,fumarate hydratase ,Cancer Research ,Pathology ,medicine.medical_specialty ,copy number alteration ,Microarray ,leiomyoma with bizarre nuclei ,Gene Dosage ,Histogenesis ,Biology ,Genome ,Necrosis ,03 medical and health sciences ,0302 clinical medicine ,Biomarkers, Tumor ,medicine ,Humans ,Nuclear atypia ,nuclear atypia ,Cell Nucleus ,Whole genome sequencing ,Principal Component Analysis ,Leiomyoma ,Sequence Analysis, RNA ,Gene Expression Profiling ,Muscle, Smooth ,Original Articles ,General Medicine ,Middle Aged ,medicine.disease ,030104 developmental biology ,Oncology ,Tissue Array Analysis ,030220 oncology & carcinogenesis ,Uterine Neoplasms ,gene expression ,Immunohistochemistry ,Original Article ,Female ,Gene Deletion - Abstract
Uterine leiomyosarcoma (LMS) is a rare but deadly disease. Due to poor understanding of the molecular and genetic causes of the disease, the diagnosis of LMS has been based primarily on histology. 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‐FH) and leiomyoma with bizarre nuclei (LM‐BN). In addition to nuclear atypia, many well recognized biomarkers used for LMS are also frequently overexpressed in LM‐BN, and the histogenesis and molecular natures for LM‐BN and LMS remain largely unknown. To characterize the molecular profiling of LMS, SMT‐FH, and LM‐BN, we performed integrated comprehensive genomic profiling including whole‐genome sequencing (WGS) and RNA sequencing and genomic microarray analyses to assess genome‐wide copy number alterations (CNAs) and immunohistochemistry (IHC) in all 3 tumor types. We found that both LM‐BN and LMS showed genomic instability and harbored extensive CNAs throughout the whole genome. By contrast, the SMT‐FH presented its characteristic 1q43‐44 deletions in all cases tested, with minimal CNAs in the rest of genomic regions. Further analyses revealed that LMS and LM‐BN groups showed similar patterns of CNAs that are tended to cluster together and separated from the SMT‐FH group. The integrated molecular profiling enabled the detection of novel and traditional biomarkers and showed excellent discrimination between LM‐BN and LMS. Our study suggests that LM‐BN, despite having similar nuclear atypia to SMT‐FH, 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., Leiomyosarcoma and 2 benign mimics (leiomyoma with FH alteration [SMT‐FH] and leiomyoma with bizarre nuclei [LM‐BN]) have characteristic nuclear atypia and often cause diagnostic challenge. LM‐BN and LMS are highly genomically unstable and harbor extensive CNAs in the genome, whereas SMT‐FH shows simple 1q43‐44 deletions. Integrated molecular profiling enabled the detection of novel and traditional biomarkers and showed excellent discrimination between LM‐BN and LMS.
- Published
- 2021
- Full Text
- View/download PDF