Genomic Insights into Uterine Leiomyomas: A Systematic Review of Whole-Genome and Whole- Exome Sequencing Studies

Background: Although hormonal factors modulate their growth, recent genomic investigations have established that tumorigenesis is primarily driven by somatic mutations. Despite numerous sequencing studies, findings remain heterogeneous, and a unified genomic framework for leiomyoma classification is lacking. To address this, we conducted a systematic synthesis of whole-genome and whole-exome sequencing (WGS/WES) data to identify recurrent driver mutations and clarify their clinical correlations. Results: Following PRISMA guidelines, relevant studies published within the past decade were retrieved from PubMed, Scopus, and ScienceDirect. From 66 screened records, 11 studies encompassing more than 3,500 leiomyomas met inclusion criteria. The synthesis revealed four major genomic subtypes: MED12 mutations (70%), HMGA2 rearrangements (10–20%), FH deficiency (rare but clinically aggressive), and SRCAP-complex mutations (25%). MED12-mutant leiomyomas were characterized by multiple small nodules with a higher recurrence rate, whereas HMGA2-rearranged tumors tended to be solitary, larger, and associated with abnormal bleeding and infertility. FH-deficient leiomyomas demonstrated rapid growth and early surgical intervention, often linked to hereditary leiomyomatosis and renal cell cancer, while SRCAP-associated mutations defined a moderate-penetrance subtype presenting with early onset and multiple nodules. Conclusion: These findings demonstrate that uterine leiomyomas represent a genetically heterogeneous disease with distinct molecular subtypes that correlate with clinical behavior. The predominance of MED12, HMGA2, FH, and SRCAP alterations provides a framework for genomic-based classification and risk stratification. Integration of multi-omics and functional studies will be essential to translate these genomic insights into precision approaches for fibroid management.