Genomic Characteristics of Leiomyosarcoma: An AACR Project GENIE Study

<h3>Background/Aim:</h3> Leiomyosarcoma is a rare and aggressive malignant smooth muscle tumor with limited treatment options and poor outcomes. Large-scale molecular characterization is needed to better understand tumor biology and support precision oncology, as prior studies have been limited by small cohort sizes, single-institution data, and restricted gene panels. This study aimed to characterize clinicogenomic features of leiomyosarcoma using the AACR Project GENIE 19.0 public dataset. <h3>Patients and Methods:</h3> We analyzed 1,017 tumor samples from 957 patients, evaluating demographic patterns, somatic mutation frequencies, copy number alterations, and genomic co-occurrence and exclusivity across primary and metastatic disease sites. <h3>Results:</h3> Females comprised 65.7% of cases and White patients 61.4%. The most frequently altered genes were <i>TP53</i> (50.3%), <i>RB1</i> (17.9%), and <i>ATRX</i> (15.9%), followed by <i>KMT2D, MED12, NOTCH1, ATM, PTEN, ROS1, FAT1, BRCA2</i>, and <i>NOTCH3</i>. Recurrent copy number alterations included <i>RB1</i> homozygous deletion (24.4%), <i>MAP2K4</i> amplification (18.4%), and <i>TP53</i> homozygous deletion (15.5%). Significant co-occurrence was observed among <i>TP53, RB1, ATRX</i>, and <i>PTEN</i> alterations (q&lt;0.05). Most genomic alterations were driven by primary tumors, whereas metastatic samples showed enrichment of <i>IGF2</i> and <i>AXIN1</i> alterations. <h3>Conclusion:</h3> These findings highlight recurrent alterations in <i>TP53, RB1</i>, and <i>ATRX</i> and suggest potential roles for <i>IGF2</i> and <i>AXIN1</i> in leiomyosrcoma metastatic disease that warrant further investigation.