Introduction Uterine leiomyosarcomas (uLMS) have high recurrence rates and frequently harbor structural aberrations in TP53 and RB1. We sought to compare molecular profiles of primary uLMS and matched serial recurrences to assess tumor evolution over time.
Methods Patients diagnosed with uLMS between 1/1/2000 – 11/31/2020 who had primary tumor, ≥2 serial recurrences, and normal tissue available were identified. All slides were reviewed by an expert gynecologic pathologist. Samples were microdissected to enhance for tumor purity and subjected to tumor-normal targeted DNA next-generation sequencing (NGS).
Results Tumor-normal NGS was performed on 42 tumor samples from 10 patients. The median age at diagnosis was 54 (range 30–69). The median number of recurrences was 3 (range 2–7); the median progression free survival was 45 months (range 4–163). At least one homozygous deletion affecting RB1 (50%), PTEN (30%), TP53 (30%), and/or BRCA2 (20%), as well as clonal mutations affecting TP53 (30%) and ATRX (10%), were early events and present across all samples of a given patient. Non-oncogene missense mutations were frequently shared across samples from a given case. As a group, chromosomal instability was found to be significantly higher across recurrences compared to primary tumors (mean fraction of genome altered 50% v 37.5%, p=0.035).
Conclusion/Implications Primary uLMS and subsequent recurrences display genomic intra-individual concordance, with sustained driver mutations over time. Chromosomal instability was higher in recurrent tumors. The high BRCA2 homozygous deletion rate warrants exploration as a potential prognostic factor in uLMS.
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