Genomic and Spatial Landscapes of Leiomyosarcoma with Germline Pathogenic Variants
Background and Significance: Leiomyosarcoma (LMS) is one of the most common sarcoma types and is characterized by high metastatic rates and mortality. LMS arises from smooth muscle cells of various tissues and organs. Despite a relative uniform appearance under the microscope, LMS show a wide range of clinical presentations. LMS occur either sporadically or in the setting of cancer-predisposing conditions associated with specific mutations in all cells of the body (syndromic LMS). Although sarcomas represent a common cancer type in certain syndromes (Li-Fraumeni, etc.), the incidence and characteristics of LMS among the entire spectrum of cancer-predisposing conditions are not known. Extensive genomic studies have been conducted in adult LMS, yet none have focused on LMS in patients with germline predisposition (syndromic LMS). We aim to fill this gap. Hypothesis and Goals: First, we explore the genomic features of LMS in individuals with a germline predisposition, who tend to have a young age of onset, contrasting them with young adults without this predisposition. Employing advanced spatial techniques, our second goal is to understand the step-by-step transformation from normal cells to cancer. We hypothesize distinct tumor progression paths exist in germline vs sporadic LMS, with the latter requiring multiple somatic alterations. Additionally, we believe LMS development varies based on the type of smooth muscle cell affected, which is crucial for understanding malignant transformation. We have a particular interest in understanding how genetic variations might enhance the cell’s ability to repair DNA damage. Preliminary Findings: Our investigation of LMS in retinoblastoma syndrome revealed germline RB1 changes and frequent TP53 alterations. Variations in DNA damage repair genes suggest their role in LMS development. A cohort of young adults with sporadic LMS was selected for genomic analysis as a comparison group. Approach: We will identify LMS cases with germline mutations and a control group without such mutations in the same age range. Both groups will undergo clinical and genomic analysis on a unified platform. Our second goal examines early stages of LMS development in sporadic versus syndromic disease using advanced techniques of cellular-level RNA expression (spatial transcriptomics). Sections that depict best the transition from the tissue of origin (smooth muscle wall of a vessel, uterine wall) to sarcoma will be chosen for analysis. Impact: This research is crucial for understanding LMS variability and tailoring treatments. By pinpointing early tumor progression changes, our study aims to define a disease blueprint, aiding biomarker discovery and treatment optimization. The unique approach combining genetic and developmental insights positions us to identify therapeutic targets, particularly in enhancing DNA damage repair. Ultimately, our study seeks to advance personalized treatments for those genetically predisposed to LMS.