Investigating the molecular characteristics underlying desmoid tumor clinical trajectory.

Abstract

11583 Background: Desmoid tumors are locally aggressive mesenchymal neoplasms that primarily affect adolescents and young adults. They demonstrate a range of clinical behavior from spontaneous regression to refractory growth leading to morbidity and sometimes mortality. However, there are no prognostic biomarkers for patients with desmoid tumors and we have a limited understanding of the biology behind the range of clinical behavior. Thus, we aimed to characterize the clinical course of patients with banked desmoid tumors at our institution from across the age spectrum, and correlate clinical behavior with genetic alterations and gene expression signatures. Methods: We identified 64 adult patients through our adult sarcoma biobank and 5 patients through our pediatric biobank with desmoid fibromatosis and banked samples. Retrospective chart review was conducted including patient characteristics, disease features, treatment course, and outcomes. Genetic analysis was completed on 61 patients (43 targeted exome sequencing, OncoPanel). To characterize gene expression, we performed single nucleus RNA sequencing (snRNAseq) on 15 samples from 12 patients, with concurrent CTNNB1 genotyping to accurately identify tumor cells. Primary analyses included cell annotation of clusters and differential gene expression between progressing and stable/regressing tumors. Results: A total of 69 patients were included in this study. Median age at diagnosis was 35 years (range 2–83), with 68% female. Median tumor size at diagnosis was 5.2cm (range 0.7–25.0). Tumor location included abdominal wall (41%), mesenteric (25%), trunk/breast (14%), extremity (16%), and head/neck (5%). At time of tissue collection 39% of tumors were progressing, 23% were stable, and 10% were regressing (28% unknown). Among 61 sequenced tumors, 72% and 21% harbored CTNNB1 and APC mutations, respectively, and 7% showed no mutations in either gene. snRNAseq resulted in a dataset of over 180,000 high-quality nuclei. Cell composition differences were identified across the spectrum of disease states. Concurrent single-nucleus CTNNB1 genotyping revealed expression differences in the tumor cell compartment between progressing and non-progressing tumors, including collagen/extracellular matrix proteins and mesenchymal transcription factors. Conclusions: In this cohort of adult and pediatric desmoid tumors, integration of clinical annotation and molecular characteristics identified gene expression programs associated with tumor progression. These findings provide new insights into the biology underlying variable clinical trajectory in desmoid tumors, implicating altered collagen/extracellular matrix and mesenchymal transcription factor programs. Ongoing bulk RNA sequencing and immunohistochemical analyses are being performed to assess the potential of these signatures as predictive biomarkers and therapeutic targets.