Abstract PR14: Immune cell transcript levels, metastatic progression, and survival in osteosarcoma: A comparative transcriptome analysis

Abstract

Abstract Background: Human osteosarcoma (OS) is a rare bone disease primarily affecting children and adolescents that has proven challenging to study, due both to its rarity and its genetic heterogeneity. OS is very common in large-breed dogs and can be genetically induced in mice, making the disease ideal for comparative genomic analyses across species. The overall survival rate of patients with OS is ~60% in patients under 30 years old and only ~30% for patients aged 50 years or older---rates that have not significantly improved over the past two decades. Understanding how intertumor transcriptional variation is conserved across species and associated with progression to metastasis resulting in patient death will enable us to more efficiently develop effective strategies to manage OS and improve therapy. Methods and Findings: Transcriptional profiles of OS tumors and cell lines derived from humans (n=49), mice (n=103), and dogs (n=34) were generated using RNA sequencing. We identified conserved intertumor transcriptional variation present in tumor sets from all 3 species, comprising gene clusters associated with cell cycle/mitosis and with the presence/absence of immune cells. Further, we developed a novel Gene Cluster Expression Summary Score (GCESS) technique to quantify intertumor transcriptional variation and demonstrate that these GCESS values are associated with patient outcome. Specifically, we show that human OS tumors with GCESS values indicative of decreased immune cell presence are associated with metastasis and poor survival. These results were validated in an independent human OS tumor cohort and in 15 different tumor data sets obtained from The Cancer Genome Atlas (TCGA). Conclusions: Utilizing GCESS-based analyses of primary OS tumors to characterize the extent to which immune cells are absent and the tumor cells are undergoing mitosis may provide key information to identify novel drug targets, better inform therapeutic decisions, and improve overall survival for OS patients. This abstract is also being presented as Poster A07. Citation Format: Milcah Scott, Nuri Temiz, Anne Sarver, Rebecca LaRue, Susan Rathe, Jyotika Varshney, Natalie Wolf, Branden Moriarity, Timothy Obrien, Logan Spector, David Largaespada, Jaime Modiano, Subbaya Subramanian, Aaron Sarver. Immune cell transcript levels, metastatic progression, and survival in osteosarcoma: A comparative transcriptome analysis [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr PR14.