Investigating the genomic landscape of sarcoma in India: Discoveries from a retrospective observational approach

ABSTRACT Background: Due to the complex histological and genomic nature of sarcomas, diagnosing and treating them has proven challenging. Delving into the genomic profiles and molecular markers linked to different sarcoma subtypes will aid in overcoming these obstacles and identifying new potential therapeutic targets. Objectives: The primary objective of this study was to investigate the genomic complexity of sarcoma, while the secondary objective was to identify potential therapeutic targets in the patients with sarcoma from India. Materials and Methods: This retrospective observational study was conducted from January 2020 to February 2024 at 4basecare Precision Health Pvt. Ltd., Bengaluru, India. We carried out comprehensive genomic profiling using gene panels or exome sequencing, including assessment of immunotherapy biomarkers (tumor mutation burden (TMB), microsatellite instability (MSI), programmed death-Ligand 1 ( PD-L1 )), in a cohort of 263 patients with sarcoma, categorized into 25 sarcoma types, for the present retrospective analysis. Results: We included 263 patients with sarcoma in our study and identified a diverse landscape of pathogenic variants across 138 genes, in 69.5% (183 patients) of the cohort. SNVs were prevalent in TP53 (25.1%; 66 patients), KIT (5.7%; 15 patients), PTEN (4.6%; 12 patients), and RB1 (4.6%; 12 patients), while CDK4 (5.2%; 17 patients) and MDM2 (5.7%; 15 patients) gene amplifications and SS18-SSX2 (1.1%; 3 patients), EWSR1-FLI1 (0.8%; 2 patients), and ASPSCR1-TFE3 (0.8%; 2 patients) gene fusions were recurrent. The majority of the patients harbored mutations affecting cell cycle control (39.2%; 103 patients), PI3K/AKT/MTOR (17.9%; 47 patients), and RAS/RAF/MAPK (14.8%; 39 patients) pathways. The average TMB was 7 mutations/mb, with 13.3% (35 patients) classified as TMB-H. Around 59.3% of the cohort (156 patients) harbored clinically actionable variants of therapeutic significance, including 8.7% of the cohort (23 patients) who were eligible for FDA/NCCN approved therapies. Conclusion: The findings emphasize the clinical usefulness of genomic profiling in guiding precision medicine for sarcoma treatment. Our research offers valuable insights into the genetic makeup of sarcomas, serving as a basis for devising efficient and precise diagnostic approaches and for planning preclinical and clinical studies to develop innovative treatment strategies.