Abstract 6292: Comprehensive whole-Genome profiling reveals Cooperative PI3K-TP53-RB1-ATRX pathway alterations and immune-modulatory drivers in myxoid liposarcoma.

Abstract Background: Myxoid liposarcoma (MLS), a genetically stable soft-tissue sarcoma driven by FUS-DDIT3 fusions, harbors additional somatic alterations contributing to progression and microenvironmental adaptation. These remain underexplored in non-European populations. Methods: We conducted whole-genome sequencing (WGS) on tumors from 56 Mexican MLS patients using a standardized pipeline (BWA-MEM2 alignment, GATK Mutect2 variant calling, VEP annotation). We analyzed somatic SNVs/indels, mutational signatures, gene-specific clustering (OncodriveCLUST), and co-occurrence patterns via cohort-level MAF files. Results were visualized with oncoplots and positional analyses. Results: Tumors exhibited moderate mutational burden (median 6. 4 × 104 variants/sample), dominated by missense substitutions and CT transitions (SBS1 and SBS5 signatures). Recurrent alterations enriched in structural genes (e. g. , MUC3A, MUC4, MUC5AC, MUC16, AHNAK2, FLG, TTN, ZNF) suggested extracellular and cytoskeletal remodeling. Key oncogenic hits included PIK3CA (89%; activating p110α variants), TP53 (98%; DNA-binding loss-of-function), RB1 (87%; RBA/RBB disruptions), and ATRX (98%; helicase/ADD domain mutations), implicating PI3K-TP53-RB1-ATRX pathway cooperation and telomere instability. Co-occurrence clustered in adhesion/matrix genes without exclusivity, while OncodriveCLUST hotspots (DEFB4A, DEFB107A, USP17L17, FOXD4L4) pointed to immune and epigenetic modulation. Conclusions: Beyond FUS-DDIT3 fusions, MLS features coordinated PI3K-TP53-RB1-ATRX alterations, structural remodeling, and immune hotspots. This first WGS study in Mexican (and one of few in Latin American) MLS patients establishes a genomic atlas for diverse populations, informing targeted therapies like PI3K inhibitors. Citation Format: Jonathan Gonzalez, Hayde Caro-Sánchez, Dorian Y. García-Ortega, Andrea Ramírez, Rodrigo Cruz-Nieto, Claudia García-Cuellar, Diddier Prada. Comprehensive whole-Genome profiling reveals Cooperative PI3K-TP53-RB1-ATRX pathway alterations and immune-modulatory drivers in myxoid liposarcoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (7 Suppl): Abstract nr 6292.