Cooperative Alterations in PI3K-TP53-RB1-ATRX Pathway in Myxoid Liposarcoma

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 C>T 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%; RB_A/RB_B 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.