Comprehensive whole-Genome profiling reveals Cooperative PI3K-TP53-RB1-ATRX pathway alterations and immune-modulatory drivers 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 p110alpha 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.