PO.PS01.08 · 人群科学
全基因组综合分析揭示黏液样脂肪肉瘤中协同的PI3K-TP53-RB1-ATRX通路改变及免疫调节驱动因素
Comprehensive whole-Genome profiling reveals Cooperative PI3K-TP53-RB1-ATRX pathway alterations and immune-modulatory drivers in myxoid liposarcoma
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摘要 Abstract
中文摘要
背景：黏液样脂肪肉瘤（MLS）是一种由FUS-DDIT3融合驱动、遗传学上稳定的软组织肉瘤，其携带有促进进展和微环境适应的额外体细胞改变。这些改变在非欧洲人群中仍未得到充分研究。
方法：我们采用标准化流程（BWA-MEM2比对、GATK Mutect2变异检出、VEP注释），对56例墨西哥MLS患者的肿瘤进行了全基因组测序（WGS）。我们分析了体细胞SNV/indel、突变特征、基因特异性聚集（OncodriveCLUST），并通过队列水平的MAF文件分析共现模式。结果通过oncoplot图和位置分析进行可视化。
结果：肿瘤表现出中等突变负荷（中位数6.4×10^4个变异/样本），以错义替换和C>T转换（SBS1和SBS5特征）为主。富集于结构基因（如MUC3A、MUC4、MUC5AC、MUC16、AHNAK2、FLG、TTN、ZNF）中的复发性改变提示细胞外和细胞骨架重塑。关键的致癌命中包括PIK3CA（89%；激活性p110alpha变异）、TP53（98%；DNA结合功能丧失）、RB1（87%；RB_A/RB_B破坏）和ATRX（98%；解旋酶/ADD结构域突变），提示PI3K-TP53-RB1-ATRX通路协同作用及端粒不稳定性。共现聚集于黏附/基质基因，且无互斥性，而OncodriveCLUST热点（DEFB4A、DEFB107A、USP17L17、FOXD4L4）指向免疫和表观遗传调节。
结论：除FUS-DDIT3融合外，MLS还具有协调的PI3K-TP53-RB1-ATRX改变、结构重塑和免疫热点。这项在墨西哥（也是拉丁美洲少数几项之一）MLS患者中开展的首个WGS研究，为多样化人群建立了基因组图谱，可为PI3K抑制剂等靶向治疗提供信息。
查看英文原文 English 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 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.
利益披露 Disclosure
J. Gonzalez, None..
H. Caro-Sánchez, None..
A. Ramírez, None..
R. Cruz-Nieto, None..
C. García-Cuellar, None.