生殖细胞肿瘤（GCT）可能会转化为体细胞性恶性肿瘤（STM），导致细胞命运转变为通常在体细胞组织中发现的肿瘤，如横纹肌肉瘤或腺癌。STM与不良预后有关，但触发STM的分子和表观遗传机制仍然神秘，源组织存在争议，缺乏生物标志物。为了解决这些问题，我们使用TSO测定、850k DNA甲基化芯片和质谱等现代高通量方法，对一批独特的STM组织进行了突变、表观遗传和蛋白质水平的特征分析。我们首次展示了基于DNA甲基化和蛋白质组数据，与肿瘤相关的STM更接近于卵黄囊瘤，而肉瘤相关的STM更接近畸胎瘤。STM携带FGF信号通路因子（FGF6/23、FGFR1/4）的突变，突显了该通路作为治疗靶点的重要性。此外，STM利用信号通路，如AKT、FGF、MAPK和WNT，介导应对氧化应激、毒素转运、DNA解旋酶活性、细胞凋亡和细胞周期等分子功能。总体而言，这些数据可能解释了STM的高治疗抗性。最后，我们鉴定了STM分泌的潜在新生物标志物，如EFEMP1、MIF和特定CpG二核苷酸位点的DNA甲基化。© 2023. 作者

Germ cell tumors (GCT) might undergo transformation into a somatic-type malignancy (STM), resulting in a cell fate switch to tumors usually found in somatic tissues, such as rhabdomyosarcomas or adenocarcinomas. STM is associated with a poor prognosis, but the molecular and epigenetic mechanisms triggering STM are still enigmatic, the tissue-of-origin is under debate and biomarkers are lacking.To address these questions, we characterized a unique cohort of STM tissues on mutational, epigenetic and protein level using modern and high-throughput methods like TSO assays, 850k DNA methylation arrays and mass spectrometry.For the first time, we show that based on DNA methylation and proteome data carcinoma-related STM more closely resemble yolk-sac tumors, while sarcoma-related STM resemble teratoma. STM harbor mutations in FGF signaling factors (FGF6/23, FGFR1/4) highlighting the corresponding pathway as a therapeutic target. Furthermore, STM utilize signaling pathways, like AKT, FGF, MAPK, and WNT to mediate molecular functions coping with oxidative stress, toxin transport, DNA helicase activity, apoptosis and the cell cycle. Collectively, these data might explain the high therapy resistance of STM. Finally, we identified putative novel biomarkers secreted by STM, like EFEMP1, MIF, and DNA methylation at specific CpG dinucleotides.© 2023. The Author(s).