Leveraging the conserved cancer genomes across mammals has the potential to transform driver gene discovery in orphan cancers. Here, we combine cross-species genomics with validation across human-dog-mouse systems to uncover a new bone tumor suppressor gene. Comparative genomics of spontaneous human and dog osteosarcomas (OS) expose Disks Large Homolog 2 (DLG2) as a tumor suppressor candidate. DLG2 copy number loss occurs in 42% of human and 56% of canine OS. Functional validation through pertinent human and canine OS DLG2-deficient cell lines identifies a regulatory role of DLG2 in cell division, migration and tumorigenesis. Moreover, osteoblast-specific deletion of Dlg2 in a clinically relevant genetically engineered mouse model leads to acceleration of OS development, establishing DLG2 as a critical determinant of OS. This widely applicable cross-species approach serves as a platform to expedite the search of cancer drivers in rare human malignancies, offering new targets for cancer therapy.

中文翻译：

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跨物种基因组学将 DLG2 鉴定为骨肉瘤的肿瘤抑制因子。

利用哺乳动物中保守的癌症基因组有可能改变孤儿癌症中驱动基因的发现。在这里，我们将跨物种基因组学与跨人-狗-小鼠系统的验证相结合，以发现一种新的骨肿瘤抑制基因。自发性人和狗骨肉瘤 (OS) 的比较基因组学揭示了 Disks Large Homolog 2 (DLG2) 作为肿瘤抑制候选者。DLG2 拷贝数丢失发生在 42% 的人类和 56% 的犬 OS 中。通过相关的人和犬 OS DLG2 缺陷细胞系的功能验证确定了 DLG2 在细胞分裂、迁移和肿瘤发生中的调节作用。此外，临床相关基因工程小鼠模型中成骨细胞特异性 Dlg2 缺失导致 OS 发展加速，将 DLG2 确立为 OS 的关键决定因素。