Journal
ONCOGENE
Volume 38, Issue 2, Pages 291-298Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41388-018-0444-4
Keywords
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Funding
- Canadian Institutes of Health Research (CIHR)
- Ontario Institute for Cancer Research (OICR)
- Global Leadership Round in Genomics and Life Sciences (GL2)
- OVC Pet Trust
- National Natural Science Foundation of China [81702665]
- National Postdoctoral Program for Innovative Talents [BX201600196]
- China Postdoctoral Science Foundation [2017M610571]
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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.
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