Osteosarcoma driver genes are enriched in the ERBB, PI3K–AKT–mTOR, MAPK, and axon guidance pathways.
Major finding: Osteosarcoma driver genes are enriched in the ERBB, PI3K–AKT–mTOR, MAPK, and axon guidance pathways.
Concept: A forward genetic screen identified genes that accelerate primary and metastatic osteosarcoma.
Impact: Lineage tracing using common insertion sites reveals multiple patterns of metastatic spread.
Osteosarcoma is a common primary bone cancer with high metastatic potential. However, characterization of cancer driver genes and potential therapeutic targets has been limited due to the highly heterogeneous and genomically unstable nature of osteosarcoma tumors. To identify genes that are involved in driving osteosarcoma, Moriarity and colleagues performed a Sleeping Beauty (SB) transposon-based forward genetic screen in mice harboring wild-type (SBmut) or mutant Trp53 (Trp53-SBmut). SB mutagenesis promoted the formation of osteosarcomas that faithfully recapitulated the human disease and accelerated tumor formation in Trp53-mutant mice. Analysis of common insertion sites (CIS) from 96 Trp53-SBmut and 23 SBmut osteosarcomas identified known osteosarcoma-associated genes, as well as 36 putative proto-oncogenes and 196 potential tumor suppressor genes, including Nf1 and Pten, which were observed in both genetic backgrounds. Pathway analysis highlighted an enrichment of genes involved in the PI3K–AKT–mTOR, MAPK, and ERBB signaling cascades, as well as mutations in upstream regulators of CIS-associated genes, including miRNAs that have been previously implicated in osteosarcoma. Comparison of CIS-associated gene expression, genomic alterations, and methylation across human osteosarcoma samples revealed that a significant proportion of candidate genes was altered in tumor samples compared with normal tissue. Functional validation of CIS-associated genes reinforced the notion that loss of Pten and Trp53 cooperatively accelerate osteosarcomagenesis in mice and confirmed that overexpression of the axon guidance genes SEMA4D and SEMA6D in human osteosarcoma cells was sufficient to promote anchorage-independent growth and xenograft formation via activation of the PI3K and MAPK pathways. Furthermore, analysis of 134 metastases identified 43 CIS-associated candidate metastasis driver genes and revealed multiple patterns of metastatic spread, including both parallel and clonal evolution. Together, these data demonstrate that forward genetic screens represent a useful tool to identify cancer driver genes in tumors with high genetic variability and highlight oncogenic pathways that may be targetable in osteosarcoma.
Moriarity BS, Otto GM, Rahrmann EP, Rathe SK, Wolf NK, Weg MT, et al. A Sleeping Beauty forward genetic screen identifies new genes and pathways driving osteosarcoma development and metastasis. Nat Genet 2015;47:615–24.
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