TAF12, NFYC, and RAD54L are oncogenes required to initiate and maintain choroid plexus carcinoma (CPC).

  • Major finding: TAF12, NFYC, and RAD54L are oncogenes required to initiate and maintain choroid plexus carcinoma (CPC).

  • Approach: Candidate oncogenes were identified via cross-species mapping of syntenic chromosome gains.

  • Impact: Suppression of aberrant DNA repair with ATR inhibitors may be therapeutically beneficial in CPC.

Choroid plexus carcinoma (CPC) is a highly malignant and rare type of brain tumor associated with large-scale chromosomal alterations comprising many genes. Although loss of tumor suppressors has been implicated in CPC pathogenesis, oncogenes that drive malignant transformation have yet to be identified. To address this question, Tong and colleagues developed a mouse model of CPC using deletion of Trp53, Rb, and Pten in the embryonic hindbrain choroid plexus epithelium (CPE), and performed a cross-species genome-wide search for syntenic chromosome fragments that were gained in both human and mouse CPCs. Integration of copy-number and gene expression analyses identified 21 lead candidate oncogenes on chromosome 1p31.3-ter/4qC6-qE2, which underwent copy-number gain early in CPC tumorigenesis. In vivo functional analyses revealed that expression of three candidate oncogenes, Taf12, Nfyc, and Rad54l, induced aberrant proliferation and dysplasia of CPE cells. Depletion of these genes reduced the survival of primary mouse CPC cells and significantly impaired CPC development in mice, indicating that these genes are required to initiate and maintain CPC. In addition, although these genes were not sufficient to initiate CPC formation, overexpression of Taf12, Nfyc, and Rad54l accelerated CPC tumorigenesis in cooperation with deletion of Trp53, Rb, and Pten. Consistent with the functional roles of TAF12, NFYC, and RAD54L, genes involved in DNA replication and repair and the maintenance of genome integrity were upregulated in both mouse CPCs and human CPCs lacking chromosome 1 gain, and CPC cells were sensitive to treatment with ataxia telangiectasia and RAD3-related protein (ATR) inhibitors, suggesting that aberrant DNA metabolism may be a common mechanism underlying CPC formation. These findings validate TAF12, NFYC, and RAD54L as oncogenic drivers of CPC and suggest inhibition of DNA repair as a potential therapeutic strategy.

Tong Y, Merino D, Nimmervoll B, Gupta K, Wang YD, Finkelstein D, et al. Cross-species genomics identifies TAF12, NFYC, and RAD54L as choroid plexus carcinoma oncogenes. Cancer Cell 2015;27:712–27.

©2015 American Association for Cancer Research.
2015