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OBJECTIVE  Chordoma is a slow-growing but clinically malignant tumor, and the prognosis remains poor in many cases. There is a strong impetus to develop more effective targeted molecular therapies. On this basis, the authors investigated the potential of Brachyury, a transcription factor involved in notochord development, as a candidate molecular target for the treatment of chordoma.    METHODS   Brachyury  gene copy number and expression levels were evaluated by quantitative polymerase chain reaction in 27 chordoma samples, and the transcriptomes of  Brachyury  high-expression tumors (n = 4) and  Brachyury  low-expression tumors (n = 4) were analyzed. A chordoma cell line (U-CH2) was used to investigate the signaling pathways that regulate  Brachyury  expression.    RESULTS  All chordoma specimens expressed  Brachyury , and expression levels varied widely. Patients with higher  Brachyury  expression had significantly shorter progression-free survival (5 months, n = 11) than those with lower expression (13 months, n = 16) (p = 0.03). Somatic copy number gain was confirmed in 12 of 27 (44%) cases, and copy number was positively correlated with  Brachyury  expression (R = 0.61, p &lt; 0.001). Expression of PI3K/Akt pathway genes was upregulated in  Brachyury  high-expression tumors, and suppression of PI3K signaling led to reduced  Brachyury  expression and inhibition of cell growth in the U-CH2 chordoma cell line.    CONCLUSIONS  Activation of the PI3K/Akt pathway and  Brachyury  copy number gain are strongly associated with  Brachyury  overexpression, which appears to be a key event in chordoma growth regulation. These findings suggest that targeting Brachyury and PI3K/Akt signaling may be an effective new approach for treating chordoma.

journal of neurosurgery

Brachyury gene copy number gain and activation of the PI3K/Akt pathway: association with upregulation of oncogenic Brachyury expression in skull base chordoma