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

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          Abstract

          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 < 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.

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          Author and article information

          Journal
          Journal of Neurosurgery
          Journal of Neurosurgery Publishing Group (JNSPG)
          0022-3085
          1933-0693
          May 2018
          May 2018
          : 128
          : 5
          : 1428-1437
          Affiliations
          [1 ]1Department of Neurosurgery, Graduate School of Medicine, The University of Tokyo; and
          [2 ]2Department of Neurosurgery, Dokkyo Medical University, Tochigi, Japan
          Article
          10.3171/2016.12.JNS161444
          28753115
          a20d6b20-e9b5-4fd9-a7e8-c804da62c283
          © 2018
          History

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