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Loss of the AP-2 Transcription Factor Is Associated with the Grade of Human Gliomas

Departments of ¹ Neurosurgery, ² Cancer Biology, and ³ Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas and ⁴ Hilton Head Regional Medical Center, Hilton Head, South Carolina

Requests for reprints: Amy B. Heimberger, Department of Neurosurgery, University of Texas M.D. Anderson Cancer Center, Unit 442, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-2400; Fax: 713-794-4950; E-mail: aheimber{at}mdanderson.org.

Purpose: The activator protein (AP)-2 transcription factor plays a crucial role in the progression of several human tumors, including malignant melanoma, prostate, and breast cancer. Loss of AP-2 results in deregulation of several genes with AP-2 binding motifs such as E-cadherin, p21^WAF1, MMP-2, MCAM/MUC18, VEGF, and c-KIT. The purpose of our study was to determine AP-2 expression distribution among grades of gliomas and any possible effect on prognosis.

Experimental Design: A tissue microarray was assembled from all surgical glioma cases with available tissue samples at M.D. Anderson Cancer Center since 1986 to include 72 glioblastomas, 49 anaplastic astrocytomas, 9 low-grade astrocytoma, 37 oligodendrogliomas, 37 anaplastic oligodendrogliomas, 15 mixed oligoastrocytomas, 20 anaplastic mixed oligoastrocytomas, and 7 gliosarcomas. The microarray included normal brain tissue, and AP-2 expression was determined by immunohistochemistry.

Results: AP-2 expression was lost on 99% (P < 0.001) and 98% (P < 0.001) of glioblastomas and anaplastic astrocytomas, respectively, compared with grade 2 astrocytomas and normal brain, all of which (100%) maintained expression of AP-2. The loss of AP-2 was a negative prognostic indicator within the overall category of gliomas by univariate analysis (rate ratio, 4.30; 95% confidence interval, 2.60-7.10; P < 0.001). However, there was no significant effect of loss of AP-2 expression on survival observed after adjustment for patient age, Karnofsky Performance Scale score, tumor grade, and extent of resection (rate ratio, 1.2; 95% confidence interval, 0.6-2.2; P = 0.6).

Conclusions: AP-2 expression correlates inversely with glioma grade, suggesting a direct role in glioma tumorigenicity, possibly through subsequent deregulation of target genes. Of all the previously characterized markers of progression, the loss of AP-2 would be the most common (96.2%) molecular marker as an astrocytic tumor evolves from grade 2 to 3.

Key Words: astrocytoma • oligodendroglioma • glioblastoma multiforme • activator protein

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