Loss of the AP-2alpha transcription factor is associated with the grade of human gliomas.
OBJECTIVE
The activator protein (AP)-2alpha transcription factor plays a crucial role in the progression of several human tumors, including malignant melanoma, prostate, and breast cancer. Loss of AP-2alpha results in deregulation of several genes with AP-2alpha binding motifs such as E-cadherin, p21WAF1, MMP-2, MCAM/MUC18, VEGF, and c-KIT. The purpose of our study was to determine AP-2alpha expression distribution among grades of gliomas and any possible effect on prognosis.


METHODS
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-2alpha expression was determined by immunohistochemistry.


RESULTS
AP-2alpha 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-2alpha. The loss of AP-2alpha 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-2alpha 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-2alpha 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-2alpha would be the most common (96.2%) molecular marker as an astrocytic tumor evolves from grade 2 to 3.
Heimberger
Amy B
AB
Department of Neurosurgery, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA. aheimber@mdanderson.org
McGary
Eric C
EC
Suki
Dima
D
Ruiz
Maribelis
M
Wang
Huamin
H
Fuller
Gregory N
GN
Bar-Eli
Menashe
M
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020816:Amino Acid Motifs; D015703:Antigens, CD / Q000096:biosynthesis; D001254:Astrocytoma / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D001932:Brain Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000401:mortality; D051929:CD146 Antigen; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology*; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000175:diagnosis / Q000378:metabolism* / Q000401:mortality; D006801:Humans; D007150:Immunohistochemistry; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D008875:Middle Aged; D019006:Neural Cell Adhesion Molecules / Q000096:biosynthesis; D009837:Oligodendroglioma / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D016016:Proportional Hazards Models; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis; D013997:Time Factors; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000096:biosynthesis* / Q000502:physiology*; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
D015703:Antigens, CD; D051929:CD146 Antigen; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; C497902:MCAM protein, human; D019006:Neural Cell Adhesion Molecules; C493673:TFAP2A protein, human; D050656:Transcription Factor AP-2; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D019009:Proto-Oncogene Proteins c-kit; D020778:Matrix Metalloproteinase 2