Genotype-Phenotype Correlation in Gemistocytic Astrocytomas

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Abstract
Gemistocytic astrocytomas often behave aggressively and carry the least favorable prognosis among diffuse astrocytomas. The frequency of p53 mutations has been reported to be significantly higher in the gemistocytic variant as compared with other astrocytomas. Between 1985 and 1998, we selected 25 tumor samples from among 201 samples from patients with gemistocytic astrocytomas operated on at the Mayo Clinic. Exons 5 to 8 of the p53 gene were sequenced using an automated deoxyribonucleic acid sequencer. Morphometric characterization of individual gemistocytes was performed using an image analysis program. Of 25 tissue samples analyzed, 16 were found to carry a p53 missense mutation (three in exon 5, three in exon 6, one in exon 7, and nine in exon 8), and one sequence variant was synonymous. Mutations were clustered at codons 151 (2 of 17 mutations), 193 (3 of 17 mutations), and 273 (5 of 17 mutations) of the p53 gene. Patients whose tumors carried a p53 mutation were significantly younger than other patients, and their tumors tended to accumulate more p53 protein than those of other patients. Phenotype analysis of gemistocytes revealed that the sizes of tumor cell nuclei and of entire tumor cells in the same tissue area were positively correlated. Smaller tumor cell nuclei tended to be less circular or more atypical. In addition, more atypical gemistocytes were found in tumors lacking a wild-type p53 allele as well as in tissue from patients whose postoperative survival was shorter. Our data confirm that the frequency of p53 mutations is significantly higher (approximately twofold) in gemistocytic astrocytomas as compared with other astrocytoma subtypes. Whether the high frequency of p53 mutations contributes to the more aggressive behavior of gemistocytic astrocytomas, however, remains unclear.