p53 mutation, expression, and DNA ploidy in evolving gliomas: evidence for two pathways of progression.
BACKGROUND
Two lines of evidence indirectly implicate the tumor suppressor p53 (also known as TP53) gene in glioma development. First, germline mutations of the p53 gene are associated with increased susceptibility to glioma. Second, chromosome 17p deletions and p53 gene mutations are found frequently in sporadic gliomas of all malignancy stages. These observations suggest that mutations of the p53 gene may be early events in glioma development.


OBJECTIVE
Our purpose was to analyze 15 low-grade astrocytic gliomas that progressed to higher-grade gliomas, examining the status of the p53 gene in both the initial and recurrent tumors. Also, we explored the relationships between p53 status, DNA ploidy, tumor grade, and patient survival.


METHODS
Fifteen low-grade gliomas that recurred as tumors of higher grade 17-102 months after initial treatment (biopsy, resection, radiotherapy, or chemotherapy) were identified from hospital records of patients (eight male and seven female) aged 31-68 years. Pathologic diagnosis was re-evaluated. Polymerase chain reaction (PCR)-single-strand conformation polymorphism and DNA sequencing were performed on tissue samples from the initial and recurrent tumors of each patient, using oligonucleotide PCR primers directed to exons 5-9 of the p53 gene. p53 expression was determined by immunohistochemistry and DNA ploidy evaluated by DNA flow cytometry.


RESULTS
Eight (53%) of fifteen tumors had p53 mutations in exons 5-9. Nine (64%) of fourteen were immunopositive initially, and eight of these were also immunopositive at recurrence. p53 gene status was significantly associated with p53 expression in the initial tumor (P = .02), and p53 expression at initial diagnosis was significantly related to tumor pathology at recurrence (P = .03). Patients with p53 mutant tumors survived nearly twice as long as those without mutations (median survival, 61 versus 33 months; P = .031). There was no significant difference in recurrence-free survival between patients with p53 mutant and nonmutant tumors (48 versus 33 months; P = .37), but there was a significant difference in postrecurrence survival (17 versus 2 months; P = .019).


CONCLUSIONS
Low-grade tumors that recurred as anaplastic gliomas were characterized by p53 gene mutation, immunopositivity, and DNA non-diploidy. Low-grade tumors that recurred as glioblastomas generally had intact p53 genes and were immunonegative. These findings suggest that histologically indistinguishable, low-grade astrocytic gliomas that are destined to progress to higher grades, do so along two distinct clinicopathologic pathways (either stepwise to anaplastic glioma, then glioblastoma, or directly to glioblastoma) marked by the presence or absence of p53 mutation.
van Meyel
D J
DJ
Department of Oncology, University of Western Ontario.
Ramsay
D A
DA
Casson
A G
AG
Keeney
M
M
Chambers
A F
AF
Cairncross
J G
JG
D000328:Adult; D000368:Aged; D001254:Astrocytoma / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D016158:Genes, p53; D006801:Humans; D007120:Immunochemistry; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D011003:Ploidies; D016133:Polymerase Chain Reaction; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000032:analysis* / Q000235:genetics
D004273:DNA, Neoplasm; D016159:Tumor Suppressor Protein p53