p53 mutation and loss of heterozygosity on chromosomes 17 and 10 during human astrocytoma progression.
The human brain tumor, astrocytoma, typically progresses through three histopathologically defined stages with the passage of time: one premalignant stage, low-grade astrocytoma; and two malignant stages, anaplastic astrocytoma and glioblastoma multiforme. We correlated the results of a sequence analysis of the tumor suppressor gene, p53, and a restriction fragment length polymorphism analysis of chromosomes 17 and 10 in 45 patients with cerebral astrocytomas at different stages. To detect p53 mutations in tumor DNA, we analyzed polymerase chain reaction products corresponding to every p53-coding exon for single-strand conformation polymorphisms and confirmed the mutations by sequencing. Loss of heterozygosity (LOH) was determined by Southern transfer analysis of somatic and tumor DNA from these same patients using polymorphic markers for various loci on chromosomes 10 and 17. p53 mutations were found in 7 of 25 glioblastomas (28%), in 5 of 14 anaplastic astrocytomas (36%) but in 0 of 6 low-grade astrocytomas. p53 mutations were found in 62% of patients with LOH on chromosome 17p. These results indicated that p53 inactivation is a common genetic event in astrocytoma progression that may signal the transition from benign to malignant tumor stages. LOH on chromosome 10 was found in 61% of glioblastomas, in 23% of anaplastic astrocytomas, but in 0% of low-grade astrocytomas. LOH on chromosome 10 and p53 mutation were found together only in patients with glioblastoma multiforme (22%), suggesting that these genetic changes may accumulate during astrocytoma progression.
Division of Neurosurgery, University of Utah School of Medicine, Salt Lake City 84132.
D
D
Fults
D
D
Brockmeyer
M W
MW
Tullous
C A
CA
Pedone
R M
RM
Cawthon
D000595:Amino Acid Sequence; D001254:Astrocytoma / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D002872:Chromosome Deletion; D002879:Chromosomes, Human, Pair 10; D002886:Chromosomes, Human, Pair 17; D003001:Cloning, Molecular; D003062:Codon / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D005091:Exons; D016158:Genes, p53; D005819:Genetic Markers; D005909:Glioblastoma / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D009838:Oligodeoxyribonucleotides; D016133:Polymerase Chain Reaction / Q000379:methods; D012150:Polymorphism, Restriction Fragment Length
D003062:Codon; D004273:DNA, Neoplasm; D005819:Genetic Markers; D009838:Oligodeoxyribonucleotides